Assessment of Primary Prevention Patients Receiving An ICD - Systematic Evaluation of ATP (APPRAISE ATP)
Phase: NA
Conditions: Sudden Cardiac Death
Sponsor: Boston Scientific Corporation

 
 
 
 
Assessment of Primary Prevention Patients  
Receiving An ICD – Systematic Evaluation of ATP 
 
APPRAISE ATP 
 
 
CLINICAL INVESTIGATION PLAN 
 
Reference Number: C1924 
Date: 02Aug2016 
Version AB 
 
Sponsored By 
Boston Scientific, Rhythm Management (RM) 
4100 Hamline Avenue North 
St. Paul, MN 55112 
 
 
Guidant Europe NV, 
A Boston Scientific Company 
Clinical Department Rhythm Management 
Green Square 
Lambroekstraat 5D 
1831 Diegem, 
Belgium 
 
 
 
 
 
This protocol contains confidential information for use by the Investigators and their 
designated representatives participating in this clinical investigation. The protocol should be 
held confidential and maintained in a secure location. 
Do not copy or distribute without written permission from Boston Scientific Corporation. 
 

Study Reference Number: C1924 
               Form No. 90702637 Rev/Ver AG 
Confidential                                                                                     
Boston Scientific 
APPRAISE ATP CIP 
91165305 Ver AB 
Page 2 of 72 
 
Contact Information 
Role 
Contact  
Clinical Contact 
Tina Cordaro 
Clinical Trial Manager 
Tel: 585-330-6218 
E-mail: tina.cordaro@bsci.com 
 
US Technical Services:  
1.800.CARDIAC (227.3422)/651-582-3422 
 
International Technical Services: 
+32(0)2 416 7222 
 
 
Coordinating 
Principal 
Investigator 
Claudio Schuger, MD 
Professor  Of Medicine, Wayne State University 
Director Cardiac Electrophysiology  
Edith and Benson Ford Heart and Vascular Institute 
Henry Ford Health System 
2799 W Grand Blvd, M322 
Detroit, MI 48202 
Tel: 313-916-2417 
United States 
cschuge1@hfhs.org 
 
 
Clinical Investigation Plan (CIP) development and review: 
• 
Claudio Schuger, MD, FACC, FHRS; Henry Ford Health System; 
Detroit, MI 
• 
Pat Yong; Fellow, Clinical Scientist, Boston Scientific; St. Paul, MN 
• 
Tina Cordaro; Clinical Trial Manager, Boston Scientific; St. Paul, 
MN 
• 
Nicholas Wold; Principal Biostatician, Boston Scientific; St. Paul, 
MN  
• 
Dr. Torsten Kayser; Sen Fellow, Boston Scientific; Diegem, Belgium 
• 
Arjun D. Sharma, MD,FACC,FRCPC; VP Medical Safety, Boston 
Scientific RM; St. Paul, MN, USA  
• 
Sally Duffy, Principal; RM Safety Trial Operations, Boston 
Scientific; St. Paul, MN 
• 
Sharda Mehta; Regional Clinical Manager, Boston Scientific; St. 
Paul, MN 
• 
Joan Bjerke, Principal, RM Medical Safety, Boston Scientific; St. 
Paul, MN 
 
 

Study Reference Number: C1924 
               Form No. 90702637 Rev/Ver AG 
Confidential                                                                                     
Boston Scientific 
APPRAISE ATP CIP 
91165305 Ver AB 
Page 3 of 72 
 
 
 
 
 
 
 
 
Role 
Contact  
Steering 
Committee 
Members  
Daniel Cantillon, MD  
Cleveland Clinic 
Cleveland, OH 
 
James P. Daubert, MD 
Duke University 
Durham, NC 
 
Darren Peress, MD 
Pima Heart 
Tucson, AZ 
 
Prof. Pier Lambiase 
Barts Heart Centre 
London, UK 
 
Prof. Lluis Mont 
Universitat de Barcelona 
Barcelona, Spain 
 
Kenji Ando, MD 
Kokura Memorial Hospital 
Japan 
 
Vendors/Labs 
A list of vendors/laboratories involved in the trial is maintained 
by the sponsor. A complete listing of applicable vendors will be 
provided to investigational sites.  

Study Reference Number: C1924 
               Form No. 90702637 Rev/Ver AG 
Confidential                                                                                     
Boston Scientific 
APPRAISE ATP CIP 
91165305 Ver AB 
Page 4 of 72 
 
Original Release: 18 Jul 2016 
Current Version: 02 Aug 2016 
 
Revision History 
Revision Number 
Release Date 
Template 
number and 
version 
Section 
Change 
Reason for 
Change 
AA 
18Jul2016 
Template 
90702637 
Ver. AG 
N/A 
Initial Release  
N/A 
AB 
02Aug2016 
Template 
90702637 
Ver. AG 
Section 11.5: 
Tables 11.5-
1 and 11.5-2 
Removed column in 
tables under VT-1 
Zone:  Rhythm 
Detection 
Enhancement On 
Clarification of 
programmable 
parameters 
 
 

Study Reference Number: C1924 
               Form No. 90702637 Rev/Ver AG 
Confidential                                                                                     
Boston Scientific 
APPRAISE ATP CIP 
91165305 Ver AB 
Page 5 of 72 
2. Protocol Synopsis 
Assessment of Primary Prevention Patients Receiving An ICD –  
Systematic Evaluation of ATP (APPRAISE ATP) 
Study 
Objective(s) 
The primary objective is to understand the role of antitachycardia pacing 
(ATP) in primary prevention patients indicated for ICD therapy.  The 
incidence of all-cause shocks in subjects programmed with shocks only 
will be compared with subjects programmed to standard therapy (ATP 
and shock) to assess equivalency.   
Planned 
Indication(s) for 
Use  
All implanted devices will be used within the current labeled indications 
for use in the applicable geography.   
Test Device 
All commercially approved Boston Scientific single and dual chamber 
transvenous ICD (TV-ICD) devices will be included in the trial. 
Study Design 
APPRAISE ATP is a global, prospective, randomized, multi-center, 
clinical trial. 
Planned 
Number of 
Subjects 
Approximately 2,600 patients will be enrolled in this trial. 
Planned 
Number of 
Investigational 
Sites / Countries 
The study will be conducted at up to 200 sites globally.  
  
Primary  
Endpoint 
The primary endpoint is time to first all-cause shock after randomizing 
subjects to one of the treatment arms. 
 
Additional 
Endpoints 
• All-cause mortality 
• Time to first appropriate shock 
• Time to first inappropriate shock  
• Identification of baseline clinical factors  associated with the use of 
ATP, bradycardia pacing, and the need for future CRT-D pacing 
therapy     

Study Reference Number: C1924 
               Form No. 90702637 Rev/Ver AG 
Confidential                                                                                     
Boston Scientific 
APPRAISE ATP CIP 
91165305 Ver AB 
Page 6 of 72 
Assessment of Primary Prevention Patients Receiving An ICD –  
Systematic Evaluation of ATP (APPRAISE ATP) 
Method of 
Assigning 
Patients to 
Treatment 
1:1 randomization will occur in the electronic data capture (EDC) 
system. Subjects will be randomized to ATP and shock, or shock only. 
Follow-up 
Schedule 
• Enrollment (occurs ≤ 60 calendar days post successful device 
implant) 
• Randomization (obtained in the EDC the same calendar day of 
device  programming to randomized arm) 
• Programming to randomized treatment arm (Index procedure day 0) 
o Device programming must be done the same calendar day of 
obtaining randomization assignment, and cannot exceed 60 
calendar days post implant 
• In clinic follow-up visits for subjects not monitored on LATITUDE: 
o Every 180±60 calendar day intervals from the Index 
procedure date (i.e. 180±60 days, 360±60 days, 540±60 
days) up to 60 months 
• For subjects who are remotely monitored on LATITUDE: 
o Annual in-clinic visits, subject phone calls, and device 
uploads via LATITUDE will be required per the data 
collection schedule in this protocol. 
 
Study Duration The trial duration is estimated to be 5.5 years from 1st enrollment to 
study closure. 
Key Inclusion 
Criteria 
• Subject with a Boston Scientific transvenous ICD (de novo implant 
or upgrade from pacemaker to ICD ) implanted because of one of the 
following: 
 Prior MI and left ventricular ejection fraction (LVEF) 
less than or equal to  (≤ )30%  OR 
 Ischemic or non-ischemic cardiomyopathy, and  
LVEF ≤ 35% , and NYHA class II or III   
• Subject is age 21or above, or is considered of legal age per given 
geography 
• Subject is willing and capable of providing informed consent 

Study Reference Number: C1924 
               Form No. 90702637 Rev/Ver AG 
Confidential                                                                                     
Boston Scientific 
APPRAISE ATP CIP 
91165305 Ver AB 
Page 7 of 72 
Assessment of Primary Prevention Patients Receiving An ICD –  
Systematic Evaluation of ATP (APPRAISE ATP) 
• Subject is willing and capable of complying with follow-up visits as 
defined by this protocol 
Key Exclusion 
Criteria 
• History of spontaneous sustained VT (≥ 160 bpm at ≥ 30 seconds in 
duration) or VF not due to a reversible cause  
• NYHA Class IV documented in the medical records within 90 
calendar days prior to enrollment  
• Subject is eligible and scheduled for cardiac resynchronization 
(CRT) implant 
• Subjects with a previous subcutaneous ICD (S-ICD)  
• Subject with existing TV-ICD device implanted for greater than 60 
days 
• Subjects with coronary artery bypass graft surgery or percutaneous 
coronary intervention within the past 90 calendar days prior to 
enrollment 
• Subjects with documented myocardial infarction within the past 90 
calendar days  prior to enrollment  
• Subjects on the active heart transplant list  
• Subject who has a VAD or is to receive VAD 
• Life expectancy shorter than 18 months due to any medical 
condition (e.g., cancer, uremia, liver failure, etc…) 
• Subjects currently requiring hemodialysis  
• Subject who is known to pregnant or plans to become pregnant over 
the course of the trial 
• Subject is enrolled in any other concurrent clinical study, with the 
exception of local mandatory governmental registries and 
observational studies/registries, without the written approval from 
Boston Scientific  
 
Statistical Methods  
Primary 
Statistical 
Hypothesis 
The primary endpoint will assess equivalence of the programming 
schemes, employing a relative equivalence margin of 35% in each 
direction. 
H0:  Hazard Ratio ≤ 0.65 or Hazard Ratio ≥ (1/0.65) 
HA:  0.65 < Hazard Ratio < (1/0.65) 

Study Reference Number: C1924 
               Form No. 90702637 Rev/Ver AG 
Confidential                                                                                     
Boston Scientific 
APPRAISE ATP CIP 
91165305 Ver AB 
Page 8 of 72 
Assessment of Primary Prevention Patients Receiving An ICD –  
Systematic Evaluation of ATP (APPRAISE ATP) 
Statistical Test 
Method 
Cox Proportional Hazards Modeling 
O’Brien-Fleming group-sequential testing (4 total tests) will be 
performed, to allow for early stopping if one programming scheme is 
superior to the other.  Overall study alpha will equal 5%. 
 
Sample Size  
Parameters  
Total Sample size = 2600 subjects (1300 per group) 
• Expected all-cause shock rate in each group = 7% 
• 5% alpha 
• Power ≥ 90% 
• Equivalence Margin = (0.65 – [1/0.65]) = (0.65 – 1.54) 
• Attrition at 18 months = 10% 
• Estimated enrollment period = 42 months 
• Expected Follow-up period = minimum of 18 months for last 
patient enrolled to maximum of 60 months for first patient 
enrolled 
 
 
 
 
 

Study Reference Number: C1924 
               Form No. 90702637 Rev/Ver AG 
Confidential                                                                                     
Boston Scientific 
APPRAISE ATP CIP 
91165305 Ver AB 
Page 9 of 72 
 
 
3. Table of Contents 
1. 
TITLE PAGE  .......................................................................................................................1 
2. 
PROTOCOL SYNOPSIS .........................................................................................................5 
3. 
TABLE OF CONTENTS .........................................................................................................9 
3.1. Table of Figures .....................................................................................................12 
3.2. Table of Tables ......................................................................................................13 
4. 
INTRODUCTION ................................................................................................................14 
5. 
DEVICE DESCRIPTION ......................................................................................................17 
5.1. Medical Equipment Description ..........................................................................17 
6. 
STUDY OBJECTIVES .........................................................................................................17 
7. 
STUDY ENDPOINTS ...........................................................................................................17 
8. 
STUDY DESIGN .................................................................................................................18 
8.1. Scale and Duration ................................................................................................18 
8.2. Treatment Assignment..........................................................................................19 
 
Treatment Arms ........................................................................................19 
8.3. Justification for the Study Design ........................................................................19 
9. 
SUBJECT SELECTION ........................................................................................................20 
9.1. Study Population and Eligibility ..........................................................................20 
9.2. Inclusion Criteria ..................................................................................................20 
9.3. Exclusion Criteria .................................................................................................20 
10. SUBJECT ACCOUNTABILITY .............................................................................................21 
10.1. Point of Enrollment ...............................................................................................21 
10.2. Withdrawal ............................................................................................................22 
10.3. Subject Status and Classification .........................................................................22 
10.4. Enrollment Controls .............................................................................................23 
11. STUDY METHODS .............................................................................................................23 
11.1. Data Collection ......................................................................................................23 

