Strategic Management to Optimize Response To Cardiac Resynchronization Therapy
Phase: NA
Conditions: Heart Failure
Sponsor: Boston Scientific Corporation

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Strategic MAnagement to Optimize Response To Cardiac Resynchronization Therapy 
 
SMART CRT 
 
CLINICAL INVESTIGATION PLAN 
 
Reference Number C2067 
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. 
 
 
 
 
 
 
 
 
 

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Contact Information 
Role 
Contact  
Clinical Contact (US) Allison Anderson 
Clinical Trial Manager 
4100 Hamline Avenue North  
Arden Hills, MN  55126 
 
Cell: 919-345-6001 
E-mail: Allison.anderson@bsci.com 
Technical Service: 1.800.CARDIAC (227.3422) 
Clinical Contact 
(Europe) 
Ursula Appl 
Senior Clinical Trial Manager 
Boston Scientific, Guidant Europe SA/NV 
Green Square, Lambroekstraat 5D 
1831 Diegem 
Belgium 
Tel: +32-2-41-67-213 
Cell: +32-477-31-92-18 
E-mail: ursula.appl@bsci.com 
Technical Services (International): +32-2-41-67-222 
Coordinating 
Principal 
Investigator 
Dr. Michael Gold 
Medical University of South Carolina 
Division of Cardiology 
114 Doughty Street 
MSC 592 
Charleston, SC 29425-5290 
United States 
Vendors/Labs 
A list of vendors involved in the trial is maintained by the sponsor. 
 
 

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Original Release: Dec 21, 2016 
Current Version: April 10, 2017 
 
Revision History 
 
Release Date 
Template 
number and 
version 
Section 
Change 
Reason for Change 
A 
21 Dec 2016 
90702637 
Rev./Ver. AH 
N/A 
Original Release 
N/A 
B 
25 Jan 2017 
90702637 
Rev./Ver. AH 
9.3 Exclusion 
criteria 
Revised exclusion 
criteria to match the 
synopsis for 
pregnancy criterium 
Correction: Was updated 
in the synopsis, but not in 
the body of the protocol 
C 
28 Mar 2017 
90702637 
Rev./Ver. AH 
Current 
Version 
Current Version was 
not updated to match 
Rev B release date 
Correction: Updated 
Current Version to March 
28, 2017 
11.4; 11.5.2.2 “Should” changed to 
“must” 
Correction: Criteria is 
required for the study. 
11.4.2;  
Updated: 
“Echocardiography 
will be used” 
Correction: grammatical 
error 
11.6.2 
Corrected format: 
“directed to the 
patient to address 
how well” 
Correction: grammatical 
error 
 
 
 
11.5.1; 
11.5.2.1; 
11.6.1 
Instructions for 
SmartDelay and 
VectorGuide 
printouts removed 
Updated programmer 
software 
 
 
 
11.6 
Device testing not 
required to be 
completed prior to 
other assessments.  
Correction: Requirement 
removed. 
D 
10 Apr 2017 
90702637 
Rev./Ver. AH 
N/A 
Removal of redlines 
in version C. 
New version required in 
order to remove redlines 
existing in previous 
document. No content 
change from version C. 
 
 

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2. Protocol Synopsis 
Strategic MAnagement  to Optimize Response To  Cardiac Resynchronization Therapy 
SMART CRT 
Study 
Objective(s) 
The primary objective is to show the benefit of SmartDelay™ in patients 
with a prolonged RV-LV interval.  
Planned 
Indication(s) for 
Use  
All implanted devices will be used within the current labeled indications 
for use. Cardiac Resynchronization Therapy Defibrillators (CRT-D) are 
intended to provide cardiac resynchronization therapy and provide anti-
tachycardia pacing and defibrillation therapy. 
Device 
Description 
All commercially approved Boston Scientific X4 quadripolar CRT-D 
devices and future generations of BSC X4 CRT-Ds approved by the 
appropriate regulatory bodies will be included in the trial in combination 
with a Boston Scientific ACUITY™ X4 quadripolar LV lead. CRT-D 
devices must be capable of providing SmartDelay recommendations for 
both biventricular pacing (BiV) and left ventricular (LV) only pacing. 
A list of approved ACUITY X4 LV leads and CRT-D models is available 
upon request.  
Study Design 
SMART CRT is a prospective, double-blind, multicenter, international, 
randomized controlled trial. 
Planned 
Number of 
Subjects 
An estimated 726 subjects will be enrolled in the study in order to achieve 
a target of at least 370 subjects to complete the Six Month Follow-Up. 
The study progress will be monitored, and if necessary, the number of 
patients enrolled may be increased to ensure that an adequate number of 
patients complete the Six Month Follow-Up.  
Planned 
Number of 
Investigational 
Sites / Countries 
The study will be conducted at up to 100 sites globally. 
Primary 
Endpoint 
The primary endpoint is comparing cardiac resynchronization therapy 
(CRT) response rates between AV Delay programming schemes defined 
by SmartDelay or a Fixed AV Delay of 120ms. CRT response is defined 
by a decrease in Left Ventricular End Systolic Volume (LVESV) ≥ 15% 
at 6 months compared to pre-implant baseline.  

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Strategic MAnagement  to Optimize Response To  Cardiac Resynchronization Therapy 
SMART CRT 
Additional 
Analyses 
Additional analyses include: 
• 
Clinical Composite Endpoint 
• 
All-cause mortality 
• 
Heart failure events 
• 
NYHA Class 
• 
Quality of Life (patient Global Assessment instrument) 
• 
Six-minute walk distance 
• 
Kansas City Cardiomyopathy Questionnaire 
• 
Left-ventricular ejection fraction (LVEF) 
Method of 
Assigning 
Patients to 
Treatment 
For all subjects enrolled and implanted with a BSC X4 CRT-D system, 
the RV-LV delay will be measured at the Post-Implant Assessment.  
For those subjects identified with an RV-LV delay ≥70ms, 1:1 
randomization will occur in the electronic data capture (EDC) system. 
Subjects will be randomized to have an AV Delay determined by 
SmartDelay or by a Fixed AV Delay of 120ms.  
Those subjects identified with an RV-LV < 70ms will be exited from the 
study after 30 day contact to assess for any reportable safety events. 
Follow-up 
Schedule 
Study procedures or clinic visits will occur at the following time periods: 
• Enrollment Visit (<30 days prior to implant procedure) 
• Pre-Implant Visit (<30 days prior to implant procedure) 
• Post-Implant Assessment (0-14 days post-implant) and 
Randomization, if applicable  
• Six Month Follow-Up Visit (180 to 210 days after 
Randomization) 
Study Duration 
The trial duration is estimated to be approximately 2.5 years from first 
enrollment to the last patient follow-up. 

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Strategic MAnagement  to Optimize Response To  Cardiac Resynchronization Therapy 
SMART CRT 
Key Inclusion 
Criteria 
• Subject must be indicated to receive a de novo quadripolar Boston 
Scientific Cardiac Resynchronization Therapy Defibrillator (CRT-
D) in conjunction with an ACUITY X4 LV lead. This includes 
subjects who are indicated to receive an upgrade to a BSC X4 
CRT-D from a previously implanted device.   
• In order to achieve a homogenous population for the study, 
qualifying subjects are those with heart failure who meet BSC US 
indications for use defined as those subjects who receive stable 
optimal pharmacologic therapy (OPT) for heart failure and who 
meet any one of the following classifications: 
o Moderate to severe heart failure (NYHA Class III-IV) with 
EF ≤ 35% and QRS duration ≥ 120 ms 
o Left bundle branch block (LBBB) with QRS duration ≥ 
130 ms, EF ≤ 30%, and mild (NYHA Class II) ischemic or 
nonischemic heart failure or asymptomatic (NYHA Class 
I) ischemic heart failure 
• Subject is age 18 or above, or of legal age to give informed 
consent specific to each country and national laws 
• Subject is willing and capable of providing informed consent 
• Subject is willing and capable of complying with visits and 
procedures as defined by this protocol 
Key Exclusion 
Criteria 
• Subjects with documented permanent complete AV block 
• Subjects with permanent or chronic atrial fibrillation (AF) or in 
AF at the time of enrollment 
• Subjects who have previously received cardiac resynchronization 
therapy with pacing in the left ventricle  
• Subjects on the active heart transplant list or who has or is to 
receive ventricular assist device (VAD) 
• Life expectancy shorter than 12 months due to any medical 
condition (e.g., cancer, uremia, liver failure, etc…) 
• Subject with a known or suspected sensitivity to dexamethasone 
acetate (DXA) 
• 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  
• Women of childbearing potential who are or plan to become 
pregnant during the course of the trial  
• Subjects currently requiring dialysis  

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Strategic MAnagement  to Optimize Response To  Cardiac Resynchronization Therapy 
SMART CRT 
Statistical Methods  
Primary 
Statistical 
Hypothesis 
The following set of hypotheses will be used to evaluate the Primary 
Endpoint: 
 
Ho: p (SmartDelay) ≤ p (Fixed) 
H1: p (SmartDelay) > p (Fixed) 
 
Where p represents the proportion of CRT responders.  Response is 
defined as a >15% decrease LVESV ([LVESV6M – LVESVBL]/ LVESVBL 
< - 15%). 
Statistical Test 
Method 
A chi-square test will compare the proportion of responders between the 
groups. 
Sample Size 
Parameters 
Approximately 726 subjects are required in order to achieve 370 subjects 
to complete the Six Month Follow-Up. 
Sample size was calculated using the following assumptions: 
• Effect size = 14.25% difference (based on ability to detect at least 
75% of the 19% difference observed in SMART AV) 
• Randomization allocation = 1:1 
• Subjects contributing to analysis = 370 (51%) of enrolled subjects 
o 436 (60%) with RV-LV ≥ 70 ms 
o 370 (85% of randomized subjects) with complete datasets 
at 6 months among subjects with RV-LV ≥ 70 ms 
Our sample size parameters for patient enrollment were estimated based 
on experience from prior studies. These parameters will be re-evaluated 
while the study is in progress, and if necessary, adjustments may be 
made. 
 
