Strategic Management to Improve CRT Using Multi-Site Pacing Post Approval Study (Reference # C1918)
Phase: NA
Conditions: Left Ventricular Dysfunction
Sponsor: Boston Scientific Corporation

Form/Template 90702637 Rev/Ver AH 
                                   SMART MSP Study Protocol, 92050975, Rev/Ver F  
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Strategic MAnagement to Improve CRT Using Multi-Site Pacing 
Post Approval Study 
  
SMART MSP 
 
CLINICAL INVESTIGATION PLAN 
 
Protocol#: C1918 
 
 
Sponsored By 
Boston Scientific, CRM 
4100 Hamline Avenue North 
St. Paul, MN 55112 
Tel: (800) CARDIAC 
(800) 227-3422 
 
 
 
 
 
 
 
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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Confidential                                         SMART MSP Study Protocol, 92050975, Rev/Ver F 
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Contact Information 
Role 
Contact  
Clinical Contact 
Ming Duanmu 
Clinical Trial Manager 
Rhythm Management – High Voltage 
4100 Hamline Avenue North  
Arden Hills, MN  55126 
651-582-6403  
Ming.Duanmu@bsci.com 
David Neuberger 
Clinical Trial Manager 
Rhythm Management - High Voltage 
4100 Hamline Avenue North  
Arden Hills, MN 55126 
651-582-5406 
David.Neuberger@bsci.com 
Coordinating Principal 
Investigator 
Samir Saba, MD, FACC, FHRS 
Associate Professor of Medicine 
Associate Professor in Clinical and Translational Science  
Associate Chief of Cardiology, Clinical Affairs  
Director, Cardiac Electrophysiology  
University of Pittsburgh Medical Center 
200 Lothrop Street, PUH B535 
Pittsburgh, PA 15213 
(412) 647-6272 
sabas@upmc.edu 
 
 
 
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C1918 
              Form/Template 90702637 Rev/Ver AH 
Confidential                                         SMART MSP Study Protocol, 92050975, Rev/Ver F 
                                                                                                                               Page 3 of 92 
  
 
Original Release: November 30, 2016 
Current Version: November 15, 2017 
 
Revision History 
Revision 
Number 
Release 
Date 
Template 
number and 
version 
Section 
Change 
Reason for 
Change 
Revision A 
November 
30, 2016 
90702637 
Rev/Ver AH 
NA 
Original Release 
NA 
Revision B 
December 
2, 2016 
90702637 
Rev/Ver AH 
9.3  
 
 
 
11.4.8, 
11.5.9, 
11.6.8, and 
26.1 
 
 
 
Multiple 
sections 
Changed the order of how exclusion 
criteria are listed. 
 
 
Clarified the electrical interval values 
to be measured from the ECG/EGM 
strip 
 
 
 
 
Clarifications and corrections 
Clarifications 
and 
corrections 
Revision C 
March 13, 
2017 
90702637 
Rev/Ver AH 
 
Section 
Change 
Reason for 
Change 
2 
8.1,  
10.5 
Update number of enrollment, 
number of US sites, and attrition 
percentage 
 
Update due to 
change in study 
design per FDA 
request 
11.5.1 and 
multiple 
sections 
Use the term “HF event” to match 
its definition 
Clarification 
10.1,  
10.4, 
11.3 
Clarify definition of enrollment 
Consistency 
11,  
Table 11.1-1, 
all sub-
sections of 11 
Additional testing and data 
collection: 
- 
Smart Delay interval test, 
ECG/EGM strip  
- 
RVp-LVs interval test, 
ECG/EGM strip 
- 
Sleep Incline Trend 
calibration 
Data collection 
to support 
future feature 
and algorithm 
development 
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              Form/Template 90702637 Rev/Ver AH 
Confidential                                         SMART MSP Study Protocol, 92050975, Rev/Ver F 
                                                                                                                               Page 4 of 92 
  
 
Revision History 
Revision 
Number 
Release 
Date 
Template 
number and 
version 
Section 
Change 
Reason for 
Change 
- 
“Save All” device data 
11,  
Table 11.1-1, 
all sub-
sections of 11 
Additional data collection: 
- 
Echo measurement value, 
if performed per standard 
of care 
- 
Charge Remaining 
Per FDA 
request 
11.5.2,  
11.6.2 
Add blinded NYHA Class 
assessment 
Per FDA 
request 
12.1.1 
Update LV MSP feature 
relatedness categories, clarify 
method of analysis, and add 
sensitivity analysis 
Correction 
12 
Update sample size, power 
calculation, attrition estimate for 
primary effectiveness endpoint and 
overall study 
Update due to 
change in study 
design  per FDA 
request 
12.1.1.3 
Clarify time-to-event analysis 
language for primary safety 
endpoint  
Clarification 
12.2.1 
Add ancillary assessment of Echo 
Measurements and CCS Response 
Status Outcomes in Non-
Responders 
Per FDA 
request 
19.3 and 19.6 
Update risks of worsening HF; 
Update risks associated with 
participating in study 
Update risk per 
FDA request  
 