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11.2. Study Candidate Screening ..................................................................................29 
11.3. Informed Consent and Enrollment .....................................................................29 
11.4. Randomization Assignment .................................................................................29 
11.5. Programming to Treatment Arm – Index Procedure (Day 0) ..........................30 
11.6. Semi-Annual Follow-up Visits .............................................................................33 
11.7. Subjects who are monitored on LATITUDE ......................................................35 
 Phone Call Visits for Subjects ON LATITUDE .......................................36 
11.7.2 Annual Follow-Up Visits for Subjects monitored on LATITUDE ..............36 
11.8. Unscheduled Visits: ICD Interrogation and Evaluation after ICD therapy ...37 
11.9. Device reprogramming outside of Investigational Plan ....................................39 
11.10. 
Study Completion ...................................................................................39 
11.11. 
Source Documents ..................................................................................39 
12. STATISTICAL CONSIDERATIONS ......................................................................................40 
12.1. Endpoints ...............................................................................................................40 
 Primary Endpoint - Time-to-First All-Cause Shock .................................40 
 Hypotheses ...............................................................................40 
 Sample Size ..............................................................................40 
 Statistical Methods ...................................................................41 
 Secondary Endpoint 1 - Time-to-First All-Cause Shock or Death from 
Any Cause .................................................................................................42 
 Hypotheses ...............................................................................42 
 Statistical Methods ...................................................................42 
 Secondary Endpoint 2 – Time-to-Death from Any Cause ........................42 
 Hypotheses ...............................................................................42 
 Statistical Methods ...................................................................43 
 Secondary Endpoint 3 – Time-to-First Appropriate Shock ......................43 
 Hypotheses ...............................................................................43 
 Statistical Methods ...................................................................43 
 Secondary Endpoint 4 – Time-to-First Inappropriate Shock ....................44 
 Hypotheses ...............................................................................44 
 Statistical Methods ...................................................................44 
 Tertiary Objectives ...................................................................................44 
 Multivariate analyses ...............................................................44 
 Latitude Alerts .........................................................................45 
12.2. General Statistical Methods .................................................................................45 
 Analysis Sets .............................................................................................45 
 Control of Systematic Error/Bias ..............................................................45 

Study Reference Number: C1924 
               Form No. 90702637 Rev/Ver AG 
Confidential                                                                                     
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APPRAISE ATP CIP 
91165305 Ver AB 
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 Number of Subjects per Investigative Site ...............................................45 
12.3. Data Analyses ........................................................................................................46 
 Interim Analyses .......................................................................................46 
 Subgroup Analyses ...................................................................................46 
 Justification of Pooling .............................................................................46 
 Changes to Planned Analyses ...................................................................47 
13. DATA MANAGEMENT .......................................................................................................47 
13.1. Data Collection, Processing, and Review ............................................................47 
13.2. Data Retention .......................................................................................................47 
13.3. Core Laboratories .................................................................................................48 
14. AMENDMENTS ..................................................................................................................48 
15. DEVIATIONS .....................................................................................................................48 
16. COMPLIANCE ....................................................................................................................49 
16.1. Statement of Compliance ......................................................................................49 
16.2. Investigator Responsibilities ................................................................................49 
 Delegation of Responsibility ....................................................................51 
16.3. Institutional Review Board/ Ethics Committee ..................................................51 
16.4. Sponsor Responsibilities .......................................................................................51 
 Role of Boston Scientific Representatives ...............................................52 
16.5. Insurance ................................................................................................................53 
17. MONITORING ....................................................................................................................53 
18. POTENTIAL RISKS AND BENEFITS ...................................................................................53 
18.1. Anticipated Adverse Events .................................................................................53 
18.2. Anticipated Adverse Device Effects .....................................................................55 
18.3. Risks Associated with Participation in the Clinical Study ................................55 
18.4. Risk Minimization Actions ...................................................................................55 
18.5. Anticipated Benefits ..............................................................................................55 
18.6. Risk to Benefit Rationale ......................................................................................56 
19. SAFETY REPORTING .........................................................................................................56 
19.1. Reportable Events by investigational site to Boston Scientific .........................56 
19.2. Definitions and Classification ..............................................................................57 

Study Reference Number: C1924 
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APPRAISE ATP CIP 
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19.3. Relationship to Study Device(s) ...........................................................................59 
19.4. Investigator Reporting Requirements .................................................................61 
19.5. Boston Scientific Device Deficiencies ...................................................................63 
19.6. Reporting to Regulatory Authorities / IRBs / ECs / Investigators ...................63 
19.7. Subject Death Reporting ......................................................................................63 
20. INFORMED CONSENT........................................................................................................64 
21. COMMITTEES ...................................................................................................................66 
21.1. Data Monitoring Committee ................................................................................66 
21.2. Steering Committee ...............................................................................................66 
22. SUSPENSION OR TERMINATION .......................................................................................66 
22.1. Premature Termination of the Study ..................................................................66 
22.2. Criteria for Premature Termination of the Study .............................................66 
22.3. Termination of Study Participation by the Investigator or Withdrawal of 
IRB/ EC Approval .................................................................................................67 
22.4. Requirements for Documentation and Subject Follow-up ................................67 
22.5. Criteria for Suspending/Terminating a Study Site ............................................67 
23. PUBLICATION POLICY ......................................................................................................67 
24. REIMBURSEMENT AND COMPENSATION FOR SUBJECTS .................................................68 
24.1. Compensation for Subject’s Health Injury ........................................................68 
25. BIBLIOGRAPHY .................................................................................................................68 
26. ABBREVIATIONS ...............................................................................................................70 
26.1. Abbreviations ........................................................................................................70 
27. APPENDICES .....................................................................................................................71 
 
 
3.1. Table of Figures 
Figure 8.1-1: APPRAISE ATP Study Design ........................................................................ 18 
 

Study Reference Number: C1924 
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Page 13 of 72 
3.2. Table of Tables 
Table 9.2-1: Inclusion Criteria ................................................................................................ 20 
Table 9.3-1: Exclusion Criteria ............................................................................................... 21 
Table 11.1-1: Data Collection Schedule - Subjects NOT on LATITUDE…………………..23 
 
Table 11.1-2: Data Collection Schedule - Subjects on LATITUDE………………………24 
Table 11.3-1: Source Documentation Requirements – Enrollment Visit ............................... 29 
Table 11.5-1: Required Programming: ARM 1: ATP and Shock……………………………28 
 
Table 11.5-2: Required Programming: ARM 2: Shock Only………………………………29 
 
Table 11.6-1: Source Documentation Requirements - Follow Up Visits - Subjects NOT on  
LATITUDE………………………………………………………………………………….31 
 
Table 11.7-1: LATITUDE Follow Up Data – Device Report Upload ................................... 36 
Table 11.7-2: Source Documentation Requirements: Subject Phone Call Visit .................... 36 
Table 11.7-3: Source Documentation Requirements: Annual Follow Up Visits for Subjects 
on LATITUDE ..................................................................................................... 37 
Table 11.8-1: Source Documentation Requirements: Unscheduled Visits: ICD Interrogation 
and Evaluation after ICD therapy ........................................................................ 38 
Table 18.1-1: Potential Adverse Events for Implantation of a Pulse Generator and/or Lead 
System Implants……………………………………………………………………………51  
Table 19.2-1: Safety Definitions ............................................................................................. 54 
Table 19.3-1: Criteria for Assessing Relationship of Study Device or Procedure to 
Adverse Event .................................................................................................... 59 
Table 19.4-1: Investigator Reporting Requirements ......................................................... 61 
Table 26.1-1: Abbreviations ................................................................................................... 70 
 

Study Reference Number: C1924 
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Confidential                                                                                     
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APPRAISE ATP CIP 
91165305 Ver AB 
Page 14 of 72 
4. Introduction 
 
Antitachycardia pacing (ATP) is programmed electrical stimulation delivered by an 
implantable cardioverter defibrillator (ICD) that is intended to terminate re-entrant 
ventricular tachycardia (VT).  Non-randomized trials of ICDs in the early 1990s 
demonstrated the safety and efficacy of ATP in secondary prevention patients, that is, 
patients with a history of ventricular tachyarrhythmias.  ATP has been shown to be valuable 
in terminating potentially lethal ventricular tachyarrhythmias without shocks.1, 2, 3   Success 
in terminating VT was achieved in approximately 90% of patients.  In 2-4% of patients, 
however, ATP accelerated VT into ventricular fibrillation (VF), requiring a shock for 
arrhythmia termination. 
Three studies were to follow that expanded the indications for use of ICDs beyond those 
patients with a history of VT/VF:  MADIT4, MADIT II5, and SCD-HeFT6.  MADIT was 
designed and initiated in 1991 before ATP was commercially available and consequently was 
not designed to study ATP use.  MADIT II allowed physicians to program devices according 
to investigator discretion and many did program it on.  Although ATP successfully 
terminated VT in some patients, it was not programmed in a systematic way in MADIT II 
and the study results were not prospectively designed for analysis.  In SCD-HeFT, devices 
were programmed to deliver shocks alone and the use of ATP was not permitted.  Thus, 
while these studies made ICDs available to a wider population, they did not provide medical 
evidence to help guide the use of ATP. 
Different manufacturers have different programming methods for determining the time to 
delivery of ATP.  Figure 1 compares the timing used in the MADIT-RIT study7 , using 
Boston Scientific devices, to other studies of ATP performed using Medtronic devices to 
permit comparisons of the time to therapy delivery delays between studies under the 
assumption that the detected tachyarrhythmia has a 300 ms cycle length.  Both manufacturers 
employ algorithms in which a programmable number of pre-defined fast intervals must be 
detected before therapy is delivered.  The Boston Scientific devices used in MADIT-RIT 
were capable of being programmed to permit an incremental duration delay above and 
beyond that needed to declare the presence of tachyarrhythmia requiring treatment.  Note that 
this table provides the approximate time to initiation of therapy only.  The time to complete 
delivery of ATP and confirm that the rhythm has been successfully converted may add an 
additional 2-3 seconds. 
 
 
 
 
 
 
 

Study Reference Number: C1924 
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APPRAISE ATP CIP 
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Figure 1: Comparison of Programmed Detection Delays for ATP Delivery 
 
 
Studies undertaken that elucidate the role of ATP are summarized as follows: 
MADIT-RIT8 :  The MADIT-RIT study was designed to test whether inappropriate shocks in 
primary prevention patients could be reduced through at least one of two treatment strategies 
when compared to a third control arm consisting of patients with conventional programming:  
increasing the rate cutoff (high rate therapy) or prolonging the time before delivering device 
therapy (delayed therapy).  Patients were enrolled in MADIT-RIT from September 2009 
through October 2011 and were followed for a mean of 1.4 years and the use of both CRT-D 
devices (50%) and ICDs (50%) were permitted.  Both strategies were successful in reducing 
the risk of occurrence of first inappropriate ICD therapy, with high rate therapy associated 
with a 79% reduction (p<0.001) and delayed therapy associated with a 76% reduction 
(p<0.001).  Furthermore, MADIT-RIT demonstrated that both programming strategies can be 
employed without increasing all-cause mortality or syncope. 
Examination of appropriate ATP delivered in MADIT-RIT revealed 446 episodes in the 
convention programming arm, compared to 113 episodes in the high rate therapy arm and 
143 episodes in the delayed therapy arm.  The authors noted that this finding suggests that 
much of the ATP delivered in the conventional programming arm was prematurely delivered 
for non-sustained ventricular tachyarrhythmias.  The delivery of ATP in these instances, 
while consistent with the programming of the device may also be clinically unnecessary. 
PainFREE Rx II9:  PainFREE Rx II, preceded by the PainFREE Rx10  pilot study, was 
designed to determine whether fast VT, defined as ventricular rhythms detected between 
188-250 bpm, could be successfully and safely treated with ATP.  The primary outcome 
measure was ATP effectiveness.  This study enrolled patients from January 2001 to March 
2002 and included a mix of patients with secondary indications and MADIT indications but 
ceased enrollment prior to the availability of ICD indications for the MADIT II and SCD-
HeFT populations.  Patients were randomized to two arms: one arm received ATP for fast 
VT with detection of 18/24 fast intervals with a rate cutoff of 188 bpm while the other arm 
was randomized to shocks only using the same rate cutoff of 188 bpm.  After 11 months of 
follow-up, ATP was found to have successfully terminated 229/284 episodes of fast VT 
(81% unadjusted, 72% after adjusting for multiple events) and it was considered to be safe in 

Study Reference Number: C1924 
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Page 16 of 72 
this population as well without an appreciable increase in syncope, mortality, episode 
duration, or acceleration. 
PREPARE11:  The PREPARE study was a one-armed observational study that compared the 
effect of prolonged detection intervals on a morbidity index, which was a composite of all-
cause shocks delivered to treat spontaneous episodes, syncope of arrhythmic or presumed 
arrhythmic origin, and untreated sustained symptomatic VT/VF events.  The control group 
was a historical cohort taken from the MIRACLE ICD and EMPIRIC studies.  Patients 
enrolled in PREPARE were programmed to a detection interval of 30/40 fast beats with a 
rate cutoff of 182 bpm.  All patients enrolled were from a primary prevention population and 
patients were implanted with either CRT-D devices (35%) and ICDs (65%).  The enrollment 
period extended from October 2003 through May 2005.  The mean follow-up was not 
reported, but patients were followed for a minimum of 12 months.  The authors reported a 
significant reduction in the morbidity index, from 0.26 events/year in the PREPARE cohort 
and 0.69 events/year in the historical cohort (p=0.003). 
ADVANCE III 12:  This study tested the hypothesis that further prolongation of the delay prior 
to initiating therapy may reduce ICD therapies, consisting of both shock and ATP delivery.  
Patients were enrolled from March 2008 to December 2010 and considered of both 
secondary and primary prevention patients (25% and 75%, respectively) as well as both 
CRT-D devices and ICDs (41% and 59%, respectively).  Patients were randomized to one of 
two arms:  ATP delivery with standard detection parameters (18/24 intervals as studied in 
PainFREE Rx II) versus ATP delivery with long detection parameters (30/40 fast intervals).  
Rate cutoffs of 188 bpm were used in both arms.  Assuming a ventricular tachyarrhythmia 
with a 300 ms cycle length, this analysis in effect compared a 5.4 second to a 9.0 second 
delay.  After an average follow-up interval of 12 months, the authors reported a 37% 
reduction in the incidence of a composite of shock and ATP therapies (p<0.001) that was 
driven predominantly by a 42% reduction in the incidence of ATP alone (p<0.001).  The 
reduction in the incidence of shocks approached but did not achieve statistical significant 
(23%, p=0.06).  The authors concluded that a strategy of prolonged device detection 
significantly reduced the rate of ICD therapies. 
The MADIT-RIT study was not prospectively designed to assess the role of ATP, but 
analysis of the two types of ICD therapies revealed that the incidence of shocks, whether 
appropriate or inappropriate, was consistent across all three arms (~5% and ~3% for 
appropriate and inappropriate shocks, respectively) with no significant difference in shock 
rates.  Both of the new treatments strategies were associated with substantial reductions in 
ATP, however.  The incidence of appropriate and inappropriate ATP in the control group 
(18% and 17%, respectively) were significantly less with high rate therapy (5% appropriate 
and 2% inappropriate, p<0.001) and with delayed therapy (2% appropriate and 3% 
inappropriate, p<0.001).  An analysis of mortality in MADIT-RIT13  revealed a statistically 
significant association between inappropriate ATP and all-cause mortality [hazard ratio = 
3.25, 95% confidence interval (1.33-7.94), p=0.10] while no association was found between 
appropriate ATP and all-cause mortality [hazard ratio=1.02, 95% confidence interval (0.36-
2.88), p=0.977].  An association does not necessarily imply causality, however, and further 
investigation into ATP is warranted. 
 