 

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3. Table of Contents 
1. 
TITLE PAGE  ........................................................................................................................ 1 
2. 
PROTOCOL SYNOPSIS .......................................................................................................... 4 
3. 
TABLE OF CONTENTS .......................................................................................................... 8 
3.1. Table of Figures ...................................................................................................... 11 
3.2. Table of Tables ....................................................................................................... 12 
4. 
INTRODUCTION ................................................................................................................. 13 
5. 
DEVICE DESCRIPTION ....................................................................................................... 15 
5.1. Medical Equipment Description ........................................................................... 15 
 
Boston Scientific’s ACUITY X4 Quadripolar LV Lead and Accessories 15 
 
SmartDelay ................................................................................................ 16 
 
LV VectorGuide ........................................................................................ 17 
6. 
STUDY OBJECTIVES .......................................................................................................... 18 
7. 
STUDY ENDPOINTS ............................................................................................................ 18 
8. 
STUDY DESIGN .................................................................................................................. 18 
8.1. Scale and Duration ................................................................................................. 18 
8.2. Treatment Assignment .......................................................................................... 18 
 
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 ............................................................................................................. 21 
10.3. Subject Status and Classification .......................................................................... 22 

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10.4. Enrollment Controls .............................................................................................. 23 
11. STUDY METHODS .............................................................................................................. 23 
11.1. Data Collection ....................................................................................................... 23 
11.2. Study Candidate Screening ................................................................................... 25 
11.3. Informed Consent and Enrollment ...................................................................... 25 
11.4. Pre-Implant Assessment ........................................................................................ 25 
 Physical Assessment .................................................................................. 25 
 Echocardiography ...................................................................................... 26 
 Six-Minute Walk Test ................................................................................ 26 
 Kansas City Cardiomyopathy Questionnaire ............................................. 27 
11.5. Post-Implant Assessment and Randomization .................................................... 27 
 RV-LV Timing Assessment and LV Pacing Vector Selection .................. 28 
 Randomization Assignment and Programming ......................................... 30 
11.6. Six Month Follow-Up Visit .................................................................................... 31 
 SmartDelay Test ........................................................................................ 32 
 Quality of Life Global Assessment ............................................................ 32 
11.7. Additional Follow-Up Visits .................................................................................. 33 
11.8. Device Programming Outside of the Investigational Plan ................................. 34 
11.9. Study Completion ................................................................................................... 34 
11.10. 
Source Documents ................................................................................... 35 
12. STATISTICAL CONSIDERATIONS ....................................................................................... 35 
12.1. Primary Endpoint .................................................................................................. 35 
 Hypotheses ................................................................................................. 35 
 Sample Size ............................................................................................... 35 
 Statistical Methods ..................................................................................... 36 
12.2. General Statistical Methods .................................................................................. 36 
 Analysis Sets .............................................................................................. 36 
 Control of Systematic Error/Bias ............................................................... 36 
 Number of Subjects per Investigative Site ................................................ 37 
12.3. Additional Data Analyses ...................................................................................... 37 
 Other Endpoints/Measurements ................................................................. 37 
 Tertiary/Exploratory Analyses ................................................................... 37 
 Primary Endpoint Sensitivity Analyses ..................................................... 37 
 Interim Analyses ........................................................................................ 38 

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 Subgroup Analyses .................................................................................... 38 
 Multivariable Analyses .............................................................................. 38 
 Changes to Planned Analyses .................................................................... 39 
13. DATA MANAGEMENT ........................................................................................................ 39 
13.1. Data Collection, Processing, and Review ............................................................. 39 
13.2. Data Retention ........................................................................................................ 39 
13.3. Core Laboratories .................................................................................................. 40 
14. AMENDMENTS ................................................................................................................... 40 
15. DEVIATIONS ...................................................................................................................... 40 
16. COMPLIANCE ..................................................................................................................... 41 
16.1. Statement of Compliance ....................................................................................... 41 
16.2. Investigator Responsibilities ................................................................................. 41 
 Delegation of Responsibility ..................................................................... 42 
16.3. Institutional Review Board/ Ethics Committee ................................................... 43 
16.4. Sponsor Responsibilities ........................................................................................ 43 
 Role of Boston Scientific Representatives ................................................ 43 
16.5. Insurance ................................................................................................................. 44 
17. MONITORING ..................................................................................................................... 45 
18. POTENTIAL RISKS AND BENEFITS .................................................................................... 45 
18.1. Anticipated Adverse Events .................................................................................. 45 
18.2. Anticipated Adverse Device Effects ...................................................................... 46 
18.3. Risks Associated with Participation in the Clinical Study ................................. 47 
18.4. Risk Minimization Actions .................................................................................... 47 
18.5. Anticipated Benefits ............................................................................................... 47 
18.6. Risk to Benefit Rationale ....................................................................................... 47 
19. SAFETY REPORTING .......................................................................................................... 47 
19.1. Reportable Events by investigational site to Boston Scientific .......................... 47 
19.2. Definitions and Classification ............................................................................... 48 
19.3. Relationship to Study Device(s) ............................................................................ 50 
19.4. Investigator Reporting Requirements .................................................................. 52 

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19.5. Boston Scientific Device Deficiencies .................................................................... 53 
19.6. Reporting to Regulatory Authorities / IRBs / ECs / Investigators .................... 54 
19.7. Subject Death Reporting ....................................................................................... 54 
20. INFORMED CONSENT ......................................................................................................... 55 
21. COMMITTEES .................................................................................................................... 56 
21.1. Safety Monitoring Process ..................................................................................... 56 
21.2. Steering Committee ................................................................................................ 56 
21.3. Clinical Events Committee .................................................................................... 56 
22. SUSPENSION OR TERMINATION ......................................................................................... 57 
22.1 Premature Termination of the Study ................................................................... 57 
22.1.1 
Criteria for Premature Termination of the Study ....................................... 57 
22.2 Termination of Study Participation by the Investigator or Withdrawal of 
IRB/ EC Approval .................................................................................................. 57 
22.3 Requirements for Documentation and Subject Follow-up ................................. 57 
22.4 Criteria for Suspending/Terminating a Study Site ............................................. 58 
23. PUBLICATION POLICY ....................................................................................................... 58 
24. REIMBURSEMENT AND COMPENSATION FOR SUBJECTS .................................................. 58 
25. BIBLIOGRAPHY .................................................................................................................. 58 
26. ABBREVIATIONS ................................................................................................................ 61 
27. APPENDICES ...................................................................................................................... 63 
27.1. Echocardiography Protocol .................................................................................. 63 
27.2. Six-Minute Walk Test ............................................................................................ 64 
27.3. Kansas City Cardiomyopathy Questionnaire (KCCQ) ...................................... 66 
27.4. SmartDelay Step-by-Step Guidance ..................................................................... 66 
 
3.1. Table of Figures 
Figure 5-1: ACUITY X4 Leads and Electrode Placement ..................................................... 16 
Figure 5-2: SmartDelay Example ........................................................................................... 17 
Figure 5-3: LV VectorGuide Example ................................................................................... 17 

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Figure 8-1: SMART CRT Study Design ................................................................................ 18 
Figure 11-1: Post-Implant Assessment ................................................................................... 29 
Figure 11-2: Quality of Life Global Assessment .................................................................... 32 
 
3.2. Table of Tables 
Table 8-1: Treatment Arms ..................................................................................................... 19 
Table 9-1: Inclusion Criteria ................................................................................................... 20 
Table 9-2: Exclusion Criteria .................................................................................................. 21 
Table 11-1: Data Collection Schedule .................................................................................... 24 
Table 11-2: Source Documentation Requirements – Enrollment Visit .................................. 25 
Table 11-3: NYHA Classifications ......................................................................................... 26 
Table 11-4: Source Documentation Requirements – Pre-Implant Assessment ...................... 27 
Table 11-5: Source Document Requirements – Post-Implant Assessment and Randomization
 ............................................................................................................................. 31 
Table 11-6: Source Document Requirements – Six Month Visit ........................................... 33 
Table 11-7: Additional Follow-Up Visit Data Collection ...................................................... 34 
Table 18-1-1: Potential Adverse Events for Implantation of a Pulse Generator and/ or Lead 
System Implants ................................................................................................... 45 
Table 19-1: Safety Term Definitions ...................................................................................... 48 
Table 19-2: Criteria for Assessing Relationship of Study Device or Procedure to Adverse 
Event .................................................................................................................... 51 
Table 19-3: Investigator Reporting Requirements .................................................................. 52 
Table 26-1: Study Abbreviation .............................................................................................. 61 

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4. Introduction 
Heart failure may be exacerbated by the presence of an interventricular conduction delay.  
This delay in conduction, evidenced by QRS prolongation on an ECG, often results in an 
inefficient asynchronous contraction pattern. Cardiac resynchronization therapy (CRT) is the 
application of electrical stimuli to both ventricles with an implanted device.   
Cardiac resynchronization therapy, when combined with defibrillation (CRT-D) was first 
demonstrated to be safe and effective in the CONTAK CD study1. This study showed that 
defibrillator patients with NYHA Class III-IV heart failure, reduced ejection fraction, and 
wide QRS who randomized to CRT-D On had significantly improved exercise performance, 
reduction in symptoms, increased quality of life, and improved cardiac structure and function 
when compared to patients randomized to CRT-D Off.   
The COMPANION study was a subsequent study of patients NYHA Class III-IV heart 
failure, reduced ejection fraction, and wide QRS. Unlike the prior CONTAK CD study, 
patients in COMPANION were not indicated for a defibrillator. Patients in this study were 
randomized on a 2:2:1 basis to CRT-D, CRT-P (CRT without a defibrillator), or optimal 
pharmacological therapy. COMPANION not only confirmed the results from the CONTAK 
CD study, but demonstrated additional benefits of CRT that included significant reduction in 
all-cause mortality, both alone and in combination with hospitalization due to all-causes, 
cardiovascular causes, or heart failure2.    
The study of CRT-D was extended in the MADIT CRT trial to defibrillator patients with 
NYHA Class I-II, reduced ejection fraction, and wide QRS. Like the COMPANION study 
before it, MADIT CRT showed that CRT-D was associated with significant reduction in all-
cause mortality in combination with heart failure hospitalization when compared to patients 
receiving a defibrillator alone3. MADIT CRT also demonstrated significant reduction in left 
ventricular volumes and improvement in left ventricular ejection fraction. 
The benefits of CRT-D are not conferred on every patient implanted with a device, however.  
Patients who fail to show improvement are typically referred to as “non-responders”. There is 
no universally accepted metric for defining response. Commonly used outcome measures in 
clinical practice include symptomatic relief, quality of life, or exercise tolerance.  
Improvements in echocardiographic parameters (left ventricular dimensions/volumes and left 
ventricular ejection fraction) may also be used. Large scale clinical trials tend to use 
composite endpoints, of which the Clinical Composite Endpoint (CCE)  is the most widely 
used4. This endpoint combines four metrics: all-cause mortality, heart failure hospitalization, 
NYHA Class, and quality of life as measured with the patient global assessment instrument. 
When clinical metrics are used, the typical non-response rate cited is one-third of patients are 
non-responders. When echo-based measures are used, the non-response rate is somewhat 
higher. 
The potential reasons for non-response are varied and include5: 
• Poor lead location 

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• Lack of baseline electrical dyssynchrony 
• Improper programming 
• Irreversibly advanced heart failure 
• Myocardial scar 
 