Update to align 
with additional 
testing and 
clarification of 
study risks 
20.7 
Update death reporting time 
period to 3 calendar days. 
Correction 
22.2 
Clarify roles and responsibilities of 
CEC in HF event adjudication and 
adjudication process. 
Update per FDA 
request 
Multiple 
Sections 
Minor clarification, modification, 
and correction 
 
Minor 
clarification, 
modification, 
and correction 
Revision D 
May 16, 
2017 
90702637 
Rev/Ver AH 
26 
 
Appendix Section removed. The 
recommended step-by-step guidance on 
Modification 
 
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C1918 
              Form/Template 90702637 Rev/Ver AH 
Confidential                                         SMART MSP Study Protocol, 92050975, Rev/Ver F 
                                                                                                                               Page 5 of 92 
  
 
Revision History 
Revision 
Number 
Release 
Date 
Template 
number and 
version 
Section 
Change 
Reason for 
Change 
 
 
 
Figure 
12.3-1 
testing will be provided in investigator 
and site training. 
 
Death is removed from the description 
of attrition between 6 and 12 month 
visit 
 
 
 
Correction 
Revision E 
September 
8, 2017 
90702637 
Rev/Ver AH 
Synopsis 
and 
Section 9.3 
 
 
Table 
11.1-1, 
Section 
11.4.14, 
Section 
11.5.18, 
Section 
11.6.18 
 
Section 
22.2 
 
 
Section 
11.5.5 
 
 
Section 
11.5.9 
Adding one exclusion criteria: Women 
of childbearing potential who are 
pregnant or plan to become pregnant 
over the course of the clinical trial.   
 
Adding data collection on HeartLogic 
Alert assessment.  
 
 
 
 
 
 
Clarify that the CEC’s role is to 
adjudicate heart failure event 
 
 
Clarify that both hospitalization and 
IV therapy event are used in CEC 
adjudication 
 
In the determination of 2 viable pacing 
vectors, clarify the original protocol 
language that could have led to 
different interpretation 
Update 
 
 
 
 
Update 
 
 
 
 
 
 
Clarification 
 
 
 
Clarification 
 
 
 
Clarification 
Revision F 
November 
15, 2017 
90702637 
Rev/Ver AH 
Table 
11.1- 1: 
Data 
Collection 
Schedule 
Section 
11.5 and 
11.6 6 
Month 
Visit and 
12 Month 
Visit list of 
data 
Provide clarification regarding 
HeartLogic Alert feature data 
collection 
Clarification 
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Revision History 
Revision 
Number 
Release 
Date 
Template 
number and 
version 
Section 
Change 
Reason for 
Change 
collection 
Section 
11.5.18 
and 
Section 
11.6.18 
 
 
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2. Protocol Synopsis 
SMART MSP  
Post Approval Study 
Study 
Objective(s) 
Evaluate the effectiveness of Boston Scientific (BSC)’s LV MSP (Left 
Ventricular MultiSite Pacing) feature in the Resonate family of CRT-D 
devices1 and confirm safety in a post approval study when used in 
accordance with its approved labeling.    
Planned 
Indication(s) for 
Use  
The BSC Cardiac Resynchronization Therapy Defibrillators (CRT-Ds) 
are indicated for patients with heart failure who receive stable optimal 
pharmacologic therapy (OPT) for heart failure and who meet any one of 
the following classifications: 
• Moderate to severe heart failure (NYHA Class III-IV) with EF ≤ 
35% and QRS duration ≥ 120 ms 
• Left bundle branch block (LBBB) with QRS duration ≥ 130 ms, 
EF ≤ 30%, and mild (NYHA Class II) ischemic or non-ischemic 
heart failure or asymptomatic (NYHA Class I) ischemic heart 
failure  
The LV MSP is a feature of the BSC’s Resonate family of CRT-D 
devices and is intended for use with subjects who are non-responders to 
conventional Biventricular (BiV) CRT-D therapy. The CRT-D device and 
the LV MSP feature will be used within the current BSC labeled 
indications for CRT-D therapy.   
Description of 
Device under 
Evaluation  
Eligible CRT-D Device models in the study – Resonate family of CRT-D 
devices 
Resonate family of 
CRT-Ds  
Device Name 
US  
Model 
Numbers 
Description of 
Port 
RV/ LV/ RA 
Capable of  
LV Only 
pacing? 
RESONATE HF™ 
G548 
DF1/IS4/IS1 
Yes 
RESONATE HF™ 
G547 
DF4/IS4/IS1 
Yes 
RESONATE HF™ 
G528 
DF1/IS4/IS1 
No 
RESONATE HF™ 
G537 
DF4/IS4/IS1 
No 
RESONATE™ X4 
G448 
DF1/IS4/IS1 
Yes 
                                                