Study Reference Number: C1924 
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Confidential                                                                                     
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APPRAISE ATP CIP 
91165305 Ver AB 
Page 17 of 72 
We conclude from these reports in the medical literature that the value of ATP in primary 
prevention patients who receive ICDs is uncertain.  ATP success as previously reported 
potentially includes a large proportion of patients who receive unnecessary ATP for non-
sustained VT.  Although a small proportion of patients do appear to derive long-term benefit 
from ATP, other patients may also receive shocks following inappropriate ATP.  
Accordingly, it is hypothesized that a strategy of programming prolonged delay prior to 
initiating therapy may find that the benefit of appropriate ATP is offset by the consequences 
of inappropriate ATP.  This study is designed to confirm this hypothesis in a large 
prospective randomized controlled trial. 
 
5. Device Description 
5.1. Medical Equipment Description 
Commercially approved Boston Scientific (BSC) single and dual chamber transvenous (TV) 
ICD devices and future generations of BSC single and dual TV-ICD devices approved by the 
appropriate regulatory bodies will be included in the trial. Any commercially available lead 
from any manufacturer is eligible for implantation in the study. 
6. Study Objectives 
The primary objective is to understand the role of ATP in primary prevention patients 
indicated for ICD therapy.  The incidence of all-cause shocks in subjects programmed with 
shocks only will be compared with subjects programmed to standard therapy (ATP and 
shock) to assess equivalency.   
Multivariate analyses will also be performed to determine which baseline clinical factors are 
associated with the use of ATP, bradycardia pacing, and the need for CRT-D pacing therapy. 
7. Study Endpoints 
The primary endpoint collected post randomization is: 
• Time-to-First All-Cause Shock 
The secondary endpoints are: 
• Time-to-First All-Cause Shock or Death from Any Cause 
• Time-to-Death from Any Cause 
• Time-to-First Appropriate Shock 
• Time-to-First Inappropriate Shock 
 
The tertiary objective is a multivariate analysis to determine covariates associated with the 
use of ATP, bradycardia pacing, and the need for future CRT-D pacing therapy. 

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APPRAISE ATP CIP 
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Page 18 of 72 
8. Study Design 
This is a global, prospective, randomized, multi-center clinical trial that has been classified as 
a non-mandated post market trial. 
8.1. Scale and Duration 
The study will be conducted at up to 200 sites globally. Approximately 2,600 subjects will be 
enrolled, and sites may continue to enroll subjects until notified of enrollment completion.  
Subjects will be consented for follow up visits through 60 months (5 years). Their length of 
participation will differ depending when they entered the study.  Sites will continue to follow 
subjects until notified of follow-up completion.    
The study will conclude after the earliest of one of following occurrences: (1) one arm is 
determined to be superior at one of the three interim analyses (per Section 12.3.1), or (2) a 
sufficient number of shock episodes have occurred to sufficiently power the primary 
endpoint. Under current assumptions, it is expected that the last enrolled patient will be 
followed for approximately 18 months and the first enrolled patient will be followed for 
approximately 60 months.   
Figure 8.1-1: APPRAISE ATP Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
(≤60 calendar days post successful implant) 
Complete Inclusion/Exclusion Criteria, Complete Informed Consent Process,  
Collect Demographics 
Randomization 
Obtained via the EDC, the same calendar day of device programming to randomized arm 
Index Procedure: Program to Randomized Arm (Day 0) 
(Device programming must be done the same calendar day of obtaining the randomization assignment, and 
cannot exceed 60 calendar days post implant. This visit can occur at the enrollment visit) 
Device Interrogation/Programming Status, Reportable Adverse Events, Arrhythmia Evaluation, 
Medical History, Physical Assessment, Cardiac Medications, SOC ECG Upload 
Follow-Up Visits 
 In-clinic visits every  
180±60 calendar days from  
Index Procedure (Day 0) 
 
Cardiac Medication Changes, Device 
Interrogation/Programming Status,  
Reportable Adverse Events,  
Arrhythmia Evaluation  
 
Up to 10 in-clinic visits post device 
randomization, depending when subject 
gets enrolled  
 Annual In-Clinic Visits  
Every 360 days   
 
Cardiac Medication Changes, Device 
Interrogation/Programming Status,  
Reportable Adverse Events,  
 Arrhythmia Evaluation  
 
Up to 5 in-clinic visits post device 
randomization, depending when subject 
gets enrolled  
 
Subjects NOT on LATITUDE 
Subjects on LATITUDE 

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8.2. Treatment Assignment 
Any patient meeting all inclusion and no exclusion criteria is enrollment eligible for the 
APPRAISE ATP study. Patients are considered enrolled in the study once the informed 
consent form (ICF) has been executed. 
Randomization schemes can be obtained by logging onto the electronic data capture system 
(EDC) and registering the patient. Randomization will be in a 1:1 ratio of either treatment 
arm and will be stratified by ischemic etiology, history of atrial fibrillation, and diabetes.  
 
 Treatment Arms 
There will be two treatment arms of the trial:  
Arm 1: ATP and Shock OR Arm 2: Shock Only 
Table 8.2-2 Treatment Arms  
ARM 1= ATP and Shock 
ARM 2 = Shock Only 
Zone 1: Monitor Only (VT-1) 
• 170 bpm, monitor only 
• Disable therapy 
 
Zone 2 (VT) 
• 200 bpm, 12s delay 
• ATP x 1 burst of 8 pulses  
• Shocks 41J 
 
Zone 3 (VF) 
• 250 bpm, 5s delay 
• 
Shocks 41J 
Zone 1: Monitory Only (VT-1) 
• 170 bpm, monitor only 
• Disable therapy 
 
Zone 2 (VT) 
• 200 bpm, 12s delay 
• Shocks 41J 
 
 
Zone 3 (VF) 
• 250 bpm, 5s delay 
• Shocks 41J 
 
 
 
8.3. Justification for the Study Design 
The APPRAISE ATP study is designed to assess the incidence of all cause shocks in patients 
who have an indication for primary prevention of sudden cardiac death and a low ejection 
fraction that are implanted with a commercially available BSC TV-ICD (single or dual 
chamber) device. The study is intended to determine the value of ATP in this patient 
population utilizing current programming guidelines of higher rates and longer delays15, 16 
 

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Page 20 of 72 
9. Subject Selection  
9.1. Study Population and Eligibility  
Primary prevention is an indication for an ICD to prevent sudden cardiac death (SCD). It 
refers to ICDs in individuals who are at risk for, but have not yet had, an episode of sustained 
VT, VF, or cardiac arrest.14 The study population for the APPRAISE ATP trial consists of 
patients who meet the guidelines14 for ICD therapy for primary prevention patients.  
Only primary prevention patients who have had a successful implant of a BSC single or dual 
chamber TV-ICD will be enrolled. The Investigator is responsible for screening all patients 
to determine eligibility of the trial.  
 
9.2. Inclusion Criteria 
Subjects who meet all of the following criteria (see Table 9.2-1) may be given consideration 
for inclusion in this clinical investigation, provided no exclusion criterion (see Section 9.3) is 
met.  
 
Table 9.2-1: Inclusion Criteria 
Clinical 
Inclusion 
Criteria 
• Subject with a Boston Scientific transvenous ICD (de novo implant or 
upgrade from pacemaker to ICD ) implanted because of one of the 
following: 
 Prior MI and left ventricular ejection fraction (LVEF) 
less than or equal to  (≤ )30%  OR 
 Ischemic or non-ischemic cardiomyopathy, and  
LVEF ≤ 35% , and NYHA class II or III   
• Subject is age 21or above, or is considered of legal age per given 
geography 
• Subject is willing and capable of providing informed consent 
• Subject is willing and capable of complying with follow-up visits as 
defined by this protocol 
 
 
9.3. Exclusion Criteria 
Subjects who meet any one of the following criteria (Table 9.3-1) will be excluded from this 
clinical study. 
 

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Page 21 of 72 
Table 9.3-1: Exclusion Criteria 
Clinical 
Exclusion 
Criteria 
• History of spontaneous sustained VT (≥ 160 bpm at ≥ 30 seconds in 
duration) or VF not due to a reversible cause  
• NYHA Class IV documented in the medical records within 90 calendar 
days prior to enrollment  
• Subject is eligible and scheduled for cardiac resynchronization (CRT) 
implant 
• Subjects with a previous subcutaneous ICD (S-ICD)  
• Subject with existing TV-ICD device implanted for greater than 60 days 
• Subjects with coronary artery bypass graft surgery or percutaneous 
coronary intervention within the past 90 calendar days prior to 
enrollment 
• Subjects with documented myocardial infarction within the past 90 
calendar days  prior to enrollment  
• Subjects on the active heart transplant list  
• Subject who has a VAD or is to receive VAD 
• Life expectancy shorter than 18 months due to any medical condition 
(e.g., cancer, uremia, liver failure, etc…) 
• Subjects currently requiring hemodialysis  
• Subject who is known to pregnant or plans to become pregnant over the 
course of the trial 
• Subject is enrolled in any other concurrent clinical study, with the 
exception of local mandatory governmental registries and observational 
studies/registries, without the written approval from Boston Scientific  
 
 
 
10. Subject Accountability 
10.1. Point of Enrollment 
Subjects who meet the eligibility criteria and agree to participate will be given written 
informed consent approved by the center’s Institutional Review Board (IRB) / Ethics Review 
Committee (ERC). 
 
All subjects who complete the informed consent process, sign and date the informed consent 
form are considered enrolled in the APPRAISE ATP study.  No study related procedures can 
take place until the ICF is signed. Screening tests that are part of Standard of Care (SOC) can 

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Page 22 of 72 
be used to determine pre-eligibility. Subjects enrolled in this investigation must be followed 
per this investigational protocol.  
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. Reasons for withdrawal include, but are 
not limited to:  
o Subject found not to meet eligibility criteria 
o Subject did not get randomized  
o Subject choice to withdraw consent 
o Device explanted and not replaced with a BSC TV-ICD 
o Subject was upgraded to a CRT-D system  
o VAD insertion or heart transplant  
o Investigator discretion 
o Enrollment ceiling met  
o Lost to follow-up, despite best efforts to locate the subject; 
 Three documented attempts to contact the subject, including one certified 
letter, are required to declare a subject lost to follow up. 
o Death (see Section 19.7 for reporting requirements) 
 
If a subject withdraws from the clinical investigation, the reason(s) shall be reported on the 
End of Study electronic case report form (eCRF) in the EDC system. Data up to the point of 
withdrawal will be collected. All open adverse events should be closed or documented as 
chronic. Normal manufacturer vigilance monitoring of device performance will take place 
after a subject is withdrawn.  
 
 
10.3. Subject Status and Classification 
All subjects who complete the informed consent process, sign and date the ICF are 
considered enrolled. Subject status will be classified as below after enrollment:  
Intent:  Refers to a subject who meets all eligibility and signs the consent, but does not get 
randomized. This classification status also refers to: 
• A subject who no longer meets eligibility criteria at the time of 
randomization  
• A subject who is no longer willing to participate in the study  
 
The original ICF and screening documentation for intent subjects must be maintained in the 
Center’s files and an End of Study form is to be completed. Patients shall be withdrawn from 
the study and followed per standard of care. No further follow-up is required. Intent patients 
will not count towards the enrollment ceiling. 

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Treatment: Refers to a subject who has been enrolled and their device has been 
reprogrammed to the arm that they have been randomized to (ATP and Shock or Shock 
Only.) 
 
 
10.4. Enrollment Controls 
Each center may enroll up to a maximum of 260 subjects. If a center wishes to exceed this 
limit, the center must obtain prior written approval from the sponsor or sponsor’s delegated 
representative.  
Subjects consented, but who do not undergo a randomization/programming to either 
treatment arm, will not count towards the 2,600 patients. Patients already consented at time 
of notification shall still be entered in the database and withdrawn from the study. 
Investigational sites will be notified when the enrollment goal is close to being reached and 
once enrollment is complete. 
 
11. Study Methods 
11.1. Data Collection 
The data collection schedule for this study is aligned with standard of care (SOC) practices at 
centers. Therefore, there are two data collection schedules for subjects: 1.) Subjects who are 
not monitored on LATITUDE and 2.) Subjects who are monitored on LATITUDE.  
 