Device-based features have been introduced that modify how CRT is delivered.  These 
include: 
• Interventricular timing (V-V timing)  
• AV Delay 
• Multi-site pacing 
• LV-only CRT 
To date, the randomized clinical studies conducted have shown equivalence with 
conventional CRT delivery without demonstrating superiority although subsequent subgroup 
analyses suggest that some patients may be helped. 
V-V Timing: The InSync III Marquis Study6 using the CCE, DECREASE HF Study7 using a 
composite of peak VO2 and LVESD, and RHYTHM ICD V-V Optimization Study8 using 
peak VO2 all demonstrated the safety of this feature and non-inferiority to conventional 
sequential biventricular pacing, but none showed superiority. 
LV Only CRT: The DECREASE HF Study7 using a composite of peak VO2 and LVESD and 
the B-LEFT HF Study9 using the CCE demonstrated safety of LV pacing but neither showed 
that LV Only CRT was superior to conventional biventricular CRT. The AdaptivCRT study, 
using the CCE, evaluated an algorithm that provided either LV or biventricular pacing 
depending on AV conduction while also periodically adjusting AV delay and V-V timing.  
This algorithm was found to be non-inferior to echocardiographic-guided optimization10.  
AV Delay: Randomized studies to determine the effectiveness of optimizing AV delay have 
been based on algorithms that use measurements of intrinsic conduction to establish an AV 
delay. These studies include FREEDOM11 (which also included a V-V timing optimization 
algorithm) and used the CCE and SMART-AV12 which used LVESV, which showed these 
methods were non-inferior to empiric programming. The RESPOND-CRT study, which 
evaluated a CRT system that employed a hemodynamic sensor to optimize both AV and VV 
timing, used a modified version of the CCE. This study as well found that the sensor was 
non-inferior to echocardiographic optimization13.  
Multi-site Pacing: To date, results from only one randomized clinical trial on multi-site 
pacing has been presented. The MPP Trial, using a modified version of the CCE, evaluated a 
CRT-D system that paced the left ventricle from two distinct sites using a quadripolar lead14. 
The study had a 3 month run-in phase that identified non-responders who were then 
randomized to MPP or conventional CRT. MPP was found to be non-inferior to conventional 
CRT in converting non-responders to responders. 
Given that no major randomized trial has prospectively shown superiority to conventional 
methods of delivering CRT, emphasis has shifted to tailoring CRT to a given patient’s 
intrinsic electrophysiologic characteristics. Left ventricular electrical delay (LVED), which is 
a measure of the difference in time between an intrinsic ventricular depolarization being 

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detected at the right ventricular lead and that of the left ventricular lead, has been examined 
as a way of identifying candidates for optimization. Longer LVEDs would be indicative of 
both underlying baseline dyssynchrony and good lead position and provide a better 
foundation for CRT optimization.  
The SMART AV12 study was reexamined in this light by Gold et al15 and the results of the 
fixed AV delay and SMART AV-determined AV delay arms were divided into quartiles 
based on the LVED as measured at the time of implant using the Q-wave from the surface 
lead II ECG as one timing reference and appearance of unpaced ventricular depolarization on 
the left ventricular lead as the other. In this retrospective analysis that used reduction in 
LVESV as its primary endpoint, prolonged values of QLV were significantly associated with 
progressively greater degrees of reverse remodeling. The role of interventricular delay was 
examined again by Gold et al16, but this time using data from the implanted CRT-D device 
instead of external hardware. For this analysis, interventricular delay was measured as the 
elasped time between unpaced ventricular depolarization detected on the right ventricular 
lead and the left ventricular lead (RV-LV). The same relationship was observed with RV-LV 
based subgroups that was previously observed with QLV, namely, that progressively larger 
values of RV-LV were significantly associated with greater reductions in left ventricular 
volumes and improvement in left ventricular ejection fraction and quality of life.  
This retrospective observation that SmartDelay was more effective with prolonged RV-LV is 
the basis for the SMART CRT study. The objective of the SMART CRT study is to confirm 
this finding prospectively. 
5. Device Description 
5.1. Medical Equipment Description 
Commercially approved quadripolar Boston Scientific (BSC) Cardiac Resynchronization 
Therapy Defibrillator (CRT-D) devices and future generations of BSC X4 CRT-D devices 
approved by the appropriate regulatory bodies will be included in the trial. All devices 
utilized in the study will include SmartDelay™ (5.1.2) and must be capable of providing 
SmartDelay recommendations for both biventricular pacing (BiV) and Left Ventricular (LV) 
only pacing. Additionally, all CRT-D devices will utilize LV VectorGuide™ (5.1.3). A list of 
approved CRT-D models is available upon request. 
A commercially approved BSC Right Atrial (RA) lead and Right Ventricular (RV) lead are 
recommended to be included in this study, but any commercially available RA lead and RV 
lead from any manufacturer are eligible. Boston Scientific’s ACUITY™ X4 IS4 heart failure 
lead family for the LV lead (5.1.1) will be required. 
 Boston Scientific’s ACUITY X4 Quadripolar LV Lead and 
Accessories 
Boston Scientific’s ACUITY™ X4 IS4 heart failure lead family for the Left Ventricle (LV) 
leads are required in this study  (Figure 5-1: ACUITY X4 Leads and Electrode Placement). 
The ACUITY X4 leads are intended for chronic left ventricular pacing and sensing. A variety 

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of pace/sense configurations are possible with the four distal electrodes that can function as 
cathodes (all four electrodes) or anodes (all except E1, the most distal electrode) when used 
with a compatible pulse generator. ACUITY X4 leads are available in three tip configuration 
designs (straight tip, short tip spiral, long tip spiral)—intended to provide choices for a 
variety of patient anatomies. Available ACUITY X4 LV leads include: 4671, 4672, 4674, 
4675, 4677, 4678. 
 
Figure 5-1: ACUITY X4 Leads and Electrode Placement 
Note: Nomenclature of electrodes on the lead is E1, E2, E3, E4. The corresponding 
nomenclature on the BSC PRM is as follows: 
E1: LV Tip 1 
E2: LV Ring 2 
E3: LV Ring 3 
E4: LV Ring 4 
 
 
 SmartDelay 
The SmartDelay optimization feature quickly (<2.5 minutes) provides recommended settings 
for programming paced and sensed AV Delays and pacing chamber (LV vs. BiV) based on 
the measurement of intrinsic AV intervals. The objective of the feature is to recommend AV 
Delays that provide optimally timed CRT, which maximizes contractile function.  
The SmartDelay optimization test evaluates right and left ventricular response to both atrial 
sensed and paced events to determine suggested settings for the following: Paced AV Delay 
(PAV), Sensed AV Delay (SAV), pacing chamber(s).  

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Figure 5-2: SmartDelay Example 
 
 LV VectorGuide 
LV VectorGuide allows the clinician to evaluate multiple quadripolar LV pacing vectors 
quickly to identify the desired configuration. The following tests can be assessed in each 
pacing configuration from the LV VectorGuide screen: 
• 
RV sense (RVs) to LV sense (LVs) timing (RV-LV Delay), the delay between 
detection of an intrinsic R-waves between the RV and LV EGMs  
• 
LV lead impedance 
• 
LV pace threshold 
• 
Phrenic Nerve Stimulation (PNS) 
 
Figure 5-3: LV VectorGuide Example 

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6. Study Objectives 
The primary objective is to show the benefit of SmartDelay in patients with a prolonged RV-
LV interval.  
7. Study Endpoints 
The primary endpoint is comparing cardiac resynchronization therapy (CRT) response rates 
between AV Delay programming schemes defined by SmartDelay or a Fixed AV Delay of 
120ms.CRT response is defined by a decrease in LVESV of ≥ 15% at 6 months compared to 
the pre-implant baseline.  
8. Study Design 
SMART CRT is a prospective, double-blind, multicenter, international, randomized 
controlled trial. 
8.1. Scale and Duration 
The study will be conducted at up to 100 sites globally. An estimated 726 subjects will be 
enrolled in the study in order to achieve a target of at least 370 subjects to complete the Six 
Month Follow-Up. The study progress will be monitored, and if necessary, the number of 
patients enrolled may be increased to ensure that an adequate number of patients complete 
the Six Month Follow-Up. The final sample size will be determined via an interim sample 
size re-assessment, as described in Section 12.1.2.  
 
Figure 8-1: SMART CRT Study Design  
 
8.2. Treatment Assignment 
The RV-LV interval will be measured at the Post-Implant Assessment for all subjects 
enrolled and implanted with a BSC X4 CRT-D system. For those subjects identified with an 

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RV-LV ≥70ms, 1:1 randomization will occur via the electronic data capture (EDC) system. 
Subjects will be randomized to have either an AV Delay and pacing chamber determined by 
SmartDelay or a Fixed AV Delay of 120ms with BiV pacing. Randomization schemes can be 
obtained by logging onto the electronic data capture system (EDC) and registering the 
subject. 
Study participation ends prior to randomization assignment for subjects with an RV-LV < 
70ms (as shown in Figure 8-1: SMART CRT Study Design). Subjects with an RV-LV < 
70ms will be exited from the study after 30 day contact to assess for any reportable safety 
events. 
 Treatment Arms 
There will be two treatment arms of the trial:  
Table 8-1: Treatment Arms  
ARM 1= AV Delay and pacing chamber 
determined by SmartDelay 
ARM 2 = Fixed AV Delay at 120ms with 
BiV pacing 
8.3. Justification for the Study Design 
NYHA Class I-II patients are now eligible for CRT following the MADIT CRT study3, and 
there are no prior data for these patients using the SmartDelay feature.  Furthermore, in the 
intervening seven years since the SMART AV trial results were first published, there have 
been changes in technology. Quadripolar leads are available and in use today rather than the 
unipolar/bipolar leads previously available. Potential changes in implant technique 
(optimizing lead position for position rather than electrical performance) as well as potential 
changes in the practice of medicine when treating heart failure patients.  Accordingly, a 
randomized controlled trial was chosen.  This study design helps assure that two comparable 
patient populations are obtained while mitigating bias such that any observed changes are 
due to the use of SmartDelay alone. 
The parameters for the study design were taken from the predicate SMART AV study. The 
SMART AV study was designed to detect a decrease in LVESV of at least 15mL. The 
SMART CRT study is designed to detect a decrease in LVESV of at least 15%. The 
modification in the response definition for SMART CRT was made to represent a more 
appropriate clinical definition of CRT response. Increasing values of RV-LV were associated 
with an increased effect size. The cutoff value of 70 ms was chosen because it maximized the 
potential yield of screened patients while still preserving a clinically important effect 
size. New studies based on previous retrospective analyses may not precisely duplicate the 
magnitude of effect originally reported. Accordingly, this study was designed to detect at 
least 75% of the effect size to conserve a clinically meaningful proportion of the effect 
observed in SMART AV. 
 

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9. Subject Selection  
9.1. Study Population and Eligibility  
Subjects included in the SMART CRT Study should be selected from the investigator’s 
general patient population of patients who are indicated for CRT-D implantation per BSC 
labeled indication provided in Section 9.2. Investigators are responsible for screening all 
potential subjects and selecting those who meet the eligibility criteria for the study as 
described in Sections 9.2 and Section 9.3 below. 
9.2. Inclusion Criteria 
Subjects who meet all of the following criteria (see Table 9-1) may be given consideration 
for inclusion in this clinical investigation, provided no exclusion criterion (see Table 9-2) is 
met.  
Table 9-1: Inclusion Criteria 
Clinical 
Inclusion 
Criteria 
• Subject must be indicated to receive a de novo quadripolar Boston 
Scientific Cardiac Resynchronization Therapy Defibrillator (CRT-D) 
in conjunction with an ACUITY X4 LV lead. This includes subjects 
who are indicated to receive an upgrade to a BSC X4 CRT-D device 
from a previously implanted device.   
• In order to achieve a homogenous population for the study, qualifying 
subjects are those with heart failure who meet BSC US indications for 
use defined as those subjects who receive stable optimal 
pharmacologic therapy (OPT) for heart failure and who meet any one 
of the following classifications: 
o Moderate to severe heart failure (NYHA Class III-IV) with EF 
≤ 35% and QRS duration ≥ 120 ms 
o Left bundle branch block (LBBB) with QRS duration ≥ 130 
ms, EF ≤ 30%, and mild (NYHA Class II) ischemic or 
nonischemic heart failure or asymptomatic (NYHA Class I) 
ischemic heart failure 
• Subject is age 18 years old or above, or of legal age to give informed 
consent specific to each country and national laws 
• Subject is willing and capable of providing informed consent 
• Subject is willing and capable of complying with visits and procedures 
as defined by this protocol 
 
9.3. Exclusion Criteria 
Subjects who meet any one of the following criteria (Table 9-2) will be excluded from this 
clinical study. 