1 Resonate refers to all trademarked devices in this family of pulse generators, including RESONATE HF, 
RESONATE, VIGILANT, and MOMENTUM. 
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SMART MSP  
Post Approval Study 
RESONATE™ X4 
G447 
DF4/IS4/IS1 
Yes 
RESONATE™ X4 
G428 
DF1/IS4/IS1 
No 
RESONATE™ X4 
G437 
DF4/IS4/IS1 
No 
VIGILANT™ X4 
G248 
DF1/IS4/IS1 
Yes 
VIGILANT™ X4 
G247 
DF4/IS4/IS1 
Yes 
VIGILANT™ X4 
G228 
DF1/IS4/IS1 
No 
VIGILANT™ X4 
G237 
DF4/IS4/IS1 
No 
MOMENTUM™ X4 
G138 
DF1/IS4/IS1 
Yes 
MOMENTUM™ X4 
G128 
DF1/IS4/IS1 
No 
Study Design 
Prospective, multi-center, single arm, post approval study to be conducted 
in the United States. 
Planned 
Number of 
Subjects 
The study will enroll approximately 586 subjects. 
 
Planned 
Number of 
Study Sites 
Approximately 60 US sites. 
Primary Safety 
Endpoint(s) 
LV MSP feature-related complication-free rate between the 6 Month Visit 
and the 12 Month Visit in non-responders with the LV MSP turned on for 
any duration 
Primary 
Effectiveness 
Endpoint(s) 
Proportion of the LV MSP Group subjects with Improved Clinical 
Composite Score (CCS) from the 6 Month Visit through the 12 Month 
Visit 
Ancillary 
Analyses 
• Assessment of Echocardiographic Measurements and CCS Response 
Status Outcomes in Non-responders 
• Assessment of effectiveness of the LV MSP in SMART MSP PAS 
and SMART Registry 
• Assessment of Worsened LV MSP Group 
• Assessment of RV-LV electrical delay and response 
• Assessment of battery consumption 
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SMART MSP  
Post Approval Study 
• Assessment of SmartDelay and SmartVector usage 
• Assessment of percentage of pacing  
• Additional descriptive statistics include but are not limited to: overall 
response rate at 6 Month Visit and percentage of LV MSP Group 
subjects with two viable vectors that are furthest apart  
Method of 
Assigning 
Patients to 
Treatment 
Subjects will be selected from the investigator’s general population who 
receive a Boston Scientific Resonate family of CRT-D device in 
accordance with its labeled indication for use, as well as an ACUITYTM 
X4 coronary venous LV lead. 
Follow-up 
Schedule 
Study visits in clinic will occur at the following time periods: 
- 
Enrollment Visit: between 1 day and 21 days post-CRT-D 
implantation.  
- 
6 Month Follow-up Visit: 183 days -30 days/+0 day after 
Enrollment Visit 
- 
12 Month Follow-up Visit: 183 days -0 day/+30 days after 6 
Month Visit 
 
Subjects determined to be a responder at their 6 Month Visit will 
complete the study. Subjects in the Non-Responder Group, including 
those subjects who have no LV MSP turned on, will complete the study at 
their 12 Month Visit.  
Study Duration 
The study is expected to last approximately 36 months from the first 
enrollment to the study closure.  
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SMART MSP  
Post Approval Study 
Inclusion 
Criteria 
1. Subjects who received de novo implantation of BSC’s Resonate 
family of CRT-D devices with the LV MSP feature2 and BSC’s 
ACUITYTM X4 LV Quadripolar leads. A Resonate family of 
CRT-D device upgrade from previous single or dual chamber 
pacemaker or ICD implantation is allowed.  
2. Subjects must meet BSC labeled indication for CRT-D 
implantation3.  
3. Subjects must have a functional RA lead and RV lead implanted.  
4. Subjects who are willing and capable of providing informed 
consent 
5. Subjects who are willing and capable of participating in all 
testing/visits associated with this clinical study at an approved 
clinical study center and at the intervals defined by this protocol 
6. Subjects who are age 18 and above, or of legal age to give 
informed consent specific to state and national law 
Exclusion 
Criteria 
1. Subjects who received LV pacing prior to receiving the Resonate 
family of CRT-D system implantation. 
2. Subjects who received the LV MSP therapy post CRT-D 
implantation but prior to enrollment 
3. Subjects with documented history of permanent AF 
4. Subjects with documented permanent complete AV block 
5. Subjects who are expected to receive a heart transplant during the 
12 months course of the study 
6. Subjects with documented life expectancy of less than 12 months 
7. Women of childbearing potential who are pregnant or plan to 
become pregnant over the course of the clinical trial.  Note: For 
patients with uncertain pregnancy status, pregnancy tests should 
have been performed per site’s standard clinical practice prior to 
CRT-D device implant. 
8. Subjects who enrolled in any other concurrent study or registry, 
with the exception of mandatory national or governmental 
                                                
2 Resonate refers to all trademarked devices in this family of pulse generators, including RESONATE HF, 
RESONATE, VIGILANT, and MOMENTUM. 
3 For BSC labeled indication for CRT-D implantation, see Section 9.1.1. 
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SMART MSP  
Post Approval Study 
registry, without prior written approval from BSC. 
Statistical Methods  
Endpoint 
Hypotheses and 
Statistical Test 
Methods 
 