Table 11.1-1 for subjects who are NOT monitored on LATITUDE  
Table 11.1-2 for subjects who are monitored on LATITUDE

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Procedure/ 
Assessment 
 
 
 
Enrollment 
 
(≤ 60 
calendar 
days post 
successful 
implant) 
 
 
 
Randomizatio
n 
 
(Obtained day 
of device 
programming to 
assigned 
treatment arm) 
 
 
Programing  
to Assigned 
Treatment 
Arm 
(Day 0) 
(Day of 
randomization. 
Cannot exceed 
60 calendar 
days post 
implant) 
 
 
Follow Up Visits 
through 5 years 
 
6 Mo: 180±60 d 
12 Mo: 360±60d 
18 Mo:540±60d 
24 Mo: 720±60 d 
30 Mo: 900±60d 
36 Mo:  1080±60d 
42 Mo: 1260 ±60 d 
48 Mo: 1440 ± 60d 
54 Mo: 1620± 60d 
60 Mo: 1800+30d 
 
 
Unscheduled 
Visits 
 
(within 30 
calendar days 
of therapy 
delivery)  
 
Informed consent process, 
including informed consent 
signature and date 
X 
 
 
 
 
Inclusion/Exclusion  
X 
◊ 
 
 
 
ECG Upload– Standard of 
Care 
(recommended not required) 
 
 
 
SOC 
 
 
Physical assessment  
 
 
 
 
X 
 
 
Demographics 
 
 
X 
 
 
 
 
Medical History  
 
 
X 
 
 
Cardiac Medications 
 
 
X 
X** 
X** 
Randomization – obtained via 
the EDC system/Risk Stratifiers  
 
 
X 
 
 
 
Device Interrogation/ 
Programming Status 
 
 
X 
X 
X 
Reportable AE’s 
 
* 
* 
* 
* 
Arrhythmia Episodes  
 
 
* 
* 
* 
* 
Legend:  X= Required; *=Data required only if the event occurred; SOC=Recommended if Center 
Standard of Care, **= Need to document changes to cardiac meds only, ◊= Sites must verify subject 
still meets inclusion/exclusion criteria prior to randomization
Table 11.1-1 Data Collection Schedule – Subjects NOT on LATITUDE 

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Table 11.1-2 Data Collection Schedule – Subjects ON LATITUDE 

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Procedure/Assessment 
 
 
 
Enrollment 
(≤60 calendar 
days post 
implant) 
 
 
 
Randomization 
(Obtained day of 
device 
programming to 
assigned 
treatment arm) 
 
Programing  to 
Assigned Treatment 
Arm 
(Day 0) 
(Day of 
randomization. Cannot 
exceed 60 calendar 
days post implant) 
 
 
LATITUDE Follow 
Up Data 
(Automatic Device 
Report Upload) 
Done by Sponsor 
6 Mo: 180±60 d 
18 Mo:540±60d 
30 Mo: 900±60d 
42 Mo: 1260 ±60 d 
54 Mo: 1620 ±60d 
 
 
Subject Phone Call 
Visit  
Done by Center 
 
6 Mo: 180±60 d 
18 Mo:540±60d 
30 Mo: 900±60d 
42 Mo: 1260 ±60 d 
54 Mo: 1620 ±60d 
 
 
Follow Up Visits 
(In Clinic) 
 
12 Mo: 360±60d 
24 Mo: 720±60 d 
36 Mo:  1080±60d 
48 Mo: 1440 ± 60d 
60 Mo: 1800+30d 
 
 
Unscheduled 
Visits 
(per Physician 
Discretion as 
SOC) 
 
Informed consent 
process, including 
informed consent 
signature and date 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
◊ 
 
 
 
 
 
ECG Upload – 
Standard of Care 
(recommended, not 
required) 
 
 
SOC 
 
 
 
 
Physical assessment  
 
 
 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
 
 
X 
 
 
 
 
Cardiac Medications 
 
 
X 
 
X** 
X** 
X** 

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91165305 Ver AB 
Page 28 of 72 
 
 
  
Legend: X= Required; *=Data required only if the event occurred; SOC=Recommended if Center Standard of Care; LAT= Required if subject is 
on LATITUDE remote monitoring. Report will be uploaded by Latitude BSC team; **= Need to document changes to cardiac meds only;  
◊ = Sites must verify subject still meets inclusion/exclusion criteria prior to randomization
Randomization – 
obtained via the EDC 
system/Risk Stratifiers
 
 
 
X 
 
 
 
 
 
Device Interrogation/ 
Programming Status 
 
 
X 
LAT 
 
X 
X 
Reportable AE’s 
 
* 
* 
 
* 
* 
* 
 Arrhythmia Episodes  
 
 
* 
* 
LAT* 
 
* 
* 

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11.2. Study Candidate Screening 
Any subject meeting all of the inclusion criteria and not meeting any of the exclusion criteria 
is enrollment eligible for the APPRAISE ATP study. A formal screening log is not required 
to be maintained. 
 
11.3. Informed Consent and Enrollment  
Subjects who meet all of the inclusion criteria, none of the exclusion criteria, and undergo the 
informed consent process, sign, and date the informed consent form are considered enrolled 
in the study.  No data collection, data entry, or study specific procedure shall be performed 
prior to having appropriately consented the patient. Table 11.3.-1 lists the data collection 
requirements at the enrollment visit.  
Table 11.3-1: Source Documentation Requirements – Enrollment Visit 
Data Collection Requirement 
Retention of Original Source Documentation 
• 
Informed Consent Form and process, 
including informed consent and 
signature date 
• 
Inclusion/Exclusion Criteria  
• 
Demographics 
 
Investigational Center 
 
 
11.4. Randomization Assignment  
Randomization by the EDC system and device programming to randomized treatment arm 
can be performed at the enrollment visit once the patient has completed the informed consent 
process. Randomization will be obtained through the EDC system. Subject data regarding 
ischemic etiology, history of atrial fibrillation and diabetes must be entered in the EDC 
database as randomization cannot occur without these three data points. 
If randomization and subsequent device programming to randomized arm is not performed at 
the enrollment visit, the randomization and device programming visit must occur on the same 
day, and cannot exceed 60 calendar days post implant. Prior to randomization, sites need to 
verify that subjects still meet inclusion criteria and no exclusion criteria.  
 
Every reasonable attempt will be made to have subjects blinded to their randomized 
treatment arm assignment throughout the trial.  
 

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Table 11.4-1: Source Document Requirements – Randomization  
Data Collection Requirement 
Retention of Original Source 
Documentation 
• Subject randomization assignment  
• Reportable AE’s, if applicable 
Investigational Center 
 
11.5. Programming to Treatment Arm – Index Procedure (Day 0) 
If the subject’s device was not programmed to the randomized treatment arm assignment at 
the enrollment visit, programming to the randomized arm must be done the same calendar 
day of obtaining the randomization assignment, and cannot exceed 60 calendar days post 
implant. The date the device was programmed to the randomized arm will be considered the 
time of origin: Index Procedure Day 0, for the subject. Subsequent follow up visits will be 
based off of this date. Once a subject is programmed to the randomized arm, the subject will 
remain in the assigned treatment arm until the end of the study to follow the methodology of 
intention-to-treat (ITT).  
 
Tasks to be performed at this visit include: 
• Pulse generator interrogation with routine lead evaluation on implanted RA and RV 
leads which includes: 
o Intrinsic sensing (mV) 
o  Pacing impedance (Ω) 
o Shock lead impedance (Ω) 
o Pacing threshold (V) (pulse width at physician discretion) 
• Arrhythmia logbook evaluation 
o Verify subject has not had any spontaneous ventricular rhythms that were 
treated with a shock  
• Programming the device to the subject’s randomized  treatment arm 
 
Devices are required to be programmed according to this protocol. Table 11.5-1 represents 
the required device programming for subjects who are randomized to Arm 1: ATP and 
Shock.  
 
 

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Table 11.5-1: Required Programming: Arm 1: ATP and Shock 
ARM 1 =  ATP and Shock  
Programming 
Ventricular Zones 
3 
Zone 1: (VT-1)  Rate  
170 bpm 
Zone 1: (VT-1) Initial Duration  
12 seconds 
Zone 1: (VT-1)  Therapy 
Monitor Only (disable all therapy) 
 
 
Zone 2: (VT)  Rate  
200 bpm 
Zone 2: (VT) Initial Duration  
12 seconds 
Zone 2: (VT) Redetection Duration  
1.0 second (nominal)  
Zone 2: (VT)  Post-Shock Duration  
1.0 second (nominal) 
Zone 2: (VT) Rhythm Detection Enhancement 
Type  
ON (Detection enhancement type is per 
Investigator Discretion) 
Zone 2: (VT)  Therapy  
All shocks: 41 Joules 
ATP1 
 
Number of Bursts 
1 
Pulses per Burst 
-- 
   Initial 
8 
   Increment 
0 
   Coupling Interval  
88% 
   Burst Cycle Length  
88% 
   Ramp Decrement  
0 
   Minimum Interval  
220 ms 
ATP2 
OFF  
 
 
Zone 3: (VF) Rate  
250 
Zone 3: (VF) Initial Duration  
5 seconds 
Zone 3: (VF) Redetection Duration  
1.0 second  
Zone 3: (VF) Post-Shock Duration  
1.0 second  
Zone 3: (VF) QUICK CONVERT ATP 
OFF 
Zone 3: (VF) Therapy 
All shocks: 41 Joules 
 
 

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Table 11.5-2 represents the required device programming for subjects who are randomized to Arm 2: 
Shock only.  
 
 
Table 11.5-2: Required Programming: Arm 2: Shock Only 
ARM 2 = Shock Only 
Programming 
Ventricular Zones 
3 
Zone 1: (VT-1)  Rate  
170 bpm 
Zone 1: (VT-1) Initial Duration  
12 seconds 
Zone 1: (VT-1)  Therapy 
Monitor Only (disable all therapy) 
 
 
Zone 2: (VT)  Rate  
200 bpm 
Zone 2: (VT) Initial Duration  
12 seconds 
Zone 2: (VT) Redetection Duration  
1.0 second (nominal)  
Zone 2: (VT)  Post-Shock Duration  
1.0 second (nominal) 
Zone 2: (VT) Rhythm Detection Enhancement 
Type  
ON: (Detection enhancement type is per 
Investigator Discretion) 
Zone 2: (VT)  Therapy  
All shocks: 41 Joules 
ATP1 
OFF 
ATP2 
OFF  
 
 
Zone 3: (VF) Rate  
250 bpm  
Zone 3: (VF) Initial Duration  
5 seconds 
Zone 3: (VF) Redetection Duration  
1.0 second 
Zone 3: (VF) Post-Shock Duration  
1.0 second  
Zone 3: (VF) QUICK CONVERT ATP 
OFF 
Zone 3: (VF) Therapy 
All shocks: 41 Joules  
 
Bradycardia Pacing: Brady pacing programming in either treatment arm will be at the Investigator 
Discretion. It is recommended that brady programming for single chamber devices is VVI 40 and for 
dual chamber devices DDD with RHYTHMIQTM or AV Search + (± rate response). 
 
Source data requirements at Index Procedure: Programming to Treatment Arm is described in Table 
11.5-3.  
 

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Table 11.5-3: Source Documentation Requirements – Index Procedure (Day 0) 
Programming to Treatment Arm Visit  
Data Collection Requirement 
Retention of Original Source 
Documentation 
• Reportable Adverse Events, Device 
Deficiencies, and Protocol Deviations, if 
applicable  
• Physical Assessment 
• Medical History 
• Cardiac Medications 
Investigational Center  
 
• Device Follow Up Report 
• Selected Episode Electrograms, as 
applicable 
• Device Settings Report 
• Settings Change Report  
• Arrhythmia log book 
 
Printed copy of all final reports retained at 
Investigational Center 
 
Save to USB for Investigational Site. Copy 
will be sent to sponsor, if applicable  
 
Upload USB into EDC system 
• Baseline ECG – most recent, SOC* 
* NOTE: An ECG is not required to be 
performed. It is highly recommended that 
the patient’s most recent ECG, performed as 
SOC, be uploaded into the EDC system as 
available. 
 
Upload ECG into EDC system if available 
 
 
11.6. Semi-Annual Follow-up Visits 
11.6.1 Subjects who are NOT monitored on LATITUDE:  
 
After programming to treatment arm (Index procedure: Day 0), scheduled in-clinic visits are 
required to be performed at 180 day intervals (± 60days) from the programming (Day 0) date 
 (i.e. 6 Mo: 180±60d; 12 Mo: 360±60d; 18 Mo: 540±60d, etc.) in order to capture new, not 
previously reported: 
 
 
• 
Ventricular arrhythmia episodes  
• 
Reportable adverse events 

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• 
Device programming changes 
• 
Protocol deviations 
• 
Device Deficiencies  
• 
Cardiac medication changes  
 
Tasks to be performed at the in-clinic follow-up visits include: 
• Pulse generator interrogation with routine lead evaluation on implanted RA and RV 
leads which includes: 
o Intrinsic sensing (mV) 
o Pacing impedance (Ω) 
o Shock lead impedance (Ω) 
o Pacing threshold (V) (pulse width at physician discretion) 
• Arrhythmia logbook evaluation  
o Print applicable arrhythmia episodes  
• Save interrogation session to USB  
• Upload into EDC system 
 
Source data requirements at the Semi-Annual Follow-Up Visits for subjects who are not 
monitored on LATITUDE are described in Table 11.6-1  
Table 11.6-1: Source Documentation Requirements - Follow Up Visits  
Subjects NOT on LATITUDE  
 
 
Data Collection Requirement 
Retention of Original Source 
Documentation  
• Reportable Adverse Events, Device 
Deficiencies, and Protocol Deviations, if 
applicable 
• Cardiac Medication Changes  
 
 
Investigational Center 
• Device Follow Up Report 
• Selected Episode Electrograms, as 
applicable 
• Device Settings Report 
• Settings Change Report  
Printed Copy of all final reports retained at 
Investigational Center 
Save to USB for Investigational Site. Copy 
will be sent to sponsor, if applicable  
    

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Table 11.6-1: Source Documentation Requirements - Follow Up Visits  
Subjects NOT on LATITUDE  
 
 
Data Collection Requirement 
Retention of Original Source 
Documentation  
• Arrhythmia log book 
 
 
Upload USB into EDC system  
 
 
11.7. Subjects who are monitored on LATITUDE  
For subjects who are remotely monitored, the wireless LATITUDE™ Patient Management 
system will be utilized to collect and store treated tachyarrhythmia episodes. Alerts, 
diagnostic data, and all treated ventricular episodes EGMs are collected for endpoint 
evaluation directly from the LATITUDE database. Applicable reports will be uploaded 
remotely into the study database from the LATITUDE BSC team as defined on the data 
collection schedule on Table 11.1-2.  
After programming to treatment arm (Index procedure Day 0), subjects who are remotely      
monitored with the LATITUDE system must have the following yellow alerts programmed 
on in the LATITUDE database: 
 
• Ventricular shock therapy delivered to convert arrhythmia 
• Accelerated ventricular arrhythmia episode 
• Atrial Arrhythmia burden of at least {>1, 3, 6, 12, 18, or 24} hours in a 24 
hour period  
• Patient triggered event stored 
 
If the HeartLogic feature is available in the implanted device, all subjects with this feature 
will be monitored by the LATITUDE BSC team for the specific HeartLogic alerts. In the 
event of an alert, a report will be uploaded by the LATITUDE BSC team into the study 
database.  
 