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Table 9-2: Exclusion Criteria 
Clinical 
Exclusion 
Criteria 
• Subjects with documented permanent complete AV block 
• Subjects with permanent or chronic atrial fibrillation (AF) or in AF at 
the time of enrollment 
• Subjects who have previously received cardiac resynchronization 
therapy with pacing in the left ventricle 
• Subjects on the active heart transplant list or who has or is to receive 
ventricular assist device (VAD) 
• Life expectancy shorter than 12 months due to any medical condition 
(e.g., cancer, uremia, liver failure, etc…) 
• Subject with a known or suspected sensitivity to dexamethasone 
acetate (DXA) 
• 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  
• Women of childbearing potential who are or plan to become pregnant 
during the course of the trial  
• Subjects currently requiring dialysis 
10. Subject Accountability 
10.1. Point of Enrollment 
Subjects who meet the eligibility criteria and are interested in participation will be provided 
with an informed consent approved by the center’s Institutional Review Board (IRB) / Ethics 
Committee (EC). 
All subjects who complete the informed consent process, sign and date the informed consent 
form are considered enrolled in the SMART CRT study. No study related procedures can 
take place until the ICF is signed. Screening tests that are part of Standard of Care (SOC) can 
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 choice to withdraw consent 
o BSC X4 CRT-D system was not able to be implanted 
o Pre-implant echocardiography testing not completed prior to implant 

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o Device explanted and not replaced with a BSC X4 CRT-D system 
o VAD insertion or heart transplant  
o Investigator discretion 
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. 
 
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:  A subject who has been enrolled, but does not have anesthesia administered in 
preparation for a BSC CRT-D system implant procedure. The original Informed Consent 
form and screening documentation for intent patients should be maintained in the Center’s 
files and an End of Study form completed. Patients shall be withdrawn from the study and 
followed as per standard of care. No further follow-up is required. 
 
Partial Attempt: A subject who has been enrolled and has had anaesthesia administered in 
preparation for a BSC CRT-D system implant procedure, but does not undergo an 
implant/main study procedure.  The patient shall be contacted at least 30 days after the 
attempt to check for any reportable adverse event possibly related to the partial attempt and 
an End of Study form completed. No further follow-up is required after the 30 day contact. 
Attempt: A subject who has been enrolled, had anaesthesia administered in preparation for a 
BSC X4 CRT-D system implant procedure, undergoes a BSC CRT-D system implant 
procedure, but is not successfully implanted with the study system (RA lead, RV lead, 
ACUITY X4 LV lead, and BSC X4 CRT-D). The patient shall be contacted at least 30 days 
after the attempt to check for any reportable adverse event possibly related to the partial 
attempt and an End of Study form completed. No further follow-up is required after the 30 
day contact. 
Implant: A subject who has been enrolled, had anesthesia administered in preparation for a 
BSC CRT-D system implant procedure, undergoes a BSC X4 CRT-D system implant 
procedure and is successfully implanted with the study system (RA lead, RV lead, ACUITY 
X4 LV lead, and BSC X4 CRT-D).  
 

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10.4. Enrollment Controls 
Each center may enroll up to a maximum of 72 subjects, no more than 10% of 726 expected 
subjects. If a center wishes to exceed this limit, the center must obtain prior written approval 
from the sponsor or sponsor’s delegated representative.  
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 
Data will be collected from each subject at the following visits: Enrollment Visit, Pre-
Implant Assessment, Post-Implant Assessment and Randomization, and Six Month Follow-
Up. Additional follow-up visits must be collected if they are associated with a reportable 
adverse event, a suspected device deficiency, or a specified device programming change. 
Routinely scheduled office visits, for purposes other than the aforementioned events, do not 
require additional visit forms to be completed. Subjects classified as “partial attempt” and 
“attempt” will be contacted, either in person or by telephone, at least 30 days after the 
implant procedure in order to capture any reportable adverse events prior to withdrawal from 
the study.

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Table 11-1: Data Collection Schedule 
 
Procedure/Assessment 
Enrollment Visit  
(< 30 days prior 
to implant) 
Pre-Implant 
Assessment 
(< 30 days prior to 
implant) 
Post-Implant 
Assessment & 
Randomization 
(0-14 days from 
implant) 
Six Month Follow-
up 
(Day 180 to 210 
days after 
randomization) 
Additional 
Visits 
Informed consent process, 
including informed consent 
signature date 
X 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Physical assessment 
 
X 
 
X 
 
Medical history 
X 
 
 
 
 
Echocardiography 
 
X 
 
X 
 
NYHA Class 
 
X 
 
X 
 
12 lead ECG 
 
X 
 
 
 
Six-minute walk test 
 
X 
 
X 
 
Kansas City Cardiomyopathy 
Questionnaire (KCCQ) 
 
X 
 
X 
 
Patient & Physician Global 
Assessments  
 
 
 
X 
 
Cardiac medications 
X 
X** 
X** 
X** 
X** 
RV and LV lead location 
 
 
X 
 
 
Implanted device information  
 
 
X 
 
 
Randomization – obtained via the 
EDC system 
 
 
X* 
 
 
Device interrogation/ 
programming status 
 
 
X 
X 
* 
Reportable AE’s, SAE’s and HF 
events 
 
* 
* 
* 
* 
X = required; *=Data required only if the event occurred; **= Only changes to cardiac medications are required to be documented

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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 SMART CRT 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, undergo the 
informed consent process, and sign and date the informed consent form less than 30 days 
prior to implant are considered enrolled in the study.  No data collection, data entry, or study 
specific procedure shall be performed prior to having appropriately consented the subject. 
Table 11-2 lists the data collection requirements at the enrollment visit.  
Table 11-2: 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 
• Medical History 
• Cardiac Medication(s) 
Investigational Center 
11.4. Pre-Implant Assessment 
The following tests may only be performed after the Enrollment Visit and must be completed 
< 30 days prior to the implant procedure: physical assessment, echocardiogram (Appendix 
27.1), six-minute walk test (Appendix 27.2), and Kansas City Cardiomyopathy Questionnaire 
(Appendix 27.3).  
 Physical Assessment 
Physical presentation will be used to provide an assessment of the patient’s condition and 
changes in clinical symptoms.  Evaluation includes: 
• 
Resting heart rate 
• 
NYHA Class assessment 
• 
12 lead ECG* 
• 
Presenting symptoms 
• 
Blood pressure 
• 
Height/weight 
 
* Analysis of the 12 lead ECG by the investigator should include the following: ventricular rate, intrinsic PR 
interval, intrinsic QRS interval, and nature of interventricular conduction delay (left bundle branch block, 
right bundle branch block, or non-specific interventricular conduction delay).  

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• 
List of cardiac medications** 
 
The subject’s current NYHA Class must be determined based on Table 11-3. 
 
Table 11-3: NYHA Classifications 
 
 Echocardiography 
Echocardiography will be used to assess cardiac function and structure. Recordings of each 
echo session should be uploaded or mailed to the Echocardiographic Core Laboratory within 
10 days of completion.  A complete echocardiography protocol may be found in Appendix 
27.1: Echocardiography Protocol. 
  Six-Minute Walk Test 
To assess tolerance of every-day physical activity, subjects are required to complete a six-
minute walk test. To perform this test, the subject is encouraged to walk as far as possible on 
a flat surface (e.g., clinic corridor) during a six-minute time period. The total distance 
traveled is measured (in feet or meters) and used for analysis.  Detailed instructions may be 
found in Appendix 27.2: Six-Minute Walk Test. 
 
Patients with orthopedic limitations (e.g., arthritis or wheelchair/cane/scooter use), known 
non-cardiac comorbidities that prevent normal walking (e.g., emphysema or need for 
supplemental oxygen), or for whom there are safety concerns (e.g., angina) are excused from 
six-minute walk testing.  Inability to perform a six-minute walk due to medical reasons is not 
a deviation. Patients who complete a baseline six minute walk test but who cannot walk at 
least 150 m or more than 425 m or who begin the six minute walk test but terminate it for 
 
** For study purposes, cardiac medications include: diuretics, ACE inhibitors/angiotensin receptor blockers, beta 
blockers, aldosterone antagonists, Class I/III antiarrhythmics, calcium channel blockers, anti-hypertensive 
drugs, and statins. 

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non-cardiovascular reasons or safety reasons will be excluded from testing of six-minute 
walk distance at the Six Month Follow-Up.  
 
 
Kansas City Cardiomyopathy Questionnaire 
The Kansas City Cardiomyopathy Questionnaire (KCCQ) will be administered at the Pre-
Implant (baseline) Assessment and again at the Six Month Follow-Up visit. A detailed 
description of the questionnaire can be found in Appendix 27.3: Kansas City 
Cardiomyopathy Questionnaire. 
 
Table 11-4: Source Documentation Requirements – Pre-Implant Assessment 
Data Collection Requirement 
Retention of Original Source Documentation 
• Physical Assessment 
• NYHA Assessment 
• Cardiac Medication Changes 
• Six-minute walk test  
• KCCQ 
• Reportable Adverse Events, Device 
Deficiencies, and Protocol Deviations, 
if applicable 
Investigational Center 
• 12 lead ECG 
Retain at Investigational Center and upload to 
the EDC system 
• Echocardiogram  
Retain at Investigational Center, copy uploaded 
or mailed to Echocardiography Core Lab 
11.5. Post-Implant Assessment and Randomization 
Recommended programming is DDD or DDDR with a lower rate limit (LRL) of 60bpm 
throughout participation in the study. If programming is different from this recommendation 
for clinical circumstances, the rational shall be provided. The Post-Implant Assessment must 
occur 0-14 days after the implant procedure. Tasks to be performed at this visit include: 
• Documentation of device information, including manufacturer, model and serial 
number, and implant date(s) of the CRT-D device, RA lead, RV lead, and LV lead 
 
• Pulse generator interrogation with routine lead evaluation of the implanted RA, RV 
and LV leads in final programming configuration which includes: 
o Intrinsic sensing (mV) 
o Pacing impedance (Ω) 
o Shock lead impedance (Ω) 
o Pacing capture threshold (V/ms; the pulse width is at investigator discretion)  
o Pacing capture threshold, impedance, and PNS for any LV vector which meets 
criteria in 11.5.1 
 

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Note: Patients must have functional RA, RV and LV leads. If one of the leads is not 
functional, patients cannot continue in the study and must be withdrawn at this point. 
 