Endpoint 
Hypothesis 
Analysis Method 
Primary 
Safety 
LV MSP feature-related 
complication-free rate between 
6 Month Visit and 12 Month 
Visit > 90%. 
Kaplan-Meier 
methodology 
Primary 
Effectiveness 
Proportion of LV MSP Group 
with Improved CCS from 6 
Month visit through 12 Month 
Visit > 5% 
One-sided Exact 
Test for a Single 
Binomial 
Proportion 
 
 
 
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3. Table of Contents 
1. 
TITLE PAGE  ........................................................................................................................ 1 
2. 
PROTOCOL SYNOPSIS .......................................................................................................... 7 
3. 
TABLE OF CONTENTS ........................................................................................................ 12 
3.1. Table of Figures ...................................................................................................... 17 
3.2. Table of Tables ....................................................................................................... 17 
4. 
INTRODUCTION ................................................................................................................. 19 
5. 
DEVICE DESCRIPTION ....................................................................................................... 21 
5.1. CRT-D Device ......................................................................................................... 21 
5.1.1. 
LV MSP .................................................................................................. 21 
5.1.1.1. 
SmartVector ............................................................................ 22 
5.1.1.2. 
SmartOffset ............................................................................. 22 
5.1.2. 
LV Only Pacing ....................................................................................... 22 
5.1.3. 
LV VectorGuide™ .................................................................................. 22 
5.1.4. 
SmartDelay™ .......................................................................................... 22 
5.2. ACUITYTM X4 Quadripolar Coronary Venous LV Lead .................................. 23 
5.3. Other Devices .......................................................................................................... 24 
6. 
STUDY OBJECTIVES .......................................................................................................... 24 
7. 
STUDY ENDPOINTS ............................................................................................................ 24 
7.1. Primary Safety Endpoint ....................................................................................... 24 
7.2. Primary Effectiveness Endpoint ........................................................................... 24 
8. 
STUDY DESIGN .................................................................................................................. 24 
8.1. Scale and Duration ................................................................................................. 24 
8.2. Treatment Assignment .......................................................................................... 25 
8.3. Justification for the Study Design ......................................................................... 26 
9. 
SUBJECT SELECTION ......................................................................................................... 26 
9.1. Study Population and Eligibility ........................................................................... 26 
9.1.1. 
BSC Labeled Indication for CRT-D Implantation ................................... 26 
9.2. Inclusion Criteria ................................................................................................... 27 
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9.3. Exclusion Criteria .................................................................................................. 27 
10. SUBJECT ACCOUNTABILITY .............................................................................................. 28 
10.1. Point of Enrollment ................................................................................................ 28 
10.2. Point of Study Exit ................................................................................................. 28 
10.3. Study Withdrawal .................................................................................................. 29 
10.4. Subject Status and Classification .......................................................................... 29 
10.5. Enrollment Controls .............................................................................................. 29 
11. STUDY METHODS .............................................................................................................. 30 
11.1. Data Collection ....................................................................................................... 30 
11.2. Study Candidate Screening ................................................................................... 33 
11.3. Informed Consent .................................................................................................. 33 
11.4. Enrollment Visit ..................................................................................................... 33 
11.4.1. CRT-D Indication Verification ................................................................ 33 
11.4.2. Subject Demographics ............................................................................. 34 
11.4.3. Medical History and Medication ............................................................. 34 
11.4.4. NYHA Class Assessment ........................................................................ 34 
11.4.5. Device Information .................................................................................. 35 
11.4.6. Current Device Settings and Status .......................................................... 35 
11.4.7. Lead Measurements ................................................................................. 35 
11.4.8. SmartDelay Test ...................................................................................... 36 
11.4.9. LV VectorGuide Test .............................................................................. 37 
11.4.10. RVp-LVs Interval Test ............................................................................ 37 
11.4.11. LV Lead Location .................................................................................... 37 
11.4.12. Battery Consumption ............................................................................... 38 
11.4.13. Sleep Incline Trend Calibration ............................................................... 38 
11.4.14. Final Device Settings and Status .............................................................. 38 
11.4.15. Adverse Event Assessment ...................................................................... 38 
11.5. 6 Month Visit .......................................................................................................... 39 
11.5.1. Definition and Components of the Clinical Composite Score .................. 40 