 
 

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Table 11.7-1: LATITUDE Follow Up Data – Device Report Upload 
Data Collection Requirement  
Retention of Original Source 
Documentation  
• 
LATITUDE Nominal Device Report 
• Ventricular arrhythmia episodes  
• 
LATITUDE Alerts 
Reports uploaded into the study database by 
BSC LATITUDE team 
 
 
 Phone Call Visits for Subjects ON LATITUDE 
 
Subject phone call visits are required in conjunction with the LATITUDE data device 
report upload visit. The data to be collected at the subject phone call visit include: 
• An assessment of cardiac medication changes 
• An assessment of reportable adverse events 
• An assessment of device deficiencies  
Source data requirements at the subject phone call visits for subjects who are monitored on 
LATITUDE are described in Table 11.7-2. 
Table 11.7-2: Source Documentation Requirements: Subject Phone Call Visit 
Data Collection Requirement  
Retention of Original Source 
Documentation  
• Reportable Adverse Events, Device 
Deficiencies, and Protocol Deviations, if 
applicable 
• Cardiac Medication Changes 
Investigational Center 
 
 
11.7.2 Annual Follow-Up Visits for Subjects monitored on LATITUDE  
For subjects monitored on LATITUDE, annual in-clinic visits are required to be 
performed per the data collection schedule on Table 11.1-2.  
Tasks to be performed at the annual in-clinic follow-up visits include:  
• Pulse generator interrogation with routine lead evaluation on implanted RA and RV 
leads which includes: 
o Intrinsic sensing (mV) 
o  Pacing impedance (Ω) 

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o Shock lead impedance (Ω) 
o Pacing threshold (V) (pulse width at physician discretion) 
• Arrhythmia logbook evaluation  
o Print applicable arrhythmia episodes  
• Save interrogation session to USB  
•  Upload into EDC system 
 
Table 11.7-3: Source Documentation Requirements: Annual Follow Up Visits for Subjects 
on LATITUDE  
 
Data Collection Requirement  
Retention of Original Source 
Documentation  
• Reportable Adverse Events, Device 
Deficiencies, and Protocol Deviations, if 
applicable 
• Cardiac Medication Changes 
 
Investigational Center 
• Device Follow Up Report 
• Selected Episode Electrograms, as 
applicable 
• Device Settings Report 
• Settings Change Report  
• Arrhythmia log book 
 
 
Printed Copy of all final reports retained at 
Investigational Center 
 
Save to USB for Investigational Site. Copy 
will be sent to sponsor, if applicable  
 
Upload USB into EDC system  
 
 
 
11.8. Unscheduled Visits: ICD Interrogation and Evaluation after ICD therapy 
After a patient reports ICD therapy, an in-clinic visit must be scheduled within 30 calendar 
days, or as soon as possible. The following is required to be collected at all unscheduled in-
clinic visits:  
• 
Ventricular arrhythmia episodes  
• 
Reportable adverse events 
• 
Medication changes  

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• 
Device programming changes 
• 
Protocol deviations 
• 
Device Deficiencies  
 
Tasks to be performed at the unscheduled visit include:  
• Pulse generator interrogation with routine lead evaluation on implanted RA and RV 
leads which includes: 
o Intrinsic sensing (mV) 
o  Pacing impedance (Ω) 
o Shock lead impedance (Ω) 
o Pacing threshold (V) (pulse width at physician discretion) 
• Arrhythmia logbook evaluation  
o Print applicable arrhythmia episodes  
• Save interrogation session to USB  
• Upload into EDC system 
 
Table 11.8-1: Source Documentation Requirements: Unscheduled Visits: ICD Interrogation 
and Evaluation after ICD therapy  
 
Data Collection Requirement  
Retention of Original Source 
Documentation  
• Reportable Adverse Events, Device 
Deficiencies, and Protocol Deviations, if 
applicable 
• Cardiac Medication Changes 
Investigational Center 
• Device Follow Up Report 
• Selected Episode Electrograms, as 
applicable 
• Device Settings Report 
• Settings Change Report  
• Arrhythmia log book 
 
Printed Copy of all final reports retained at 
Investigational Center 
 
Save to USB for Investigational Site. Copy 
will be sent to sponsor, if applicable  
 
Upload USB into EDC system  
 
 

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For subjects remotely monitored on LATITUDE:  
If the LATITUDE database shows an alert related to a treated episode and/or the subject 
reports a treated episode, it will be at the Investigator Discretion, per their SOC if they want 
to bring the subject in to be seen for an unscheduled visit. The treated episode will be 
collected via the LATITUDE system and uploaded into the study database by the 
LATITUDE BSC team.  
If the center does not bring the patient in for a treated episode as their standard of care 
practice, the coordinating Investigational center needs to call the patient to evaluate: 
• Cardiac medication changes 
• Reportable adverse events 
• Device deficiencies  
11.9. Device reprogramming outside of Investigational Plan 
Once a subject is programmed to their respective randomized arm, every effort will be made 
to keep the subject’s device programmed per the required programming in this protocol. 
Device reprogramming can be made if clinically indicated based on safety concerns. All 
device reprogramming changes, including the reason for change, must be recorded as a 
protocol deviation and the clinical circumstances must be documented as SAE or a device 
related adverse event, as applicable. After reprogramming to device settings outside of the 
required programming per protocol, subjects will remain in the assigned treatment arm until 
the end of the study to follow the methodology of intention-to-treat (ITT). Deviated 
programming doesn’t qualify as reason for study withdrawal, and subjects will continue to be 
followed per the investigational plan. 
 
11.10. 
Study Completion  
The study will conclude after the earliest of one of following occurrences: (1) one arm is 
determined to be superior at one of the three interim analyses (per Section 12.3.1), or (2) a 
sufficient number of shock episodes have occurred to provide the desired power. It is 
expected that the last enrolled patient will be followed for approximately 18 months and the 
first enrolled patient will be followed for approximately 60 months.  Sites will continue to 
follow subjects until notified of follow-up completion. Sites will be notified when subject 
follow-up is complete for the study.    
 
11.11. 
Source Documents 
Original source documents are required to be retained at the center.  Where copies of the 
original source document as well as printouts of original electronic source documents are 

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retained, these shall be signed and dated by a member of the investigational site team with a 
statement that it is a true reproduction of the original source document. 
NOTE: If thermal paper from the device programmer was used for source documentation, 
photocopies or printed pdfs should be prepared and kept for source documentation.  
 
12. Statistical Considerations 
12.1. Endpoints 
 Primary Endpoint - Time-to-First All-Cause Shock 
The incidence of all-cause shocks in subjects programmed with shocks only will be 
compared with subjects programmed to standard therapy (ATP and shock) to assess 
equivalency.   
 Hypotheses 
The hazard ratio of all-cause shocks will be used to evaluate the equivalence of shocks only 
programming and standard therapy.  A relative equivalence margin of 35% in each direction 
will be employed.  The following hypotheses will be used. 
H0:  Hazard Ratio ≤ 0.65 or Hazard Ratio ≥ (1/0.65) 
HA:  0.65 < Hazard Ratio < (1/0.65) 
 Sample Size  
A total of 2600 subjects – 1300 per group – will be required to sufficiently power the primary 
endpoint.  The sample size of 2600 subjects will provide the number of primary endpoint 
events necessary to power the Primary Endpoint.  Two assumption scenarios were considered 
to determine the required sample size. 
 
Scenario 1 
Scenario 2 
Expected all-cause shock rate in each group 
6% 
7% 
Alpha 
5% 
5% 
Power 
90% 
90% 
Equivalence Margin 
(0.65 – [1/0.65]) = (0.65 – 1.54) 
(0.65 – [1/0.65]) = (0.65 – 1.54) 
Attrition at 18 months 
10% 
10% 
Enrollment Period 
42 months 
42 months 
Follow-up Period 
First Patient: 60 months 
Final Patient: 18 months 
First Patient: 54 months 
Final Patient: 12 months 
Maximum Trial Duration 
60 months 
54 months 
 

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 Statistical Methods 
All implanted and randomized subjects will contribute to the analysis of the Primary 
Endpoint.  Cox proportional hazards modeling will be performed, with time-to-first shock 
therapy episode used as the outcome and programming scheme used as the covariate in the 
model.  Traditional therapy will be considered the reference group in the analysis.  Each 
subject’s first shock therapy episode will contribute to the analysis.  Subjects without a shock 
therapy episode will be censored at their date of death, withdrawal, study exit or on the date 
of the data snapshot, whichever occurs first.  From the Cox model, the hazard ratio and 
corresponding confidence interval for programming scheme will be calculated.  If the 
confidence interval for the hazard ratio is fully contained within the equivalence region – 
between 0.65 and 1.54 – equivalence of shocks only and standard programming will be 
concluded.   
If equivalency cannot be established, further testing for superiority will be performed without 
need for a multiplicity adjustment to the significance level of the test beyond the adjustment 
necessary to accommodate the interim superiority tests.  This additional testing is possible 
because the equivalence test is comprised of two separate one-sided non-inferiority tests.  If 
non-inferiority is established for only one of the two one-sided non-inferiority tests, 
superiority can further be tested, per gating methodology.   
The following table outlines the possible results and conclusions that can be drawn from the 
Primary Endpoint analysis. 
 
 
Result of Lower Confidence 
Limit of Confidence 
Interval 
Result of Upper Confidence 
Limit of  Confidence 
Interval 
Conclusion 
>0.65 
<1.54 
Equivalence of shocks only to 
standard therapy 
≤0.65 
≥1 and <1.54 
Non-inferiority of shocks 
only to standard therapy 
<0.65 
<1 
Superiority of shocks only to 
standard therapy 
≤1 and >0.65 
>1.54 
Non-inferiority of standard 
therapy to shocks only 
>1 
>1.54 
Superiority of standard 
therapy to shocks only 
 

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 Secondary Endpoint 1 - Time-to-First All-Cause Shock or 
Death from Any Cause 
The incidence of all-cause shocks or death in subjects programmed with shocks only will be 
compared with subjects programmed to standard therapy (ATP and shock) to assess 
equivalency.   
 Hypotheses 
The hazard ratio of all-cause shocks or death will be used to evaluate the equivalence of 
shocks only programming and standard therapy.  A relative equivalence margin of 35% in 
each direction will be employed.  The following hypotheses will be used. 
H0:  Hazard Ratio ≤ 0.65 or Hazard Ratio ≥ (1/0.65) 
HA:  0.65 < Hazard Ratio < (1/0.65) 
 
 Statistical Methods  
All implanted and randomized subjects will contribute to the analysis of Secondary Endpoint 
1.  Cox proportional hazards modeling will be performed, with time-to-first shock therapy 
episode or death used as the outcome and programming scheme used as the covariate in the 
model.  Traditional therapy will be considered the reference group in the analysis.  Each 
subject’s death or first shock therapy episode will contribute to the analysis.  Subjects that 
survived the follow-up duration without a shock therapy episode will be censored at their 
date of withdrawal, study exit or on the date of the data snapshot, whichever occurs first.  
From the Cox model, the hazard ratio and corresponding confidence interval for 
programming scheme will be calculated.  If the confidence interval for the hazard ratio is 
fully contained within the equivalence region – between 0.65 and 1.54 – equivalence of 
shocks only and standard programming will be concluded. In the event that equivalency 
cannot be established, superiority testing will be performed, employing similar methodology 
to that described for the Primary Endpoint. 
 
 Secondary Endpoint 2 – Time-to-Death from Any Cause 
Hazard of death from any cause in subjects programmed with shocks only will be compared 
with subjects programmed to standard therapy (ATP and shock) to assess equivalency.   
 Hypotheses 
The hazard ratio of death will be used to evaluate the equivalence of shocks only 
programming and standard therapy.  A relative equivalence margin of 35% in each direction 
will be employed.  The following hypotheses will be used. 
H0:  Hazard Ratio ≤ 0.65 or Hazard Ratio ≥ (1/0.65) 

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HA:  0.65 < Hazard Ratio < (1/0.65) 
 Statistical Methods 
All implanted and randomized subjects will contribute to the analysis of Secondary Endpoint 
2.  Cox proportional hazards modeling will be performed, with time-to- death used as the 
outcome and programming scheme used as the covariate in the model.  Traditional therapy 
will be considered the reference group in the analysis.  Each subject’s death will contribute to 
the analysis.  Subjects that survived the follow-up duration will be censored at their date of 
withdrawal, study exit or on the date of the data snapshot, whichever occurs first.  From the 
Cox model, the hazard ratio and corresponding confidence interval for programming scheme 
will be calculated.  If the confidence interval for the hazard ratio is fully contained within the 
equivalence region – between 0.65 and 1.54 – equivalence of shocks only and standard 
programming will be concluded. In the event that equivalency cannot be established, 
superiority testing will be performed, employing similar methodology to that described for 
the Primary Endpoint. 
 Secondary Endpoint 3 – Time-to-First Appropriate Shock 
The incidence of appropriate shocks in subjects programmed with shocks only will be 
compared with subjects programmed to standard therapy (ATP and shock) to assess 
equivalency.   
 Hypotheses 
The hazard ratio of appropriate shocks will be used to evaluate the equivalence of shocks 
only programming and standard therapy.  A relative equivalence margin of 35% in each 
direction will be employed.  The following hypotheses will be used. 
H0:  Hazard Ratio ≤ 0.65 or Hazard Ratio ≥ (1/0.65) 
HA:  0.65 < Hazard Ratio < (1/0.65) 
 Statistical Methods 
All implanted and randomized subjects will contribute to the analysis of Secondary Endpoint 
3.  Cox proportional hazards modeling will be performed, with time-to-first appropriate 
shock therapy episode used as the outcome and programming scheme used as the covariate in 
the model.  Traditional therapy will be considered the reference group in the analysis.  Each 
subject’s first appropriate shock therapy episode will contribute to the analysis.  Subjects 
without an appropriate shock therapy episode will be censored at their date of death, 
withdrawal, study exit or on the date of the data snapshot, whichever occurs first.  From the 
Cox model, the hazard ratio and corresponding confidence interval for programming scheme 
will be calculated.  If the confidence interval for the hazard ratio is fully contained within the 
equivalence region – between 0.65 and 1.54 – equivalence of shocks only and standard 
programming will be concluded. In the event that equivalency cannot be established, 
superiority testing will be performed, employing similar methodology to that described for 
the Primary Endpoint. 