• RV and LV lead location and, if known, rationale for LV lead placement. Such 
information is typically available by reviewing lead imaging documents including in-
procedure fluoroscopy or post-implant chest X-rays, or obtained from the subject’s 
medical record.  
o LV lead location should be defined as:  
 Anterior, anterolateral, lateral, posterolateral, or posterior  
 Basal, middle, or apical  
o RV lead location should be defined as: apex, free wall, septal wall, RV 
outflow tract, or other  
 
• RV-LV timing assessment with VectorGuide as defined in section 11.5.1 
• SmartDelay test results, if applicable 
• Randomization programming, if applicable 
• Save programmer interrogation session and specified reports to USB  
  RV-LV Timing Assessment and LV Pacing Vector Selection 
VectorGuide must be utilized to assess LV pacing vectors with the following technique:  
 
1. Identify RV-LV timing for each LV electrode using VectorGuide 
 
2. Identify the impedance for each LV pacing vector with RV-LV delay ≥ 70ms using 
VectorGuide 
 
3. Assess phrenic nerve stimulation (PNS) in any LV pacing vector with an RV-LV 
delay ≥ 70ms at an output of 7.5V using VectorGuide. PNS will be assessed as per 
standard of care, based on subject complaint (such as hiccups or twitching) and 
confirmed by palpation by a qualified HCP. The PNS threshold is defined as the first 
voltage step without PNS. 
a. Presence or absence of PNS and PNS threshold must be documented in the 
LV VectorGuide Report. 
 
4. Assess the pacing capture threshold in each LV pacing vector with an RV-LV delay ≥ 
70ms using VectorGuide. The pacing capture threshold for each LV pacing vector 
with an RV-LV delay ≥ 70ms must be documented on the VectorGuide Report.  
a. The recommended maximum acceptable pacing capture threshold for any LV 
vector is 4.5V@0.5ms. 
b. It is recommended that any vector with an RV-LV delay ≥ 70ms with PNS 
have a PNS threshold  ≥3V above the pacing capture threshold. 
 
5. If there are multiple LV pacing vectors with an RV-LV delay ≥ 70ms that meet the 
above criteria, the final programmed LV pacing vector can be programmed at the 
discretion of the investigator using the following criteria: 

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a. Preference should be given to the LV pacing vector with longest RV-LV 
delay. 
b. The final programmed LV pacing vector must have an RV-LV delay within 
10ms of the longest RV-LV delay of qualifying LV vectors. 
 
If the subject does not have any LV pacing vectors that meet the above criteria, the subject 
should be programmed per physician discretion. The subject will be exited from the study 
after 30 day contact to assess for any reportable safety events.  
 
 
Figure 11-1: Post-Implant Assessment 
 
. 
 

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Source documents required for the Post-Implant Assessment are listed below in Table 11-5.  
 
 Randomization Assignment and Programming  
All subjects who have a qualifying LV vector, as determined in Section 11.5.1, will be 
randomized. The randomization programming must occur when the patient’s presenting 
rhythm is compatible with the SmartDelay algorithm.  
 
Perform the randomization assignment via the EDC system. Randomization in the EDC 
cannot occur without entry of RV-LV timing in programmed LV pacing vector. Every 
reasonable attempt will be made to have subjects blinded to their randomized treatment arm 
assignment throughout the trial.  
 
Tasks to be performed after randomization include:  
• SmartDelay test to obtain programming recommendations for the AV Delay and 
pacing chamber 
• Programming the device to the subject’s randomized treatment arm 
• Save interrogation session and specified reports to USB  
 
Devices are required to be programmed according to this protocol.  
11.5.2.1. SmartDelay Test 
It is required to perform SmartDelay test for all subjects to obtain programming 
recommendations for the AV Delay and Pacing Chamber(s). LV offset should be set to 0ms 
throughout the duration of the study. For step-by-step guidance on how to perform the 
SmartDelay test, please refer to Appendix 27.4.  
Record the following values from the SmartDelay test in the EDC system: 
• Sensed AV Delay (SAV) and Paced AV Delay (PAV) 
• Pacing Chamber (BiV or LV Only) 
 
After running SmartDelay, copy settings without programming changes, print and save to 
USB the Settings Changes Report. This report will display recommended SAV, PAV, and 
Pacing Chamber. 
 
If the SmartDelay test fails to complete, re-perform the test to obtain the recommended value. 
If the SmartDelay test was complete but not successful, the recommended value will be the 
nominal value used by SmartDelay.  
 
11.5.2.2. Programming Based on Randomization Assignment 
Fixed AV Delay: If the subject is randomized to the Fixed AV Delay treatment arm, the 
SAV and PAV values must be set to 120ms with BiV pacing. 

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SmartDelay AV Delay: If the subject is randomized to the SmartDelay treatment arm, SAV, 
PAV, and pacing chamber settings must be programmed according to the results of the 
SmartDelay optimization throughout participation in the study. The final AV Delay 
programming must be captured on the printed Device Follow Up Report.  
If the LV MultiSite Pacing feature is available in the implanted device, this feature must be 
turned OFF throughout the duration of the study. 
 
Table 11-5: Source Document Requirements – Post-Implant Assessment and 
Randomization  
Data Collection Requirement 
Retention of Original Source 
Documentation 
• Cardiac Medications Changes 
• RV and LV lead location 
• Reportable Adverse Events, Device 
Deficiencies, and Protocol Deviations, if 
applicable  
Investigational Center 
• Device Follow Up Report 
• Settings Change Report (to capture 
SmartDelay suggested settings) 
• Arrhythmia Logbook 
• LV VectorGuide Report 
• Patient Data Report 
Printed reports and electronic reports on USB 
retained at Investigational Center 
 
 
11.6. Six Month Follow-Up Visit 
Tasks to be performed at this visit include: 
 
• Pulse generator interrogation with routine lead evaluation on implanted RA, RV and 
LV 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) 
• Counter information (%RA, %RV, %LV, %AT/AF) 
• RV-LV timing assessment with VectorGuide for each LV electrode 
• SmartDelay test results 
• Save interrogation session to USB  
 
A Device Settings Report should be printed prior to completing any device testing at the Six 
Month Follow-Up. The HCP completing these assessments must be blinded to the subject’s 
treatment arm and should not have access to the patient’s randomization status or the EDC:  
• Physical Assessment (refer to 11.4.1), including NYHA Class assessment 
• Echocardiogram completed with programmed pacing therapy active (Appendix 27.1) 

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• Six-minute walk test (Appendix 27.2) 
• KCCQ (Appendix 27.3) 
• Patient Global Assessment (11.6.2) 
• Physician Global Assessment (11.6.2) 
 
The subject’s device may be programmed at the investigator’s discretion once all study 
testing has been completed. 
 SmartDelay Test 
It is required to perform the SmartDelay test for all subjects to obtain programming 
recommendations for the AV Delay and Pacing Chamber(s). For step-by-step guidance on 
how to perform the SmartDelay test, please refer to Appendix 27.4.  
Record the following values from the SmartDelay in the EDC system: 
• Sensed AV Delay (SAV) and Paced AV Delay (PAV) 
• Pacing Chamber (BiV or LV Only) 
 
After running SmartDelay, copy settings without programming changes, print and save to 
USB the Settings Changes Report. This report will display recommended SAV, PAV, and 
Pacing Chamber. 
 
If the SmartDelay test fails to complete, re-perform the test to obtain the recommended value. 
If the SmartDelay test was complete but not successful, the recommended value will be the 
nominal value used by SmartDelay. 
 Quality of Life Global Assessment 
In addition to the KCCQ, quality of life will be assessed at six months using the Patient 
Global Assessment and Physician Global Assessment. This consists of two questions, one of 
which is directed to the physician who is examining the patient and the other question is 
directed to the patient to address how well the patient is doing since enrolling in the study.  
 
Figure 11-2: Quality of Life Global Assessment 
Physician Global Assessment 
Patient Global Assessment 
How is the patient’s clinical status today 
compared to his or her status at the time of pre-
implant assessment? 
• 
Markedly improved 
• 
Moderately improved 
• 
Mildly improved 
• 
No change 
• 
Mildly worse 
How do you feel today compared to how you felt 
when you started the study? 
• 
Very much better 
• 
Much better 
• 
A little better 
• 
No change 
• 
A little worse 

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• 
Moderately worse 
• 
Markedly worse 
• 
Much worse 
• 
Very much worse 
 
Table 11-6: Source Document Requirements – Six Month Visit 
Data Collection Requirement 
Retention of Original Source Documentation 
• Physical Assessment 
• NHYA Class Assessment 
• Cardiac Medication Changes 
• Six-minute walk test 
• KCCQ 
• Patient Global Assessment 
• Physician Global Assessment 
• Reportable Adverse Events, Device 
Deficiencies, and Protocol Deviations, 
if applicable  
Investigational Center 
• Echocardiogram 
Retain at Investigational Center, copy uploaded 
or mailed to Echocardiography Core Lab 
• Device Settings Report (printed prior 
to device testing) 
• Device Follow Up Report (including 
counter information) 
• Settings Change Report 
• Arrhythmia Logbook 
• LV VectorGuide Report 
Printed reports and electronic reports on USB 
retained at Investigational Center 
 
11.7. Additional Follow-Up Visits 
Physician office visits, emergency room visits, out-patient hospital visits, and 
hospitalizations shall be recorded as an additional follow-up visit only if they are associated 
with system revision, device deficiency, reportable adverse event, protocol deviation or 
device programming change as listed below. Other scheduled and unscheduled visits 
throughout the year (e.g., standard of care device checks) that do not meet these criteria are 
not required by the protocol.   
 
Changes in the following programming settings require an Additional Visit to be completed: 
• AV Delay 
• Pacing chamber (BiV pacing or LV only pacing) 
• LV pacing vector configuration selected at the Post-Implant Assessment 
• LV Offset 
• Pacing mode (e.g. DDD, VVI) 
• LRL 
• Any time the device counter is reset 

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o Date the counter is reset 
o Percent of RV and LV pacing prior to resetting the counter in subjects 
 
A rationale of the setting changes is required. 
 