11.5.1.1. HF Event Definition ................................................................ 40 
11.5.1.2. PGA Classification .................................................................. 40 
11.5.1.3. NYHA Class Assessment ........................................................ 40 
11.5.1.4. CCS Status Classification........................................................ 41 
11.5.2. NYHA Class ............................................................................................ 41 
11.5.3. Patient Global Assessment ...................................................................... 41 
11.5.4. Physician Global Assessment .................................................................. 41 
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11.5.5. Response Status Determination ............................................................... 42 
11.5.6. Echocardiography Measurement ............................................................. 43 
11.5.7. Current Device Settings and Status .......................................................... 43 
11.5.8. Lead Measurements ................................................................................. 43 
11.5.9. LV VectorGuide Test .............................................................................. 44 
11.5.10. RVp-LVs Interval Test ............................................................................ 45 
11.5.11. SmartDelay Test ...................................................................................... 45 
11.5.12. SmartVector Operation (Non-Responders with LV MSP on) .................. 46 
11.5.13. SmartOffset Operation (Non-Responders with LV MSP on) ................... 47 
11.5.14. LV MSP Settings Programming .............................................................. 47 
11.5.15. Battery Consumption ............................................................................... 47 
11.5.16. Final device settings and status ................................................................ 47 
11.5.17. Adverse Event Assessment ...................................................................... 48 
11.5.18. HeartLogic Alert ...................................................................................... 48 
11.5.19. “Save All” Device Data ........................................................................... 48 
11.6. 12 Month Visit ........................................................................................................ 49 
11.6.1. Definition and Components of the Clinical Composite Score .................. 49 
11.6.1.1. HF Event Definition ................................................................ 50 
11.6.1.2. PGA Classification .................................................................. 50 
11.6.1.3. NYHA Class Assessment ........................................................ 50 
11.6.1.4. CCS Status Classification........................................................ 50 
11.6.2. NYHA Class ............................................................................................ 51 
11.6.3. Patient Global Assessment ...................................................................... 51 
11.6.4. Physician Global Assessment .................................................................. 51 
11.6.5. Response Status Determination ............................................................... 51 
11.6.6. Echocardiography Measurement ............................................................. 51 
11.6.7. Current Device Settings and Status .......................................................... 52 
11.6.8. Lead Measurements ................................................................................. 52 
11.6.9. SmartDelay Test ...................................................................................... 52 
11.6.10. LV VectorGuide Test .............................................................................. 53 
11.6.11. RVp-LVs Interval Test ............................................................................ 54 
11.6.12. SmartVector Operation ............................................................................ 55 
11.6.13. SmartOffset Operation ............................................................................. 55 
11.6.14. LV MSP Settings Programming .............................................................. 56 
11.6.15. Battery Consumption ............................................................................... 56 
11.6.16. Final device settings and status ................................................................ 56 
11.6.17. Adverse Event Assessment ...................................................................... 56 
11.6.18. HeartLogic Alert ...................................................................................... 56 
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11.6.19. “Save All” Device Data ........................................................................... 56 
11.7. Additional Visit ...................................................................................................... 57 
11.7.1. Adverse Event Assessment ...................................................................... 58 
11.8. Study Completion ................................................................................................... 58 
12. STATISTICAL CONSIDERATIONS ....................................................................................... 58 
12.1. SMART MSP Study Endpoints ............................................................................ 58 
12.1.1. Primary Safety Endpoint: LV MSP feature-related complication-free rate58 
12.1.1.1. Hypotheses .............................................................................. 59 
12.1.1.2. Sample Size ............................................................................. 59 
12.1.1.3. Statistical Methods .................................................................. 59 
12.1.2. Primary Effectiveness Endpoints: Proportion of LV MSP Group with an 
Improved CCS ......................................................................................... 60 
12.1.2.1. Hypotheses .............................................................................. 60 
12.1.2.2. Sample Size ............................................................................. 60 
12.1.2.3. Statistical Methods .................................................................. 61 
12.2. Ancillary Assessments ............................................................................................ 61 
12.2.1. Assessment of Echocardiographic Measurements and CCS Response 
Status Outcomes in Non-responders ........................................................ 61 
12.2.2. Assessment of Effectiveness of LV MSP in the SMART MSP PAS and 
SMART Registry ..................................................................................... 62 
12.2.3. Assessment of Worsened LV MSP Group ............................................... 62 
12.2.4. Assessment of RV-LV Electrical Delay and Response ............................ 62 
12.2.5. Assessment of Battery Consumption ....................................................... 62 
12.2.6. Assessment of SmartDelay and SmartVector Usage ................................ 62 