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 Secondary Endpoint 4 – Time-to-First Inappropriate Shock 
The incidence of inappropriate shocks in subjects programmed with shocks only will be 
compared with subjects programmed to standard therapy (ATP and shock) to assess 
equivalency.   
 Hypotheses 
The hazard ratio of inappropriate shocks will be used to evaluate the equivalence of shocks 
only programming and standard therapy.  A relative equivalence margin of 35% in each 
direction will be employed.  The following hypotheses will be used. 
H0:  Hazard Ratio ≤ 0.65 or Hazard Ratio ≥ (1/0.65) 
HA:  0.65 < Hazard Ratio < (1/0.65) 
 Statistical Methods 
All implanted and randomized subjects will contribute to the analysis of Secondary Endpoint 
4.  Cox proportional hazards modeling will be performed, with time-to-first inappropriate 
shock therapy episode used as the outcome and programming scheme used as the covariate in 
the model.  Traditional therapy will be considered the reference group in the analysis.  Each 
subject’s first inappropriate shock therapy episode will contribute to the analysis.  Subjects 
without an inappropriate shock therapy episode will be censored at their date of death, 
withdrawal, study exit or on the date of the data snapshot, whichever occurs first.  From the 
Cox model, the hazard ratio and corresponding confidence interval for programming scheme 
will be calculated.  If the confidence interval for the hazard ratio is fully contained within the 
equivalence region – between 0.65 and 1.54 – equivalence of shocks only and standard 
programming will be concluded. In the event that equivalency cannot be established, 
superiority testing will be performed, employing similar methodology to that described for 
the Primary Endpoint. 
 
 Tertiary Objectives 
 Multivariate analyses  
The purpose of this tertiary objective is to determine covariates associated with the use of 
ATP, bradycardia pacing, and the need for future CRT-D pacing therapy.  The number of 
sustained VT episodes that occur in the monitor only zone and the percentage of patients that 
have these events will also be evaluated. Each outcome will be assessed separately, resulting 
in three separate multivariate Cox proportional hazards models.  Covariates considered for 
inclusion in the final multivariate models include, but are not limited to, the characteristics 
listed in Section 12.3.2. 
 

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 Latitude Alerts 
The purpose of this tertiary objective is to (1) characterize the usage rates of HeartLogic 
among study patients, (2) characterize the alert rates among patients using HeartLogic, and 
(3) evaluate if usage and/or alerts are associated with changes in clinical therapy, the 
occurrence of adverse events, or other patient outcomes.  
 
12.2. General Statistical Methods 
 Analysis Sets 
All primary and secondary endpoint analyses will be performed following intention-to-treat 
(ITT) methodology, in which each subject is analyzed per their intended (i.e., randomized) 
treatment assignment.  An as-treated analysis may be performed as well, in which subjects 
would be analyzed per the treatment received and may be time-varying to accommodate 
cross-overs.  A per-protocol analysis may also be performed, limited to the subjects that 
adhered to important protocol criteria.  This list of criteria will be defined prior to analysis, 
but not necessarily prior to the start of the study, to allow for knowledge gained throughout 
the study execution to be reflected in the analysis. 
 
 Control of Systematic Error/Bias 
Overall Type I error for the Primary Endpoint will not exceed 5%.  Type I error will be split 
and managed for the interim superiority analyses by employing an O’Brien-Fleming-type 
error spending function.  Superiority testing for each group will be performed with an overall 
Type I error of 2.5%, resulting in a total of 5% across both groups.  As described in Section 
12.1.1.3, in the event that equivalency is not established, Type I error will be controlled for 
the additional superiority test per gating methodology and will not require further multiplicity 
adjustments 
To reduce the possible introduction of selection bias, subjects will be randomized to their 
treatment assignment.  To reduce the possible introduction of observer bias, an objective 
primary outcome of device-recorded all-cause shocks will be evaluated.  To reduce the 
possible introduction of classification bias for the secondary endpoints of appropriate and 
inappropriate shocks, shocks will be adjudicated by an independent electrogram adjudication 
core lab.  
 
 Number of Subjects per Investigative Site 
No single site is to enroll more than 10% (260 patients) without the prior written approval 
from the sponsor or sponsor’s delegated representative.  
 

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12.3. Data Analyses 
 Interim Analyses  
Interim analyses will be performed to assess the superiority of shocks only or standard 
programming.  Four analyses (three interim analyses and one final) are planned.  The Type I 
error/alpha spending will be managed using an O’Brien-Fleming-type error spending 
function.  The following alpha will be allocated for each analysis. 
Analysis 
Number 
Information Proportion 
at Time of Analysis 
Cumulative Type I 
Error (Alpha) Spending 
Significance Level Used 
for Analysis* 
1 
0.25 
0.00001 
0.00000736681 
2 
0.50 
0.00153 
0.00152000000 
3 
0.75 
0.00965 
0.00916000000 
4 
1.00 
0.02500 
0.02200000000 
*If P-value is less than specified significance level, superiority will be determined. 
 
 Subgroup Analyses  
Analyses will be performed to assess whether significant interactions exist between 
randomization group and various baseline characteristics.  Analyses will evaluate, but are not 
limited to, the following baseline characteristics and their corresponding subgroups. 
Characteristic 
Subgroup 1 
Subgroup 2 
Age 
≥ 65 
< 65 
Gender 
Female 
Male 
History of Atrial Fibrillation 
AF 
No AF 
Ischemic Status 
Ischemic 
Non-Ischemic 
Diabetes 
Diabetic 
Non-diabetic 
Regardless of the results of the interaction test for each characteristic, analyses of each 
subgroup will be performed.  Analyses will be conducted for the Primary Endpoint and all 
Secondary Endpoints. 
 
 Justification of Pooling 
The study will be conducted globally.  A Cox proportional hazards model for the Primary 
Endpoint will be performed, evaluating geography (e.g., continent) as a covariate in the 
model, to assess the poolability of the patients from different geographies. 
 

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 Changes to Planned Analyses 
Any changes to the planned statistical analyses made prior to breaking the blind will be 
documented in an amended Statistical Analysis Plan approved prior to breaking the blind. 
Changes from the planned statistical methods after breaking the blind 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 clinical database will reside on a production server hosted by EDC System. All changes 
made to the clinical data will be captured in an electronic audit trail and available for review 
by the sponsor or its representative. The associated RAVE software and database have 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. 
 
13.2. Data Retention 
The Investigator or Investigational site will maintain, at the investigative site, all essential 
study documents and source documentation that support the data collected on the study 
subjects in compliance with ICH/GCP guidelines.  Documents must be retained until at least 
2 years have elapsed since 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 country/regional/local regulations. The Investigator will 
take measures to ensure that these essential documents are not accidentally damaged or 
destroyed. If for any reason the Principal Investigator or his/her designee withdraws 
responsibility for maintaining these essential documents, custody must be transferred to an 

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individual who will assume responsibility and BSC must receive written notification of this 
custodial change. Sites are required to inform Boston Scientific in writing where paper or 
electronic files are maintained in case files are stored off site and are not readily available.  
 
 
13.3. Core Laboratories 
The Electrogram and Device Interrogation Core Laboratory will review interrogation data to 
determine primary endpoints that occur in APPRAISE ATP. Their decisions are based on 
independent physician review of the data from device interrogation. Responsibilities, 
qualifications, membership, and committee procedures are outlined in the EGM Adjudication 
Charter. Separate instructions regarding the core lab charter will be provided.  
 
14. Amendments  
If a protocol 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., 
IRB/EC/FDA/CA) of the revised protocol must be obtained prior to implementation. 
15. Deviations 
An Investigator must not make any changes or deviate from this protocol, except to protect 
the life and physical well-being of a subject in an emergency. An investigator shall notify the 
sponsor and the reviewing IRB/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 the deviation CRF in the 
EDC system. Sites may also be required to report deviations to the IRB/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, site re-training, or site 
discontinuation/termination) will be put into place by the sponsor. 
 
 

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16. Compliance 
16.1. Statement of Compliance 
This study will be conducted in accordance with post market clinical follow up guidelines 
and will follow the applicable sections of 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 IRB/EC and/or 
regulatory authority has been obtained, if appropriate. Any additional requirements imposed 
by the IRB/EC or regulatory authority shall be followed, if appropriate.  
16.2. Investigator Responsibilities 
The Principal Investigator of an investigational site is responsible for ensuring that the study 
is conducted in accordance with the Clinical Study Agreement, the clinical investigation 
plan/, ISO 14155, ethical principles that have their origins in the Declaration of Helsinki, any 
conditions of approval imposed by the reviewing IRB/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 Clinical Study Agreement and comply with the 
Investigator responsibilities as described in such Agreement.   
• Prior to beginning the study, sign the Protocol Signature page documenting his/her 
agreement to conduct the study in accordance with the protocol. 
• Provide his/her qualifications and experience to assume responsibility for the proper 
conduct of the study and that of key members of the site 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 protocol, except to protect the life and physical 
well-being of a subject in an emergency; document and explain any deviation from the 
approved protocol 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 CRFs and in all required reports. 
• Record, report, and assess (seriousness and relationship to the device/procedure) every 
adverse event as applicable per the protocol and observed device deficiency. 

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• Report to sponsor, per the protocol requirements, all SAEs and device deficiencies that 
could have led to a SADE and potential/USADE or UADE. 
• Report to the IRB/EC and regulatory authorities any SAEs and device deficiencies that 
could have led to a SADE and potential/USADE or UADE, if required by the national 
regulations or this protocol or by the IRB/EC, and supply BSC with any additional 
requested information related to the safety reporting of a particular event. 
• Maintain the device accountability records and control of the device, ensuring that the 
investigational device is used only by authorized/designated users and in accordance with 
this protocol and instructions/directions for use. 
• Allow the sponsor to perform monitoring and auditing activities, and be accessible to the 
clinical research monitor or auditor and respond to questions during monitoring visits or 
audit(s). 
• Allow and support regulatory authorities and the IRB/EC when performing auditing 
activities. 
• Ensure that informed consent is obtained in accordance with applicable laws, this 
protocol and local IRB/EC requirements. 
• Provide adequate medical care to a subject during and after a subject’s participation in a 
clinical study in the case of adverse events, as described in the Informed Consent Form 
(ICF). 
• Inform the subject of the nature and possible cause of any adverse 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, including decoding procedures for blinded/masked clinical investigations, as 
needed. 
• 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. 

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• 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. 
 Delegation of Responsibility 
When specific tasks are delegated by an investigator, including but not limited to conducting 
the informed consent process, the Principal 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. Institutional Review Board/ Ethics Committee 
Prior to gaining Approval-to-Enroll status, the investigational site will provide to the sponsor 
documentation verifying that their IRB/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 IRB/EC and/or competent authority approval of the protocol (or 
permission to conduct the study) and Informed Consent Form, must be received by the 
sponsor before recruitment of subjects into the study and shipment of investigational 
product/equipment. Prior approval must also be obtained for other materials related to subject 
recruitment or which will be provided to the subject. 
Annual IRB/EC approval and renewals will be obtained throughout the duration of the study 
as required by local/country or IRB/EC requirements. Copies of the Investigator’s reports 
and the IRB/EC continuance of approval must be provided to the sponsor.  
16.4. Sponsor Responsibilities 
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, but not limited to 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. 
Boston Scientific will keep subjects’ identifiable health information confidential in 
accordance with all applicable laws and regulations.  Boston Scientific 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. 

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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.  
 Role of Boston Scientific Representatives 
Boston Scientific personnel can provide technical support to the investigator and other health 
care personnel (collectively HCP) as needed during implant, testing required by the protocol, 
and follow-ups. Support may include HCP training, addressing HCP questions, or providing 
clarifications to HCPs concerning the operation of BSC equipment/devices (including 
programmers, 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, assist with the conduct of testing 
specified in the protocol, and interact with the subject to accomplish requested activities. 
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 or programmer 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 Pacing System Analyzers, programmers, 
and other equipment 
• Entering technical data on technical source form as long as the responsible investigator 
verifies and signs the completed worksheet  
• Print out programming reports directly from the clinician programmer and provide 
original to clinical site as source documentation 
• Provide technical expertise/support to subjects during office visits and/or during 
teleconference calls/electronic communications with the principal investigator or their 
delegated site staff and the subject.  
 
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 protocol 
compliance 
• Reviewing collected data and study documentation for completeness and accuracy 
Boston Scientific personnel will not do the following.  
• Practice medicine 

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• Provide medical diagnosis or treatment to subjects 
• Discuss a subject’s condition or treatment with a subject without the approval and 
presence of the investigator 
• Independently collect critical study data (defined as primary or secondary endpoint data) 
• Enter data in electronic data capture systems or on paper case report forms 
 
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 
protocol and applicable regulations. In addition, the clinical research 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 Principal Investigator continues to 
have sufficient staff and facilities to conduct the study safely and effectively. The Principal 
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 Principal Investigator 
and 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. Anticipated Adverse Events  
Subjects participating in this study are subject to the same risks shared by all patients 
undergoing implantation of a TV-ICD system. Based on the literature and on pulse generator 
implant experience, Table 18.1-1 includes an alphabetical list of the possible adverse events 
associated with implantation of a pulse generator and/or lead system.  
Currently, there is no known incremental risk of adverse events coming from the trial. If 
there is a difference in outcomes between the arms, the subjects will be informed of the study 
outcome and may choose to have their programming to the most suitable at the conclusion of 
the study.  
 