The following documentation is required: 
• Settings Changes Report 
• Combined Follow Up Report 
A summary of the source documentation required at the Additional Visit is described Table 
11-7.  
Table 11-7: Additional Follow-Up Visit Data Collection 
Data Collection 
Retention of Original 
Source Documentation 
• Reportable Adverse Events, Device 
Deficiencies, and Protocol Deviations, if 
applicable 
• Cardiac Medication Changes 
Investigational Center 
• Combined Follow Up Report 
• Settings Change Report 
Printed reports and electronic 
reports on USB retained at 
Investigational Center 
 
 
11.8. Device Programming Outside of the Investigational Plan 
Once a subject is programmed to a randomized treatment arm, every effort must be made to 
keep the subject’s device programmed per the required programming in this protocol. Any 
device reprogramming of AV Delay change, including the reason for change, must be 
recorded as a protocol deviation and the clinical circumstances must be documented. 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. 
11.9. Study Completion 
Subject participation in the study is considered complete for the following reasons: 
• Study completion per protocol  
o A Six Month Follow-Up visit has been recorded at least 180 days from the 
date of the randomization OR 
o Subject does not have an RV-LV delay ≥ 70ms on any electrode (E1, E2, 
E3, E4) with a qualifying pacing vector  at the Post-Implant Assessment 
• Death (see 19.7 for reporting requirements); 

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• Withdrawal for reasons that 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 CRT-D system 
o VAD insertion or heart transplant  
o Investigator discretion 
o Lost to follow-up, despite best efforts to locate the subject; 
o Three documented attempts to contact the subject, including one certified 
letter, are required to declare a subject lost to follow up. 
11.10. 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 
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. Primary Endpoint 
The primary endpoint will compare the CRT response rates of randomized subjects.  CRT 
response is defined by >15% decrease in LVESV from pre-implant baseline through 6 
months.  
 Hypotheses 
The following set of hypotheses will be used to evaluate the Primary Endpoint: 
 
Ho: p (SmartDelay) ≤ p (Fixed) 
H1: p (SmartDelay) > p (Fixed) 
 
Where p represents the proportion of CRT responders.  Response is defined as a >15% 
decrease LVESV ([LVESV6M – LVESVBL]/ LVESVBL < - 15%). 
 Sample Size  
An estimated 726 subjects will be enrolled in the study in order to achieve a target of at least 
436 subjects to complete randomization. Enrollment will continue until at least 436 patients 
are randomized or the number of required randomized subjects as determined by interim 
sample size re-assessment. A total of 370 complete datasets at 6 months are required to 
sufficiently power the endpoint. 

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Sample size was calculated using the following assumptions: 
• Patient cohort = all randomized subjects (RV-LV ≥ 70 ms) 
• Effect size = 14% difference (based on ability to detect at least 75% of the 19% 
difference observed in SMART AV) 
• Estimated CRT response rate in Fixed AV Delay group = 53% 
• Randomization allocation = 1:1 
• Subjects contributing to analysis = 51% (60%*85%) of enrolled subjects 
o 60% of enrolled subjects with RV-LV ≥ 70 ms 
o 85% of randomized subjects with complete datasets at 6 months among 
subjects with RV-LV ≥ 70 ms 
• One-sided alpha = 2.5%  
The required sample size to sufficiently power the analysis evaluating a median cutoff is 
less than the sample size described above. 
 
 Statistical Methods 
Randomized subjects with paired LVESV data – baseline and 6 months – will be included in 
the analysis.  Subjects will be analyzed according to their randomization group.  To avoid 
making erroneous assumptions about incomplete/missing endpoint data, data from subjects 
with incomplete/missing data will not be imputed; therefore the statistical analysis of the 
Primary Endpoint will be a modified intention-to-treat analysis. A chi-square test employing 
a one-sided alpha of 2.5% will compare the proportion of responders in the SmartDelay 
randomized group to the Fixed AV Delay randomized group.  If the p-value is less than 0.05, 
the null hypothesis will be rejected.  
A pure intention-to-treat analysis, in which the incomplete/missing endpoint data is imputed 
and included in the analysis, may be performed as a sensitivity analysis.  
12.2. General Statistical Methods 
 Analysis Sets 
All subjects with paired data at baseline and 6 months will be included the analysis of the 
outcome of interest (i.e., LVESV, subject global assessment, etc.).   
 Control of Systematic Error/Bias 
Subjects will be randomized to minimize subject selection bias. To eliminate the potential for 
a placebo effect to affect the Primary Endpoint results, the objective measure of LVESV was 
chosen.  Every attempt will be made to blind subjects to their randomized treatment 
assignment in order to minimize a placebo effect on qualitative analyses, such as quality of 
life.  To reduce the inter-observer variability that can occur with echocardiographic 
measurements, a core lab blinded to treatment assignment will be used.   

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 Number of Subjects per Investigative Site 
A maximum of 72 enrolled subjects will be allowed from an investigational site, equal to 
10% of the expected 726 subjects to be enrolled in the study. 
12.3. Additional Data Analyses 
 Other Endpoints/Measurements  
The following outcomes will be evaluated in addition to the Primary Endpoint analysis, each 
comparing subjects according to their randomized groups: 
• LVESV as a continuous variable 
• Clinical Composite Endpoint  
o All-cause mortality 
o Heart failure events (as defined in Section 19.1) 
o NYHA Class 
o Quality of Life (Patient Global assessment instrument) 
• Components of the Clinical Composite Endpoint 
• KCCQ 
• Left-ventricular ejection fraction (LVEF) 
 Tertiary/Exploratory Analyses 
The following tertiary analyses will be performed and considered exploratory in nature: 
• Six minute walk, compared between randomized groups. 
• Optimal cutoff analysis.  An RV-LV cutoff of 70 ms was used to identify which 
subjects will be randomized.  Analyses will be performed to find the optimal cutoff – 
greater than or equal to 70 ms – as determined by the data.    
 Primary Endpoint Sensitivity Analyses 
The Primary Endpoint, in addition to the additional analyses listed above, will be evaluated 
using modified intention-to-treat methodology, in which subjects with complete datasets are 
evaluated according to their randomized treatment groups.  Sensitivity analyses include the 
following: 
• Pure intention-to-treat – Subjects are analyzed according to their randomized group 
and missing data is imputed via multiple imputation 
• On treatment – Subjects are analyzed according to the actual treatment received 
• Per protocol – Subjects are analyzed according to their randomized group, but limited 
to subjects that received the randomized assignment. 

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 Interim Analyses  
When at least half of the required 6 month datasets (N = 185) have been completed and 
reviewed by the core lab, an interim sample size re-assessment will be performed.  The 
pooled and blinded response rate across both groups will be assessed in this interim sample 
size re-assessment cohort.  The observed rate will be weighted by the number of patients in 
each group and compared to the assumed weighted rate.  If the observed rate is less than the 
assumed rate, the number of patients required for randomization will be increased 
accordingly, up to a maximum of 456 randomized subjects.  The treatment effect will not be 
calculated, thereby maintaining the blind.   
There are no formal interim analyses planned to terminate the study for effectiveness of 
futility. 
 Subgroup Analyses 
The subgroups that will be evaluated include, but are not limited to, the following: 
• Age < 65 years vs. ≥ 65 years 
• Females vs. Males 
• Ischemic vs. Non-ischemic etiology 
• LBBB vs Non-LBBB 
• QRS < 150 ms vs. ≥ 150 ms 
• Apical vs. Non-apical lead placement (for each RV lead and LV lead placement) 
• NYHA Class I/II vs. III/IV 
• SmartDelay recommended programming 
o LV only vs. biventricular (BiV) pacing 
o AV Delay (equal to 120±20 ms vs. all others) 
 
The interaction between the subgroup and randomized groups will be evaluated (e.g., gender 
by randomization group). Additionally, each subgroup will have the SmartDelay vs. Fixed 
comparison calculated separately (e.g., SmartDelay vs. Fixed evaluated in Females). 
 Multivariable Analyses 
Multivariate analyses will be performed using characteristics listed in Section 12.3.5Error! 
Reference source not found..  Additional covariates may also be considered.  The primary 
approach to multivariate modeling will be as follows: 
• Univariate to Multivariate:  Univariate modeling is first performed.  Significant 
covariates are considered for inclusion in the final multivariate model.  Non-
significant covariates are dropped from consideration.  A model selection technique 
(e.g., best subsets, stepwise regression) is then employed to determine the final 
multivariate model. 
Additionally, the following multivariate modeling approaches may be used: 
• Recursive Partitioning:  The overall population is classified into mutually exclusive 
subgroups in the form of a decision tree.  Each characteristic is dichotomized, though 

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the cutpoint used for dichotomization is determined by the data during the analysis.  
To avoid potential problems with model overfitting, methods related to recursive 
partitioning – such as random forests or stochastic gradient boosting – may be 
employed. 
• Risk Score:  Characteristics considered to be associated with CRT Response – 
determined by analyses of SMART Registry data or by clinical/medical experts – 
will be combined and converted into a score that can be used to predict CRT 
Response.   
 Changes to Planned Analyses 
Any changes to the planned statistical analyses made prior to performing the analyses will be 
documented in the Statistical Analysis Plan approved prior to performing the analyses. 
Changes from the planned statistical methods after performing the analyses will be 
documented in the clinical study report along with a reason for the change. 
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 Principal Investigator or his/her designee 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 for at least 2 years after the last approval of a marketing application or until 
at least 2 years have elapsed since the formal discontinuation of the clinical investigation of 

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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 Principal Investigator or his/her designee 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 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 
All echocardiography measurements will be performed by an independent Echocardiography 
Core Laboratory. The Echocardiography Core Laboratory determined values will be used for 
the Primary Endpoint analysis as well as all echo related additional analyses.  
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) 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 when applicable 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 IRB 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 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. 
• Report to sponsor, per the protocol requirements, all SAEs and device deficiencies that 
could have led to a SADE and potential/USADE or UADE. 

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• 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. 
• 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. 
• 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 

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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. An investigator must not participate in study 
related tasks prior to completion of required study training.  
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. 
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). 

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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 
• 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. 

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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  
The following anticipated adverse events (AE) have been identified for anyone receiving a 
CRT-D system. 
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 

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Potential Adverse Events for Implantation of a Pulse Generator and/ or Lead System* 
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 
• Imagined shocking  
• Fear of device malfunction  
18.2. Anticipated Adverse Device Effects  
Adverse Device Effects that are part of the listing in the previous section are to be considered 
Anticipated Device Effects. 

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18.3. Risks Associated with Participation in the Clinical Study 
In addition to the risks common to all patients who receive CRT implantation, subjects 
participating in the SMART CRT study may be exposed to additional risks. Specifically, 
some subjects may be at risk for arrhythmias during the six-minute walk testing. However, 
the intensity of the exercise is at the discretion of the individual subject, and the test (without 
electrocardiogram monitoring) has been performed in thousands of subjects with HF or 
cardiomyopathy17,18,19  without serious adverse events. Moreover, risks can be minimized by 
addressing the following safety issues: performing the test in a location where a rapid, 
appropriate response to an emergency is possible with a crash cart in a near known location; 
a technician certified in cardiopulmonary resuscitation with a minimum of Basic Life 
Support20; it is up to the physician ordering the test to decide whether physician attendance at 
a specific test is required as physicians are not required to be present at all tests.  
Some additional risks may apply to those subjects for which the SmartDelay test is run. 
Tachycardia therapy is disabled during SmartDelay optimization. The SmartDelay test also 
temporarily switches to a DDD mode of pacing with a lower rate limit of 40ppm and an AV 
Delay of 400ms. Any subject with symptomatic bradycardia may be affected.  
18.4. Risk Minimization Actions 
Additional risks may exist. Risks can be minimized through compliance with this protocol, 
performing procedures in the appropriate hospital 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 additional benefit to the subject due to the study specific programming. 
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.  
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.  
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: 

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• All Serious Adverse Events 
• All Device Related Adverse Events 
o Events listed in the arrhythmia logbook should be reported only if determined 
to be clinical significant by the investigator and/or delegated site staff (i.e. 
ATR, PMT, etc.) 
o All arrhythmias which received  inappropriate shock therapy as identified by a 
study investigator must be reported 
• All Serious Adverse Device Events 
• All Device Deficiencies  
• Unanticipated Adverse Device Effects/Unanticipated Serious Adverse Device Effects 
• All Heart Failure (HF) Related Events: 
An adverse event is deemed as a HF Event if the primary cause is HF and either of 
following conditions is met: 
o Subject is admitted and discharged with a calendar date change. 
o Subject is not hospitalized but received one or more IV medications including 
diuretics, inotropes, vasodilators, other parenteral therapy, or aquapheresis. 
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 should 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 reported as AEs unless there is an increase in severity of 
frequency during the course of the investigation. Death should not be reported as an SAE, but 
should be reported as an outcome of an SAE and only one SAE should have the outcome 
documented as fatal (see Table 19-1 for AE 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 19-1. Administrative edits were made on the 
definition of serious adverse event from ISO 14155and MEDDEV 2.7/3 for clarification 
purposes. Reportable events are defined in Section 19.1. 
 