12.2.7. Assessment of Percentage of Pacing ........................................................ 62 
12.2.8. Assessment of Additional Data Collection .............................................. 63 
12.3. Sample Size Summary and Attrition .................................................................... 63 
12.4. General Statistical Methods .................................................................................. 64 
12.4.1. Study Success Criteria ............................................................................. 64 
12.4.2. Analysis Sets ........................................................................................... 64 
12.4.3. Control of Systematic Error/Bias ............................................................. 64 
12.4.4. Control of Type I Error ............................................................................ 65 
12.4.5. Number of Subjects per Investigative Site ............................................... 65 
12.5. Data Analyses ......................................................................................................... 65 
12.5.1. Interim Analyses ...................................................................................... 65 
12.5.2. Pooling Analysis ...................................................................................... 65 
12.5.3. Subgroup Analyses .................................................................................. 65 
12.5.4. Multivariable Analyses ............................................................................ 66 
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12.5.5. Changes to Planned Analyses .................................................................. 66 
13. DATA MANAGEMENT ........................................................................................................ 67 
13.1. Data Collection, Processing, and Review ............................................................. 67 
13.2. Data Retention ........................................................................................................ 67 
14. AMENDMENTS ................................................................................................................... 67 
15. DEVIATIONS ...................................................................................................................... 67 
16. DEVICE/EQUIPMENT ACCOUNTABILITY .......................................................................... 68 
17. COMPLIANCE ..................................................................................................................... 68 
17.1. Statement of Compliance ....................................................................................... 68 
17.2. Investigator Responsibilities ................................................................................. 68 
17.2.1. Delegation of Responsibility ................................................................... 70 
17.3. Institutional Review Board ................................................................................... 70 
17.4. Sponsor Responsibilities ........................................................................................ 70 
17.4.1. Role of Boston Scientific Representatives ............................................... 71 
18. MONITORING ..................................................................................................................... 72 
19. POTENTIAL RISKS AND BENEFITS .................................................................................... 72 
19.1. Anticipated Adverse Events .................................................................................. 72 
19.2. Risks Associated with the Study Device(s) ........................................................... 74 
19.3. Risks associated with Participation in the Clinical Study .................................. 74 
19.4. Risk Minimization Actions .................................................................................... 75 
19.5. Anticipated Benefits ............................................................................................... 75 
19.6. Risk to Benefit Rationale ....................................................................................... 75 
20. SAFETY REPORTING .......................................................................................................... 75 
20.1. Reportable Events by Investigational Site to BSC .............................................. 75 
20.2. Definitions and Classification ............................................................................... 76 
20.3. Relationship to Study Device(s) and/or Study Testing ....................................... 79 
20.4. Investigator Reporting Requirements .................................................................. 80 
20.5. Boston Scientific Device Deficiencies .................................................................... 81 
20.6. Reporting to Regulatory Authorities / IRBs / Investigators............................... 82 
20.7. Subject Death Reporting ....................................................................................... 82 
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20.8. Source Documents for CEC Adjudication ........................................................... 83 
21. INFORMED CONSENT ......................................................................................................... 83 
22. COMMITTEES .................................................................................................................... 84 
22.1. Safety Monitoring Process ..................................................................................... 84 
22.2. Clinical Events Committee .................................................................................... 84 
23. SUSPENSION OR TERMINATION ......................................................................................... 85 
23.1. Premature Termination of the Study ................................................................... 85 
23.1.1 
Criteria for Premature Termination of the Study ..................................... 85 
23.2. Termination of Study Participation by the Investigator or Withdrawal of IRB 
Approval ................................................................................................................. 85 
23.3. Requirements for Documentation and Subject Follow-up ................................. 85 
23.4. Criteria for Suspending/Terminating a Study Site ............................................. 86 
24. PUBLICATION POLICY ....................................................................................................... 86 
25. ABBREVIATIONS AND DEFINITIONS .................................................................................. 87 
25.1. Abbreviations ......................................................................................................... 87 
25.2. Definitions ............................................................................................................... 89 
26. REFERENCES ..................................................................................................................... 90 
 