 

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Table 18.1-1: Potential Adverse Events for Implantation of a Pulse Generator and/ or Lead 
System Implants 
Potential Adverse Events for Implantation of a Pulse Generator and/ or Lead System* 
Air embolism  
Lead dislodgment  
Allergic reaction  
Lead fracture  
Bleeding  
Lead insulation breakage or abrasion  
Bradycardia 
Lead perforation 
Cardiac tamponade  
Lead tip deformation and / or breakage  
Chronic nerve damage  
Local tissue reaction 
Component failure  
Loss of capture 
Conductor coil fracture 
Myocardial Infarction (MI) 
Death  
Myocardial necrosis 
Elevated thresholds  
Myocardial trauma (e.g., tissue damage, valve damage) 
Erosion  
Myopotential sensing  
Excessive fibrotic tissue growth  
Oversensing / undersensing  
Extracardiac stimulation (muscle/ nerve stimulation) 
Pacemaker-mediated tachycardia (PMT) (Applies to dual-
chamber devices only.) 
Failure to convert an induced arrhythmia 
Pericardial rub, effusion  
Fluid accumulation  
Pneumothorax 
Foreign body rejection phenomena  
Pulse generator migration 
Formation of hematomas or seromas  
Shunting current during defibrillation with internal or 
external paddles 
Heart block  
Syncope 
Heart failure following chronic RV apical pacing 
Tachyarrhythmias, which include acceleration of 
arrhythmias and early, recurrent atrial fibrillation  
Inability to defibrillate or pace 
Thrombus, thromboemboli 
Inappropriate therapy (e.g., shocks, and antitachycardia 
pacing [ATP] where applicable, 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) 
Insulating myocardium during defibrillation with 
internal or external paddles 
Worsening heart failure 
From the DYNAGEN, INOGEN, ORIGEN, INCEPTA, ENERGEN, PUNCTUA, TELIGEN Physician’s Technical Manual Oct 01, 2015; 
Part Number: 359403-002 
 
Patients may develop psychological intolerance to a pulse generator system and may 
experience the following: 
• Dependency 
• Depression 
• Fear of premature battery depletion  
• Fear of shocking while conscious 
• Fear that shocking capability may be lost 

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• Imagined shocking  
• Fear of device malfunction  
An addition potential risk has been identified for this study: 
• Delayed therapy delivery 
 
18.2. Anticipated Adverse Device Effects  
Adverse Device Effects that are part of the listing in the previous18.1 section are to be 
considered Anticipated Device Effects. 
18.3. Risks Associated with Participation in the Clinical Study 
Improved ICD programming to high rates and extended duration delays has been 
demonstrated to be safe and effective in the MADIT RIT3 clinical trial, and no incremental 
risks are anticipated for this study. The programming used in APPRAISE ATP aligns with 
the current 2015 HRS Consensus guidelines – Manufacturer Specific Translation of the HRS 
Consensus4. However, if a programming arm does not seem suitable for the individual 
patient, clinical judgment must be used in programming the devices after a spontaneous event 
has occurred.  
      Participation in this clinical trial occurs post device implantation, and Investigators have 
already chosen to implant a subject with an ICD for primary prevention indications. For 
women of childbearing potential, it will be at the Investigators discretion to enroll this 
population into the trial. No incremental risks are anticipated for this study to women of 
childbearing potential. 
18.4. Risk Minimization Actions 
Additional risks may exist. Risks can be minimized through compliance with this protocol, 
performing procedures in the appropriate hospital or physician office environment, adherence 
to subject selection criteria, close monitoring of the subject's physiologic status during 
research procedures and/or follow-ups and by promptly supplying BSC with all pertinent 
information required by this protocol. 
 
18.5. Anticipated Benefits 
There may be no benefit to the subject. However, medical science and future patients may 
benefit from their participation in this clinical study. If there is a superior or inferior arm, the 
subjects can be programmed at the conclusion of the study to the best programming suitable 
to their needs.  
 

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18.6. Risk to Benefit Rationale 
The implantable device systems and accessories used for this clinical study will be 
commercially available and are considered to be standard of care for patients indicated for 
such implants.  The risks involved with subject participation in this study are essentially the 
same as those for patients not participating in the study.  
The recently published Expert Consensus Statement on Optimal Implantable Cardioverter 
Programming and Testing15 includes information on optimal ICD programming for primary 
prevention patients, and the purpose is to provide evidence based expert guidance. The 
detection duration and rate programming in APPRAISE ATP is aligned with the 
recommendation for primary prevention ICD per this Consensus Statement. 
 
19. Safety Reporting 
19.1. Reportable Events by investigational site to Boston Scientific 
It is the responsibility of the investigator to assess and report to BSC any event which occurs 
in any of following categories: 
• All Serious Adverse Events  
• All Device Related Adverse Events 
o PMT does not have to be reported unless the patient is symptomatic and it is 
true PMT. Document if there was a change in programming related to the 
PMT.  
o Bradycardia only to be reported if the subject is symptomatic to the 
bradycardia 
• All Serious Adverse Device Events 
• All Device Deficiencies  
• Unanticipated Adverse Device Effects/Unanticipated Serious Adverse Device Effects 
• All Arrhythmic Related Events:  
o Any treated or untreated ventricular event if not already documented as: 
 A sustained ventricular episode in the monitoring zone  
 SAE 
 A new onset of an atrial event not reported in the Medical History 
• ATR episodes do not need to be reported if it is a response to a 
known and/or previously reported atrial arrhythmia 
• Syncope 

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o Including reports of near syncope, which could include but not limited to 
symptoms of dizziness, lightheadedness, fainting 
• For subjects with a HeartLogic Alert, any change in heart failure therapy which 
requires IV treatment should be reported as an AE.  
• New findings/updates in relation to already reported events 
 
For Event reporting the medical diagnosis must be reported. In case the diagnosis is not 
available, individual symptoms can be reported to fulfill reporting timelines. If a diagnosis 
becomes available at a later stage, it must be added to the reported event. 
If it is unclear whether or not an event fits one of the above categories, or if the event cannot 
be isolated from the device or procedure, it must be submitted as an adverse event and/or 
device deficiency. 
Any AE event required by the protocol, experienced by the study subject after informed 
consent and once considered enrolled in the study (as defined in study subject classification 
section), whether during or subsequent to the procedure, must be recorded in the eCRF. 
Underlying diseases are not reportable as AEs unless there is an increase in severity of 
frequency during the course of the investigation. For centers in Austria cancer must always 
be reported as a Serious Adverse Event. Death events itself are not be recorded as an SAE, 
but must be reflected as an outcome of ONE (1) specific SAE/ SADE or USADE (see Table 
20.2-1 for Event definitions). 
Refer to Section 18 for the known risks associated with the study device(s). 
 
19.2. Definitions and Classification 
Adverse event definitions are provided in Table 19.2-1. Administrative edits were made on 
the definition of serious adverse event from ISO 14155and MEDDEV 2.7/3 for clarification 
purposes. Adverse events to be reported per section 19.1. 
 
 
Table 19.2-1: Safety Definitions 
Term 
Definition 
Adverse Event (AE) 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3  
 
 
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. 

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Table 19.2-1: Safety Definitions 
Term 
Definition 
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 
 
Ref: MEDDEV 2.7/3  
Adverse event related to the use of an investigational medical device 
NOTE 1: This includes any adverse event resulting from insufficiencies 
or inadequacies in the 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 
intentional abnormal use of the investigational medical device. 
Serious Adverse Event (SAE) 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3  
Note: This definition meets the reporting objectives and requirements of 
ISO 14155 and MEDDEV 2.7/3. 
Adverse event that: 
• Led to death, 
• Led to  serious deterioration in the health of the subject as defined by 
either: 
o a life-threatening illness or injury, or 
o a permanent impairment of a body structure or a body function, or 
o in-patient hospitalization or prolongation of existing hospitalization 
, or 
o in medical or surgical intervention to prevent life-threatening illness 
o 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 clinical investigational plan, without a serious 
deterioration in health, is not considered a serious adverse event.  
Serious Adverse Device Effect 
(SADE) 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3  
Adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event. 
 
Unanticipated Adverse Device 
Effect (UADE) 
 
Ref: 21 CFR Part 812 
 
 
Any serious adverse effect on health or safety or any life-threatening 
problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or 
degree of incidence in the investigational plan or application (including a 
supplementary plan or application), or any other unanticipated serious 
problem associated with a device that relates to the rights, safety, or 
welfare of subjects.   
Unanticipated Serious Adverse 
Device Effect (USADE) 
 
Ref: ISO 14155 
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. 

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Table 19.2-1: Safety Definitions 
Term 
Definition 
 
Ref: MEDDEV 2.7/3  
 
 
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 
 
Ref: MEDDEV 2.7/3  
An inadequacy of an investigational medical device related to its identity, 
quality, durability, reliability, safety or performance. This may include 
malfunctions, use error, or inadequacy in the information supplied by the 
manufacturer. 
 
Abbreviations: EC=Ethics Committee; IRB=Institutional Review Board 
19.3. Relationship to Study Device(s) 
The Investigator must assess the relationship of the AE to the study device or procedure. See 
criteria in Table 19.3-1:  
Table 19.3-1: Criteria for Assessing Relationship of Study Device or Procedure to 
Adverse Event 
Classification 
Description 
Not Related 
Relationship to the device or procedures can be excluded when: 
- the event is not a known side effect of the product category the 
device belongs to or of similar devices and procedures; 
- the event has no temporal relationship with the use of the 
investigational device or the procedures; 
- the serious event does not follow a known response pattern to the 
medical device (if the response pattern is previously known) and is 
biologically implausible; 
- the discontinuation of medical device application or the reduction of 
the level of activation/exposure - when clinically feasible – and 
reintroduction of its use (or increase of the level of 
activation/exposure), do not impact on the serious event; 
- the event involves a body-site or an organ not expected to be 
affected by the device or procedure; the serious event can be 
attributed to another cause (e.g. an underlying 
or concurrent illness/ clinical condition, an effect of another device, 
drug, treatment or other risk factors); 
- the event does not depend on a false result given by the 
investigational device used for diagnosis, when applicable; harms to 
the subject are not clearly due to use error; 

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Table 19.3-1: Criteria for Assessing Relationship of Study Device or Procedure to 
Adverse Event 
Classification 
Description 
- In order to establish the non-relatedness, not all the criteria listed 
above might be met at the same time, depending on the type of 
device/procedures and the serious event. 
Unlikely Related 
The relationship with the use of the device seems not relevant and/or 
the event can be reasonably explained by another cause, but 
additional information may be obtained. 
Possibly Related 
The relationship with the use of the investigational device is weak 
but cannot be ruled out completely. Alternative causes are also 
possible (e.g. an underlying or concurrent illness/ clinical condition 
or/and an effect of another device, drug or treatment). Cases were 
relatedness cannot be assessed or no information has been obtained 
should also be classified as possible. 
Probably Related 
The relationship with the use of the investigational device seems 
relevant and/or the event cannot reasonably explained by another 
cause, but additional information may be obtained. 
Causal 
Relationship 
The serious event is associated with the investigational device or with 
procedures beyond reasonable doubt when: 
- the event is a known side effect of the product category the device 
belongs to or of similar devices and procedures; 
- the event has a temporal relationship with investigational device 
use/application or procedures; 
- the event involves a body-site or organ that 
o the investigational device or procedures are applied to; 
o the investigational device or procedures have an effect on; 
- the serious event follows a known response pattern to the medical 
device (if the response pattern is previously known); 
- the discontinuation of medical device application (or reduction of 
the level of activation/exposure) and reintroduction of its use (or 
increase of the level of activation/exposure), impact on the serious 
event (when clinically feasible); 
- other possible causes (e.g. an underlying or concurrent illness/ 
clinical condition or/and an effect of another device, drug or 
treatment) have been adequately ruled out; 
- harm to the subject is due to error in use; 

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Table 19.3-1: Criteria for Assessing Relationship of Study Device or Procedure to 
Adverse Event 
Classification 
Description 
- the event depends on a false result given by the investigational 
device used for diagnosis, when applicable; 
- In order to establish the relatedness, not all the criteria listed above 
might be met at the same time, depending on the type of 
device/procedures and the serious event. 
 
 
19.4. Investigator Reporting Requirements 
The communication requirements for reporting to BSC are as shown in 19.4-1 
Adverse events must always be reported through the EDC system for APPRAISE ATP. 
However, in the case of any issues where alternative method of reporting is necessary (i.e. 
the EDC system is not available), please report the adverse event to Boston Scientific by 
sending the Event Notification Form via email to the following email address:  
 
APPRAISEATPSafety@bsci.com 
 
 
 
Table 19.4-1: Investigator Reporting Requirements 
Event 
Classification 
Communication 
Method  
Communication Timeline post-market studies**  
(MEDDEV 2.12/2 :  
GUIDELINES ON A MEDICAL DEVICE 
VIGILANCE SYSTEM) 
Unanticipated 
Adverse Device 
Effect / 
Unanticipated 
Serious Adverse 
Device Effect  
 
Complete AE eCRF 
page with all available 
new and updated 
information.  
 
• Within 1 business day of first becoming aware of 
the event. 
• Terminating at the end of the study 
Serious Adverse 
Event  
Complete AE eCRF 
page with all available 
new and updated 
information.  
• Within 10 business days after becoming aware of 
the event or as per local/regional regulations, with 
the exception of deaths (to be reported within 3 
calendar days of center notification.) 
• For Austria: within 2 business days of first 
becoming aware of the event.  
• Reporting required through the end of the study 

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Event 
Classification 
Communication 
Method  
Communication Timeline post-market studies**  
(MEDDEV 2.12/2 :  
GUIDELINES ON A MEDICAL DEVICE 
VIGILANCE SYSTEM) 
Provide all relevant 
source documentation 
(unidentified) for 
reported event upon 
request of the sponsor 
• When documentation is available 
Serious Adverse 
Device Effects 
Complete AE eCRF 
page with all available 
new and updated 
information. 
• 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 
Provide all relevant 
source documentation 
(unidentified) for 
reported event 
• When documentation is available 
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 Device 
Deficiency eCRF with 
all available new and 
updated information.  
• Within 2 business days of first becoming aware of 
the event. Reporting required through the end of the 
study 
Adverse Event 
including Adverse 
Device Effects 
Complete AE eCRF 
page, which contains 
such information as date 
of AE, treatment of AE 
resolution, assessment 
of seriousness and 
relationship to the 
device.  
• In a timely manner  (e.g. recommend within 30 
business days) after becoming aware of the 
information 
• Reporting required through end of study 

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Event 
Classification 
Communication 
Method  
Communication Timeline post-market studies**  
(MEDDEV 2.12/2 :  
GUIDELINES ON A MEDICAL DEVICE 
VIGILANCE SYSTEM) 
 
 
 
 
 
19.5. Boston Scientific Device Deficiencies 
All device deficiencies (including but not limited to failures, malfunctions, use errors, 
product nonconformities, and labeling errors) will be documented and reported to BSC. 
Device failures and malfunctions should also be documented in the subject’s medical record. 
Device deficiencies (including but not limited to failures, malfunctions, and product 
nonconformities) are not adverse events. However, an adverse event that results from a 
device failure or malfunction would be recorded as an adverse event on the appropriate 
eCRF. 
Any 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. 
19.6. Reporting to Regulatory Authorities / IRBs / ECs / Investigators 
Boston Scientific is responsible for reporting adverse event information to all participating 
Principal Investigators, IRB/ECs, and regulatory authorities, as required by local/regional 
regulations.  The Principal Investigator is responsible for informing the IRB/EC, and 
regulatory authorities of UADE and SAE as required by local/regional regulations.  
 