Table 19-1: Safety Term Definitions 
Term 
Definition 

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Table 19-1: Safety Term 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. 
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: 
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body function, or 
3) in-patient hospitalization or prolongation of existing 
hospitalization, or 
4) medical or surgical intervention to prevent life-threatening illness 
or injury or permanent impairment to a body structure or a body 
function 
• 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 

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Table 19-1: Safety Term Definitions 
Term 
Definition 
 
of subjects.   
Unanticipated Serious Adverse 
Device Effect (USADE) 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3  
 
 
Serious adverse device effect which by its nature, incidence, severity, or 
outcome has not been identified in the current version of the risk analysis 
report. 
NOTE 1: Anticipated serious adverse device effect (ASADE) is an effect 
which by its nature, incidence, severity or outcome has been identified in the 
risk analysis report. 
Device Deficiency 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3  
A 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 19-2:  

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Table 19-2: 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; 
- 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 19-2: 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 Table 19-3. 
Adverse events must always be reported through the EDC system for SMART CRT. 
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:  
 
SMARTCRT.Safety@bsci.com 
 
Table 19-3: 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.  
• Reporting required through the end of 
study 
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 
• When documentation is available 

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Table 19-3: Investigator Reporting Requirements 
 
Event Classification 
Communication Method  
Communication Timeline post-market 
studies**  
(MEDDEV 2.12/2 :  
GUIDELINES ON A MEDICAL DEVICE 
VIGILANCE SYSTEM) 
documentation (unidentified) 
for reported event 
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 the end of 
study 
Abbreviations: AE=adverse event; CRF=case report form; IDE=Investigational Device Exemption; 
UADE=unanticipated adverse device effect 
 
19.5. Boston Scientific Device Deficiencies 
All device deficiencies (including but not limited to failures, malfunctions, use errors, 
product nonconformities, and inadequacy in the information supplied by the manufacturer) 
will be documented and reported to BSC. If possible, the device(s) should be returned to 
BSC for analysis. 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. 

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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 
BSC is responsible for reporting adverse event information to all participating Principal 
Investigators and regulatory authorities, as applicable. 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 ten (10) days or per local regulations of site 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) that provides detailed information describing the 
circumstances surrounding the death is required. A death narrative in the local 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. The Clinical Events Committee (CEC) 
must review information regarding subject deaths if heart failure could not be ruled out as the 
cause of death. 

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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: 
• 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 

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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. 
21. Committees 
21.1. Safety Monitoring Process 
To promote early detection of safety issues, the BSC Medical Safety group will provide 
evaluations of safety events. A CEC will provide evaluations of all HF events and deaths in 
which HF could not be eliminated as the cause. Success of this program requires dynamic 
collection of unmonitored data as soon as the event is reported. During regularly scheduled 
monitoring activities, clinical research monitors will support the dynamic reporting process 
through their review of source document and other data information. The BSC Medical 
Safety group includes physicians with expertise in the necessary therapeutic and subject 
matter expertise to evaluate and classify the events into the categories outlined above. 
21.2. Steering Committee 
The Steering Committee is independent of Boston Scientific RM and provides oversight for 
the overall conduct of the study with regard to protocol development, study progress, subject 
safety, and overall data quality and integrity.  
21.3. Clinical Events Committee 
A Clinical Events Committee (CEC) is an independent group of individuals with pertinent 
expertise that reviews and adjudicates predefined events as reported by study investigators. 
For this study, committee members will include a minimum of three practitioners with 
training in Electrophysiology (EP) and/ or Cardiology with the necessary therapeutic and 
subject matter expertise to adjudicate HF events and subject deaths. CEC responsibilities, 
qualifications, membership, and committee procedures are outlined in the CEC charter. 
 

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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. 
22.1.1 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. 
22.2 Termination of Study Participation by the Investigator or Withdrawal of IRB/ EC 
Approval 
Any investigator, or IRB/ EC in the SMART CRT 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. 
22.3 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. 

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22.4 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 site participation, all study devices and testing equipment, as 
applicable, will be returned to BSC unless this action would jeopardize the rights, safety or 
well-being of the subjects. 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 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 
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 
Boston Scientific Corporation will purchase an insurance policy to cover the cost of potential 
health injury for study subjects, and if required by applicable law.  
25. Bibliography 
1. 
Higgins SL HJ, Niazi IK, et al. . Cardiac resynchronization therapy for the treatment 
of heart failure in patients with intraventricular conduction delay and malignant ventricular 
tachyarrhythmias. J Am Coll Cardiol. 2003;42:1454-1459. 

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2. 
Bristow MR SL, Boehmer J, et al. Cardiac-resynchronization therapy with or without 
an implantable defibrillator in advanced chronic heart failure. New Engl J Med 
2004;350:2140-50. 
3. 
Moss AJ HW, Cannom DS, et al. Cardiac-resynchronization therapy for the 
prevention of heart-failure events. N Engl J Med 2009;361:1329-38. 
4. 
M P. Proposal for a new clinical end point to evaluate the efficacy of drugs and 
devices in the treatment of chronic heart failure. J Card Fail 2001;7:176-82. 
5. 
Delgado V vBR, Bertini M, et al. Relative merits of left ventricular dyssynchrony, 
left ventricular lead position, and myocardial scar to predict long-term survival of ischemic 
heart failure patients undergoing cardiac resynchronization therapy. Circulation 
2011;123:70-78. 
6. 
Abraham WT LA, Hannon C, Prather W, Fieberg A. Results of the InSync III 
Marquis Clinical Trial (abstract). Heart Rhythm 2005;2:S65. 
7. 
Rao RK KU, Schafer J, Viloria E, De Lurgio D, Foster E. Reduced ventricular 
volumes and improved systolic function with cardiac resynchronization therapy: a 
randomized trial comparing simultaneous biventricular pacing, sequential biventricular 
pacing, and left ventricular pacing. Circulation. 2007;115:2136-44. 
8. 
Baker JH TK, Pires LA, et al. Optimization of interventricular delay in biventricular 
pacing: Results from the RHYTHM ICD V-V Optimization Phase Study. Heart Rhythm 
2005:P3-96. 
9. 
Boriani G KW, Donal E, et al. A randomized double-blind comparison of 
biventricular versus left ventricular stimulation for cardiac resynchronization therapy: the 
Biventricular versus Left Univentricular Pacing with ICD Back-up in Heart Failure Patients 
(B-LEFT HF) trial. Am Heart J 2010;159:1052-8. 
10. 
Martin DO LB, Birnie D, et al. Investigation of a novel algorithm for synchronized 
left-ventricular pacing and ambulatory optimization of cardiac resynchronization therapy: 
results of the adaptive CRT trial. Heart Rhythm. 2012;9:1807-14. 
11. 
Abraham WT GD, Yu CM, et al. Results from the FREEDOM Trial (abstract). Heart 
Rhythm. 2010;7:2-3. 
12. 
Ellenbogen KA GM, Meyer TE, et al. Primary results from the SmartDelay 
determined AV optimization:  a comparison to other AV delay methods used in cardiac 
resynchronization therapy (SMART-AV) trial: a randomized trial comparing empirical, 
echocardiography guided, and algorithmic atrioventricular delay programming in cardiac 
resynchronization therapy. Circulation. 2010;122:2660-2668. 
13. 
Brugada Terradellas J DP, Brachmann J, et al. Clinical response to CRT with the 
SonR contractility sensor: The RESPOND-CRT Study.  . Oral presentation at Heart Rhythm 
Society, May 4-7, 2016, San Francisco CA. 2016. 
14. 
Tomassoni G BJ, Corbisiero R, et al. Safety and efficacy of multipoint pacing in 
cardiac resynchronization therapy: The MultiPoint Pacing IDE Trial. Oral presentation at 
Heart Rhythm Society, May 4-7, 2016, San Francisco CA. 2016. 
15. 
Gold MR YY, Singh JP, et al. The effect ventricular electrical delay on AV 
optimization for cardiac resynchronization therapy. Heart Rhythm 2013;10:988-93. 
16. 
Gold MR SJ, Ellenbogen KA, et al. Interventricular electrical delay is predictive of 
response to cardiac resynchronization therapy. JACCEP. 2016;2:438-47. 

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17.      Bitter V, Weiner DH, Yusuf S et al. Prediction of mortality and morbidity with a six-
minute walk test in patients with left ventricular dysfunction. SOLVD Investigators. JAMA. 
1993;270:1702-1707. 
18.      Guyatt GH, Sullivan MJ, Thompson PJ et al. The six-minute walk: a new measure of 
exercise capacity in patients with chronic heart failure. Can Med Assoc J. 1985;132:919-923. 
19.      Lipkin DP, Scriven AJ, Crake T et al. Six minute walking test for assessing exercise 
capacity in chronic heart failure. Br Med J (Clin Res Ed). 1986;292:653- 655. 
20.     Enright PL. The six-minute walk test. Respir Care. 2003;48:783-785. 
  