Table of Figures 
Figure 5.2-1: Three Types of ACUITYTM X4 LV Leads ....................................................... 23 
Figure 5.2-2: Electrode Layout and Spacing on ACUITYTM X4 LV Leads. ......................... 23 
Figure 8.2-1: Study Design Flowchart................................................................................... 26 
Figure 12.3-1: Subject Flowchart with Estimated Attrition ................................................... 64 
 
Table of Tables 
Table 5.1-1: Eligible CRT-D Device Models ........................................................................ 21 
Table 5.2-1: Electrode Spacing and Length of ACUITYTM X4 LV Lead Models ................. 24 
Table 9.2-1: Inclusion Criteria .............................................................................................. 27 
Table 9.3-1: Exclusion Criteria ............................................................................................. 28 
Table 11.1-1: Data Collection Schedule ................................................................................ 31 
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Table 11.4-1: NYHA Classifications ..................................................................................... 34 
Table 11.4-2: Source Documentation Required at Enrollment Visit ...................................... 39 
Table 11.5-1: Comparison of the Global Assessment Tool: Patient Global Assessment (PGA) 
and Physician Global Assessment (PhGA) ......................................................... 42 
Table 11.5-2: Source Documentation Requirement at the 6 Month Visit .............................. 48 
Table 11.6-1: Source Documentation Requirement at the 12 Month Visit ............................ 57 
Table 11.7-1: Source Documentation Requirement at Additional Visit ................................. 58 
Table 12.4-1: Analysis Sets for Each Primary Endpoint ....................................................... 64 
Table 20.2-1: Safety Term Definitions .................................................................................. 76 
Table 20.3-1: Criteria for Assessing Relationship of Study Device or Procedure to Adverse 
Event .................................................................................................................. 79 
Table 20.4-1: Investigator Reporting Requirement ............................................................... 81 
Table 25.1-1: Study Abbreviation ......................................................................................... 87 
Table 25.2-1: Definitions ...................................................................................................... 89 
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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 a wide QRS pattern on an ECG, 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 improve cardiac function for ICD patients with NYHA Class III-IV heart 
failure, reduced ejection fraction, and wide QRS duration in the CONTAK CD study1. 
Subsequently, the COMPANION study demonstrated additional benefits of CRT that 
included 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 ICD patients in NYHA Class I-II3. In addition to the benefits 
shown in previous studies, MADIT CRT also demonstrated significant reduction in left 
ventricular volumes and improvement in left ventricular ejection fraction (LVEF). 
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 Score (CCS) first described by Milton 
Packer 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 around 30% of the patients. When echo-based measures are used, the non-response 
rate is higher and around 50%. 
The potential reasons for non-response are varied and include5: 
• Poor lead location 
• Lack of baseline 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 
• LV-only CRT 
• Multi-site pacing 
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To date, the randomized clinical studies conducted using the device-based features have 
shown equivalence with conventional CRT delivery without demonstrating superiority, 
although subsequent subgroup analyses suggest that some patients may be helped by these 
features. 
V-V Timing: The InSync III Marquis Study6 using the CCS, 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 CCS demonstrated safety of LV pacing. The AdaptivCRT 
study10, using the CCS, 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 
optimization. Overall, the results from these studies showed that the LV only pacing is as 
effective as conventional BiV CRT pacing. 
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), which used the CCS, and SMART-AV12, which used LVESV to measure 
effectiveness of optimizing AV delay. Both studies showed that these methods were non-
inferior to empiric programming. The RESPOND-CRT study13, which evaluated a CRT 
system that employed a hemodynamic sensor to optimize both AV and VV timing, used a 
modified version of the CCS. This study also found that the sensor was non-inferior to 
echocardiographic optimization.  
Multi-site Pacing: Left ventricular multi-site pacing (MSP) has emerged as an option for 
addressing the non-responder issue with conventional CRT by using a quadripolar lead to 
pace two sites within the same coronary vein. Studies have shown that MSP improved acute 
hemodynamics and ventricular synchrony, and resulted in faster activation of myocardium 
and improved clinical responses as measured by the ventricular reverse remodeling and 
LVEF value comparing to single site LV pacing14-22. Furthermore, acute studies on MSP 
have shown no ventricular arrhythmias or other adverse events during acute testing, implant 
and pre-discharge18. Among different MSP configurations discussed in the literature, pacing 
from two sites that are farthest apart (distal to proximal) was the most common optimal 
configuration as it may recruit a larger area of the myocardium with late activation to achieve 
better ventricular synchrony15, 19. Opting for the two pacing sites that are farthest apart may 
provide a simple means for pacing vector selection in MSP, in combination with the 
evaluation of pacing threshold and impedance, and the avoidance of the phrenic nerve 
stimulation (PNS).   
The MPP Trial23, using a modified version of the CCS, evaluated a CRT-D system that paced 
the left ventricle from two distinct sites using a quadripolar lead. The study had a 3 month 
run-in phase that identified non-responders who were then randomized to MPP or 
conventional CRT. The MPP Trial provided safety data of the MPP feature. The MPP 
therapy was found to be non-inferior to conventional CRT in converting non-responders to 
responders. 
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Boston Scientific’s Left Ventricular Multi-Site Pacing (LV MSP) is intended to improve the 
cardiac resynchronization therapy response by delivering two LV pulses per pacing cycle 
using quadripolar LV leads. It provides physicians a new set of tools that allow for 
individualized patient therapy with the goal of improving clinical response in non-responders 
to conventional CRT therapy. The objective of SMART MSP study is to demonstrate the 
effectiveness of the LV MSP feature to improve CRT non-response rate and confirm the 
safety of the feature in the post-market settings. 
5. Device Description 
5.1. CRT-D Device 
Commercially approved Boston Scientific (BSC)’s Resonate family of CRT-Ds are eligible 
devices in this study. The LV MSP feature is available in the Resonate family of CRT-Ds, 
which includes RESONATE HF, RESONATE, VIGILANT, and MOMENTUM devices. 
These devices have quadripolar headers and accept LV quadripolar leads. See Table 5.1-1 
for a complete list of eligible CRT-D device models.  
Table 5.1-1: Eligible CRT-D Device Models 
Resonate family of 
CRT-Ds  
Device Name 
US  
Model Numbers 
Description of Port 
RV/ LV/ RA 
Capable of  
LV Only pacing? 
RESONATE HF™ 
G548 
DF1/IS4/IS1 
Yes 
RESONATE HF™ 
G547 
DF4/IS4/IS1 
Yes 
RESONATE HF™ 
G528 
DF1/IS4/IS1 
No 
RESONATE HF™ 
G537 
DF4/IS4/IS1 
No 
RESONATE™ X4 
G448 
DF1/IS4/IS1 
Yes 
RESONATE™ X4 
G447 
DF4/IS4/IS1 
Yes 
RESONATE™ X4 
G428 
DF1/IS4/IS1 
No 
RESONATE™ X4 
G437 
DF4/IS4/IS1 
No 
VIGILANT™ X4 
G248 
DF1/IS4/IS1 
Yes 
VIGILANT™ X4 
G247 
DF4/IS4/IS1 
Yes 
VIGILANT™ X4 
G228 
DF1/IS4/IS1 
No 
VIGILANT™ X4 
G237 
DF4/IS4/IS1 
No 
MOMENTUM™ X4 
G138 
DF1/IS4/IS1 
Yes 
MOMENTUM™ X4 
G128 
DF1/IS4/IS1 
No 
 