 
19.7. Subject Death Reporting  
A subject death during the study must be reported to Boston Scientific as soon as possible 
and, in any event, within three (3) calendar days of center notification. The center’s IRB/EC 
must be notified of any deaths in accordance with that center’s IRB/EC policies and 
procedures. Whenever possible, the device should be interrogated and BSC system 
components (e.g., the device) should be removed intact and returned promptly to BSC RM 
for analysis.  
A detailed narrative (death letter), may be requested at BSC discretion that provides detailed 
information describing the circumstances surrounding the death. A death narrative in the local 

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language is acceptable, if accompanied by a translation in English. The details listed below 
should be addressed in the death narrative, in order for BSC to understand the circumstance 
surrounding the death:   
• 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 or not the death was witnessed; 
• Whether the subject had worsening heart failure; 
• Any other circumstances surrounding the death; 
• Approximate time interval from the initiating event to death (temporal course) – items to 
consider include, but are not limited to: information regarding last time subject was seen by 
investigator, last office visit, etc. 
• Investigator or co-Investigator signature and date. 
 
Other Source documents maybe requested at BSC.  
 
20. Informed Consent 
Subject participation in this clinical study is voluntary.  Informed Consent is required from 
each subject or his/her legally authorized representative. The Investigator is responsible for 
ensuring that Informed Consent is obtained prior to the use of any investigational devices, 
study-required procedures and/or testing, or 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 Ethics Committee and/or Regulatory authority body, as applicable. The ICF must be 
accepted by BSC or its delegate (e.g. CRO), and approved by the site’s IRB/EC, or central 
IRB, if applicable. 
Boston Scientific 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 site’s IRB/EC.  Any modification requires acceptance from BSC prior to use of 
the form.  The ICF must be in a language understandable to the subject and if needed, BSC 
will assist the site in obtaining a written consent translation. Translated consent forms must 
also have IRB/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 at a minimum include the following steps, 
as well as any other steps required by applicable laws, rules, regulations and guidelines: 

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• 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, 
• 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 
competent to sign the ICF under the applicable laws, rules, regulations and guidelines and by 
the investigator and/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 site 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 (e.g., FDA requirement is within 5 working days of learning 
of such an event). Any violations of the informed consent process must be reported as 
deviations to the sponsor and local regulatory authorities (e.g. IRB/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(s) 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 applicable laws, protocol, a change in Principal Investigator, administrative changes, or 
following annual review by the IRB/EC. The new version of the ICF must be approved by 
the IRB/EC. Acceptance by Boston Scientific is required if changes to the revised ICF are 
requested by the site’s IRB/EC. The IRB/EC will determine the subject population to be re-
consented. 
 
 
 

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21. Committees 
21.1. Data Monitoring Committee 
An Independent Data Monitoring Committee (DMC) will meet periodically, or as needed, to 
review the results of the trial and to evaluate any safety issues that may arise during the 
course of the study. The DMC will include leading experts in Electrophysiology, who are not 
participating in the APPRAISE ATP study, and have no affiliation with BSC. The DMC will 
inform the study Principal Investigator on any safety concerns and other trends that would 
warrant modification or termination of the study. Responsibilities, qualifications, 
membership, and committee procedures are outlined in the DMC Charter. 
21.2. Steering Committee 
The Steering Committee is independent of Boston Scientific RM and is responsible for the 
overall conduct of the study with regard to protocol development, study progress, subject 
safety, and overall data quality and integrity. A list of the Steering Committee Members is 
provided on page 3 of this protocol.  
 
22. Suspension or Termination 
22.1. Premature Termination of the Study 
Boston Scientific Corporation 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 subjects.  Investigators, associated IRBs/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 unanticipated adverse device effects 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 Boston Scientific to suspend or discontinue development of the 
device. 

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22.3. Termination of Study Participation by the Investigator or Withdrawal of IRB/ 
EC Approval 
Any investigator, or IRB/ EC in the APPRAISE ATP Study may discontinue participation in 
the study or withdrawal approval of the study, respectively, with suitable written notice to 
Boston Scientific. Investigators, associated IRBs/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 sites by Boston Scientific. The 
IRB/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 IRB or EC terminates participation in the study, participating investigators, 
associated IRBs/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 Boston Scientific. 
In the event a Principal Investigator terminates participation in the study, study responsibility 
will be transferred to another investigator, if possible. In the event there are no opportunities 
to transfer Principal Investigator responsibility; detailed information on how enrolled 
subjects will be managed thereafter will be provided by Boston Scientific. 
The Principal Investigator or his/her designee must return all study-related documents and 
investigational product to Boston Scientific, unless this action would jeopardize the rights, 
safety, or welfare of the subjects. 
22.5. Criteria for Suspending/Terminating a Study Site 
Boston Scientific Corporation reserves the right to stop the inclusion of subjects at a study 
site at any time after the study initiation visit if no subjects have been enrolled for a period 
beyond 6 months after site initiation, or if the site has multiple or severe protocol 
violations/noncompliance without justification and/or fails to follow remedial actions. 
In the event of termination of investigator participation, the IRB/EC and regulatory 
authorities, as applicable, will be notified. All subjects enrolled in the study at the site will 
continue to be followed according to the standard of care. The Principal Investigator at the 
site must make provision for these follow-up visits unless BSC notifies the investigational 
site otherwise. 
 
23. Publication Policy 
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. BSC will submit study 

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results for publication (regardless of study outcome) following the conclusion or termination 
of the study. Boston Scientific Corporation 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 Investigator(s) and/or Executive/Steering 
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. Reimbursement and Compensation for Subjects 
24.1. Compensation for Subject’s Health Injury 
Boston Scientific Corporation will purchase an insurance policy to cover the cost of potential 
health injury for study subjects, if required by applicable law.  
 
25. Bibliography 
1US Food and Drug Administration. PCD Tachyarrhythmia Control System, approved February 11, 
1993. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=319438, Accessed April 
12, 2016 
 
2US Food and Drug Administration. Cadence Tiered Therapy Defibrillation System, approved April 
30, 1993. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=319473, Accessed 
April 12, 2016. 
 
3 US Food and Drug Administration.  VENTAK PRX AICD System, approved August 15, 1994.   
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=319527, Accessed April 12, 
2016. 
 
4 Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients 
with coronary disease at high risk for ventricular arrhythmia. N Engl J Med 1996;335:1933-40. 
 
5 Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with 
myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346-977-883. 
 

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6 Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for 
congestive heart failure. N Engl J Med 2005;352:225-237. 
 
7Schuger C, Daubert JP, Brown MW, et al. Multicenter Automatic Defibrillator Implantation Trial: 
Reduce Inappropriate Therapy (MADIT-RIT): Background, rationale, and clinical protocol. Ann 
Noninvasive Electrocardiol 2012;17(3):176-85. 
 
8Moss AJ, Schuger C, Beck CA, et al: Reduction in inappropriate therapy and mortality through ICD 
programming. N Engl J Med 2012;367:2275-83. 
 
9 Wathen MS, DeGroot PJ, Sweeney MO, et al. Prospective randomized multicenter trial of empirical 
antitachycardia pacing versus shocks for spontaneous rapid ventricular tachycardia in patients with 
implantable cardioverter-defibrillators.  Circulation 2004;110:2591-6. 
 
10 Wathen MS, Sweeney MO, DeGroot PJ, et al: Shock reduction using antitachycardia pacing for 
spontaneous rapid ventricular tachycardia in patients with coronary artery disease. Circulation 
2001;104(7):796-801. 
 
11 Wilkoff BL, Williamson BD, Stern RS, et al: Strategic programming of detection and therapy 
parameters in implantable cardioverter-defibrillators reduces shocks in primary prevention patients. J 
Am Coll Cardiol 2008;52:541-50. 
 
12 Gasparini M, Proclemer A, Klersy C, et al: Effect of long-detection interval vs standard-detection 
interval for implantable cardioverter-defibrillators on antitachycardia pacing and shock delivery.  
JAMA 2013;309(18):1903-11. 
 
13 Ruwald AC, Schuger C, Moss AJ, et al: Mortality reduction in relation to ICD programming in 
MADIT-RIT.  Circ Arrhythm Electrophysiol 2014;7:785-92. 
 
14 Russo, AM., et al., ACCF/HRS/AHA/ASE/HFSA/SCAI/SCCT/SCMR 2013 Appropriate Use 
Criteria for Implantable Cardioverter-Defibrillators and Cardiac Resynchronization Therapy. JACC 
Vol. 61, No. 12, 2013 
March 26, 2013:1318–68 . 
 
15Bruce L. Wilkoff, Laurent Fauchier, Martin K. Stiles, et al: 2015 HRS/EHRA/APHRS/SOLAECE 
Expert Consensus Statement on Optimal Implantable Cardioverter-Defibrillator Programming and 
Testing, Europace (2015)  euv411  DOI: http://dx.doi.org/10.1093/europace/euv411 First published 
online: 19 November 2015 euv411 
 
 16 The manufacturer specific programming settings/choices are based on a compilation of clinical 
expertise and clinical trial data as reported in the 2015 Consensus Statement On Optimal ICD 
Programming and Testing 
http://web.hrsonline.org/Health-Policy/Clinical-Documents/Appendix-B-Manufacturer-Specific-
Translation-of-Recommendations.pdf 
 

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26. Abbreviations  
26.1. Abbreviations 
Abbreviations are shown in Table 26.1-1.   
Table 26.1-1: Abbreviations 
 
 
 
 
Abbreviation/Acronym 
Term 
ATP 
Anti-tachycardia pacing  
bpm 
beats per minute 
BSC 
Boston Scientific  
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CRT-D 
Cardiac Resynchronization Therapy –Defibrillator  
eCRF  
Electronic Case Report Form  
EU 
European Union  
EC 
Ethics Committee  
ECG  
Electrocardiogram 
EDC 
Electronic Data Capture  
EGM 
Electrogram  
FCC 
Federal Communications Commission 
GCP 
Good Clinical Practice 
ICD 
Implantable Cardioverter Defibrillator  
ICF  
Informed Consent Form 
IRB 
Institutional Review Board 
ITT 
Intention-to-Treat 
J 
Joules 
LAT 
LATITUDE 
LVEF 
Left Ventricular Ejection Fraction 
ms 
Millisecond 
N/A 
Not Applicable 
NNT 
Number Needed to Treat 
NR 
Not Required  
NYHA 
New York Heart Association  
OUS 
Outside the United States 
PG 
Pulse Generator 

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ppm 
pulses per minute 
RM 
Rhythm Management 
SAS  
Statistical Analysis System 
SOC 
Standard of Care  
Spontaneous Episode 
Any arrhythmia that is stored within the BSC transvenous ICD PG 
TV-ICD 
Transvenous ICD 
US 
United States 
VF 
Ventricular Fibrillation  
VT 
Ventricular Tachycardia  
 
 
 
 
 
 
27. Appendices 
In addition, the definitions and classifications are applicable to RM. BSC reviews and 
codes all reported events.  
Clinical Observation 
Ref: FDA Guidance for the 
Submission of 
Research and Marketing 
Applications for Permanent 
Pacemaker Leads and for 
Pacemaker Lead Adaptor 
510(k) Submissions 
A clinical observation is a clinical event that did not result in invasive 
intervention, injury, or death, and is not an unanticipated adverse event.  
Corrective actions were simple adjustments such as reprogramming of the 
pulse generator or antibiotic treatment of a pocket infection 
Clinical Complication 
 Ref: FDA Guidance for the 
Submission of 
Research and Marketing 
Applications for Permanent 
Pacemaker Leads and for 
Pacemaker Lead Adaptor 
510(k) Submissions 
A clinical complication is a clinical event that required an invasive 
intervention, injury, or death (e.g., surgical evacuation of a hematoma, 
lead dislodgment requiring lead repositioning, generator replacement, loss 
or abandonment of therapy). 
Type I 
 Ref: FDA Guidance for the 
Submission of 
Research and Marketing 
Applications for Permanent 
Pacemaker Leads and for 
Pacemaker Lead Adaptor 
510(k) Submissions 
Related to the investigational device or therapies.  
 

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Type II 
 Ref: FDA Guidance for the 
Submission of 
Research and Marketing 
Applications for Permanent 
Pacemaker Leads and for 
Pacemaker Lead Adaptor 
510(k) Submissions 
Related to protocol or procedures.  Specifically related to protocol testing 
that is not patient standard of care.     
Type III 
 Ref: FDA Guidance for the 
Submission of 
Research and Marketing 
Applications for Permanent 
Pacemaker Leads and for 
Pacemaker Lead Adaptor 
510(k) Submissions 
Not related to the investigational device(s), system component(s), or 
labeling, but would not have occurred in the absence of the investigational 
device(s) and/or system component(s).  This includes clinical events 
related to commercially released devices that are used in conjunction with 
investigational device(s) or protocol procedures. 
Type IV 
 Ref: FDA Guidance for the 
Submission of 
Research and Marketing 
Applications for Permanent 
Pacemaker Leads and for 
Pacemaker Lead Adaptor 
510(k) Submissions 
Related to a change in patient’s condition. 
Type V 
 Ref: FDA Guidance for the 
Submission of 
Research and Marketing 
Applications for Permanent 
Pacemaker Leads and for 
Pacemaker Lead Adaptor 
510(k) Submissions 
Comments Only.  On occasion, comments were inadvertently entered in 
the adverse event text field of the case report form (CRF). Comments 
identified by the CRF reviewer were assigned a Type V code and not 
included in this report. 
Abbreviations: EC=Ethics Committee; IRB=Institutional Review Board