 

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26. Abbreviations 
Table 26-1: Study Abbreviation 
Abbreviation 
Term 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
AV 
AtrioVentricular 
BiV 
Biventricular 
BSC 
Boston Scientific Corporation 
CCE 
Clinical Composite Endpoint 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations – excluding the endpoint sections 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CRT 
Cardiac Resynchronization Therapy 
CRT-D 
Cardiac Resynchronization Therapy – Defibrillator 
DD 
Device Deficiency 
DDD/DDDR 
International Code for pacing mode: pacing site(s), sensing site(s), pacing mode, 
rate responsiveness 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FCS 
Field Clinical Specialist 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCP 
Healthcare Provider 
HF 
Heart Failure 
ICF  
Informed Consent Form 
ICD 
Implantable Cardioverter Defibrillator 
IQRMP 
Integrated Quality Risk Management Plan 
IRB 
Institutional Review Board 
IV 
Intravenous 

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Abbreviation 
Term 
LBBB 
Left Bundle Branch Block 
LRL 
Lower Rate Limit 
LV 
Left Ventricle 
LVED 
Left Ventricular End Diastolic 
LVEF 
Left Ventricular Ejection Fraction 
LVEDV 
Left Ventricular End Diastolic Volume 
LVESV 
Left Ventricular End Systolic Volume 
ms 
Millisecond 
mV 
millivolts 
NYHA 
New York Heart Association 
Ω 
Ohms 
OPT 
Optimal Pharmacologic Therapy 
PA 
Paced Atrium 
PAV 
Paced AtrioVentricular 
PCT 
Pacing Capture Threshold 
PG 
Pulse Generator 
PI 
Principal Investigator 
PNS 
Phrenic Nerve Stimulation 
QLV 
Q-Left Ventricular 
RA 
Right Atrium/ Atrial 
RM 
Rhythm Management 
RV 
Right Ventricle/ Ventricular 
RV-LV 
Right Ventricle-Left Ventricle 
RVs-LVs 
Right Ventricle sense-Left Ventricle sense 
SA 
Sensed Atrium 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAV 
Sensed AV 
US 
United States of America 
UADE 
Unanticipated Adverse Device Effect 
USADE 
Unanticipated Serious Adverse Device Effect 
UADE 
Unanticipated Adverse Device Effect 
V 
Volts 

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Abbreviation 
Term 
VF 
Ventricular Fibrillation 
VT 
Ventricular Tachycardia 
 
27. Appendices 
27.1. 
Echocardiography Protocol 
The following parameters must be measured as part of the echocardiography exam at the pre-
implant and 6 month visits:  
 
• 
LVESV / LVEDV (by Simpson’s Method of Discs) 
• 
LVEF 
• 
Valve function: tricuspid, mitral & aortic regurgitation 
• 
LA volume  
 
The measurements should be taken at the Six Month Follow-Up visit with pacing therapy 
active.  
 
Digitally store data in a DICOM format then copy to a CD-R. Maintain a copy of the study 
CD-R at the site and either send or upload a copy to the Echocardiography Core Lab within 
10 days of completion. Each site will be responsible for identifying experienced 
sonographers (echocardiographic technicians) who will perform study echocardiograms, 
which will be a limited version of the standard echocardiographic examination. Sites will be 
supplied with training materials that will describe in detail the methodology for obtaining 
study echocardiograms. Training sessions will be conducted and documented for all 
participating sites.  
 
A subset of a standard echocardiographic examination will be performed. All subjects will 
undergo 2-D echocardiography with the following views: 
 
Parasternal Long Axis View (PLAX):  
o 2D imaging of Left Ventricle to determine septal and posterior wall thickness and LV 
diameters at end diastole and end systole. Make measurements in the mid-LV 
adjacent to postero-lateral papillary muscle. LV outflow diameter is measured in the 
frame following aortic valve opening. 
o Color Doppler imaging performed for presence of mitral regurgitation. Color Doppler 
imaging should be performed with a nyquist limit (scale) .5-.6m/sec. Demonstrate 
MR jet at the coaptation of the mitral leaflets for measurement of jet width. 
 
Parasternal Short Axis View (PSAX)/right ventricular outflow view: 
o Pulsed Wave Doppler of the right ventricular outflow tract velocities should be 
obtained just proximal to the pulmonary valve leaflets to measure pre-ejection period 

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(PEP) – PEP is the time from onset of the QRS complex to the onset of RV outflow 
systolic velocity envelope. Velocities must be recorded at a 100mm/s sweep speed. 
 
 
 
Apical 4-chamber view: 
o 2D imaging to demonstrate the RA, RV, LV and LA chambers within the sector 
image at the proper depth in at least 3-5 cardiac cycles.  
o Color Doppler imaging If present, continuous-wave Doppler of the tricuspid valve 
regurgitant jet velocity for estimation of RV systolic pressures. 
o Color Doppler imaging performed for detection of mitral regurgitation. Demonstrate 
origin of the jet at the coaptation of the mitral leaflets for measurement of jet width 
and the maximal jet area. 
o Continuous wave Doppler of the mitral valve regurgitant jet velocity. Zero velocity 
baseline and scale should be adjusted to clearly display systolic jet envelope profile at 
a 100mm/s sweep speed. 
o Pulsed-wave Doppler of mitral inflow velocities should be obtained at the mitral 
leaflet tips, recorded at 100mm/s sweep speed. Measurements will include E-wave 
and A-wave velocities, E-wave deceleration time and diastolic filling time. 
o Pulsed-wave tissue Doppler imaging (TDI) is performed at the lateral and septal LV 
base (i.e., mitral annulus) to obtain systolic (S’) and diastolic myocardial velocities 
(E’). The sample volume size should be set at a 3-5mm axial length; Doppler signal 
gain and velocity scale should be adjusted to display peak S’ and Em velocities, 
recorded at 100mm/s sweep speed. Measurements include time from onset of QRS to 
peak (or onset) of S’ velocity at each site. 
 
Apical 2-chamber view: 
o 2D imaging of LV and LA endocardial borders demonstrated in the sector image at 
the proper depth setting in at least 3-5 cardiac cycles. 
o Color Doppler imaging performed for the presence of mitral regurgitation. 
 
Apical 5-chamber view: 
o Pulsed-wave Doppler sample volume of the LV outflow tract.  Display closing 
“click” of the aortic valve with well-defined systolic velocity envelope recorded at 
100mm/s sweep speed. Measurements include pre-ejection period (PEP) and velocity-
time integral (VTI). 
 
o Continuous-wave Doppler used to obtain peak aortic flow velocity, with well-defined 
spectral envelope that includes aortic valve opening and closing clicks, recorded at 
100mm/s sweep speed. 
 
27.2. 
Six-Minute Walk Test 
The six-minute walk test is a self-paced sub-maximal exercise test that has proven useful as 
an outcome measure for patients with congestive HF. Previous studies18,19 have shown that 

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this test is well tolerated by individuals and is more closely related to the patient’s daily 
activities than maximal exercise testing. 
 
The walking test should be conducted in an enclosed corridor on a course approximately 100 
feet (30.5 meters) long. The length should be marked in either feet or meters to allow easy 
measurement of the distance walked. The corridor should not be heavily transited and should 
be free of obstacles and distractions. Chairs should be placed at either end of the course so 
that subjects may rest when needed. If for any reason an individual physician does not 
recommend a subject to perform the six-minute walk then record the reason on the case 
report form. 
 
Instructions 
The subject is to take nothing by mouth except for clear liquids for at least two hours prior to 
the test. Prescribed medications should be taken as usual. Subjects should be advised not to 
smoke for at least two hours prior to exercise and to wear suitable footwear. Subjects are 
instructed to walk the marked course from end to end at their own pace, covering as much 
distance as possible in six-minutes. Subjects may slow down or stop to rest if necessary, but 
should be instructed to resume walking when they feel they are able to do so. The aim is that 
at the end of the test, the subject believes that they could not have walked any further in the 
six-minutes. 
 
The following instructions are to be read to the subject verbatim: 
 
“The purpose of this test is to determine how far you can walk in six-minutes. You will start 
here and go to the end of the hall, turn around, and walk back. After arriving back at the 
starting point, you will go back and forth again. Go back and forth as many times as you can 
in the six-minute period. If necessary, stop and rest and stay here until you can start again. 
However, the most important thing about the test is that you cover as much distance as 
possible during the six-minute period.” 
 
 “I will let you know when each minute has passed. When I say ‘STOP’ after six-minutes, 
please stand right where you are.’ 
 
“Do you have any questions about the test?” 
 
“Please explain to me what you are going to do.” 
 
“Are you ready?” 
 
“Start when I say ‘GO’.” 
 
Protocol 
 
The walk test should be performed after completing the physical assessment of the subject. 
Subject safety is the highest priority, and the walk test should not be initiated if the physician, 
coordinator or subject has concerns regarding the subject’s ability to perform the test. If the 

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subject begins the walking test, and concerns arise regarding their ability to continue, stop the 
test. 
 
1. Stand the subject at the beginning of the course. 
2. Simultaneously say ‘GO” and start the watch. Observe the subject for the six-minute 
period while recording the successful completion of each length of the course. In order to 
standardize the test, encouragement is not offered during the walk. Do not otherwise 
speak to the subject except to answer questions he or she poses. Stop the test if the subject 
reports severe shortness of breath, muscular pain, dizziness, or angina symptoms. 
3. At the end of the six-minute interval, tell the subject to “STOP”. 
4. Record the distance traveled to the nearest foot or meter. If the subject ceases participation 
prior to the end of the six-minute interval, record the distance covered (to the nearest foot or 
meter) and the subject’s heart rate at the time he or she stops walking. 
 
27.3. 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
The KCCQ is a disease-specific instrument for monitoring the health status and quality of life 
of subjects with congestive heart failure.  It includes a total of 23 items that assess quality of 
life in the following domains: physical function, symptom frequency and severity, symptom 
stability, self-efficacy and knowledge, social function, and overall quality of life.  These 
domains can be combined into a functional status summary score (derived from the physical 
function and symptom scales) and an overall summary score which combines the physical 
function, symptom, social function and quality of life domains.  The KCCQ has been 
validated in subjects with CHF using a variety of standard techniques (1), is highly 
reproducible among stable subjects. In cross-sectional analyses, the KCCQ has been shown 
to be highly correlated with event-free survival. Finally, the responsiveness of the KCCQ as 
assessed by the “responsiveness statistic” (ratio of mean change among subjects with 
improved CHF to the standard deviation among stable subjects) is superior to other measures 
including the SF-36, the Minnesota Living with Heart Failure Questionnaire, and NYHA 
classification (Spertus JA, personal communication).   
 
 
References 
1.  Green CP, Porter CB, Bresnahan DR, Spertus JA.  Development and evaluation of the 
Kansas City Cardiomyopathy Questionnaire:  a new health status measure for heart failure.  J 
Am Coll Cardiol 2000;35:1245-55. 
 
27.4. 
SmartDelay Step-by-Step Guidance 
Follow these steps to perform SmartDelay test. 
Step 1. Navigate to the SmartDelay Optimization screen  
• From the programmer (PRM) main screen, choose the Settings tab 
• From the Settings tab, choose Settings – Normal Brady/CRT,  

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• From the Settings – Normal Brady/CRT screen, choose SmartDelay Optimization 
• The nominal Temporary Paced LRL is set at 80 bpm. Set the LRL at 10 to 15 beats 
above the subject’s intrinsic heart rate. 
• Program LV Offset to 0ms. 
Step 2. Run the SmartDelay test 
• From the SmartDelay Optimization screen, choose Start Test. The test typically last 
up to 2.5 minutes. 
• SmartDelay will recommend AV delay and Pacing Chamber (BiV or LV Only).  
• If the SmartDelay test fails, the nominal value will be displayed. 
Step 3. Program AV Delays and Pacing Chambers 
• If following the recommended AV Delay and Pacing Chamber value determined by 
the SmartDelay, choose Copy Suggested Settings and push the program button to 
program the device. 
Step 4. Record the required value  
• Record in the follow-up eCRF both the SmartDelay recommendation and final 
programmed value for AV Delay and Pacing Chamber. Also record the final 
programmed LV offset. 
• Once the Pacing Chamber is selected for a subject at Randomization Visit, the same 
Pacing Chamber must be used throughout the trial for that subject.