5.1.1. LV MSP  
A new feature available in these CRT-D devices is the LV MultiSite Pacing (LV MSP). 
The LV MSP feature allows the clinician to program cardiac resynchronization therapy 
(CRT) to deliver two LV paces per cardiac cycle during Normal Brady operation compared 
to the one LV pace per cardiac cycle as done in conventional CRT with single-site LV 
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pacing. Each of the LV paces has its own independently programmable pacing vector and 
output (LVa vector and LVb vector). Depending on the pacing chamber selected, the LV 
MSP feature can deliver BiV MSP pacing or LV Only MSP pacing.  
Two features associated with the LV MSP are described below: 
5.1.1.1. SmartVector 
The SmartVector feature provides recommendations for the LV MSP pacing sequence, LV 
pacing vectors and LV pacing characteristics (amplitude and pulse width) based on data 
gathered via the LV VectorGuide feature and on LV electrode spacing. 
5.1.1.2. SmartOffset 
The SmartOffset feature provides recommendations for the LV MSP programmed delays 
between the ventricular paces based on data gathered via the LV VectorGuide data and the 
current LV MSP pacing vectors. 
5.1.2. LV Only Pacing  
Another new feature available in these CRT-D devices is the LV only pacing feature. The 
clinician can program Pacing Chamber settings so that the system delivers CRT pacing 
therapy to both ventricular chambers (BiV Pacing) or just to the left ventricular chamber (LV 
Only).    
5.1.3. LV VectorGuide™ 
The LV VectorGuide allows the clinician to quickly evaluate multiple quadripolar LV pacing 
vectors 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 
• 
LV lead impedance 
• 
Phrenic Nerve Stimulation (PNS) 
• 
LV pace threshold 
The LV VectorGuide feature is available in previous generations of BSC CRT-D devices. 
5.1.4. SmartDelay™ 
The SmartDelay optimization feature provides recommended settings for programming the 
paced and sensed AV Delay 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 cardiac contractile function. The AV delay optimization provided by SmartDelay 
is expected to be applicable to the functioning of the LV MSP feature. 
The SmartDelay feature is available in previous generations of BSC CRT-D devices. 
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5.2. ACUITYTM X4 Quadripolar Coronary Venous LV Lead 
Boston Scientific’s ACUITY™ X4 heart failure lead family for the Left Ventricle (LV) 
quadripolar leads is required in this study. The ACUITYTM X4 leads are intended for chronic 
left ventricular pacing and sensing. A variety of pace/sense configurations are possible with 
the four 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. ACUITYTM 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. 
The ACUITY™ X4 LV lead models are required to be used in this study but they are not 
under evaluation. 
See Figure 5.2-1 and Figure 5.2-2 for images of the ACUITYTM X4 leads and the layout and 
spacing of the electrodes on the lead. 
Figure 5.2-1: Three Types of ACUITYTM X4 LV Leads 
 
 
Figure 5.2-2: Electrode Layout and Spacing on ACUITYTM X4 LV Leads. 
 
The nomenclature of the electrodes on the LV lead (E1, E2, E3, E4) is an industry standard. 
The corresponding nomenclature on the BSC PRM is as follows: LVTip1, LVRing2, 
LVRing3, and LVRing4. 
E1: LV Tip 1 
E2: LV Ring 2 
E3: LV Ring 3 
E4: LV Ring 4 
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Table 5.2-1: Electrode Spacing and Length of ACUITYTM X4 LV Lead Models 
Tip 
Configuration 
Electrode 
Spacing 
Length 
86cm  
95cm  
Model Number 
Straight 
Even  
4671 
4672 
Spiral  
Short tip  
4674 
4675 
Long tip  
4677 
4678 
 
5.3. Other Devices 
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 is eligible.  
6. Study Objectives 
The objective of the study is to evaluate the effectiveness of the Boston Scientific’s LV MSP 
feature in the BSC’s Resonate family of CRT-D devices, and confirm safety in a post 
approval study when used in accordance with its approved labeling.    
7. Study Endpoints 
7.1. Primary Safety Endpoint 
• LV MSP feature-related complication-free rate between the 6 Month Visit and the 12 
Month Visit in non-responders with the LV MSP on for any duration.  
7.2. Primary Effectiveness Endpoint 
• Proportion of the LV MSP Group subjects with Improved CCS from the 6 Month 
Visit through the 12 Month Visit.  
8. Study Design 
The SMART MSP study is designed as a prospective, single arm, multi-center, post-approval 
study to be conducted within the US.     
8.1. Scale and Duration 
The SMART MSP study’s sample size is approximately 586 subjects. See Section 8.2 and 
Section 12.3 for further details on the sample size and attrition estimate. This study will be 
conducted in approximately 60 US sites. All study required visits will be completed as part of 
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the subject’s regularly scheduled clinic follow-up visits. The subject participation is complete 
when the final actively enrolled subject in the Non-Responder Group completes the 12 
Month Visit. Study completion is anticipated to be approximately 36 months after first 
enrollment.   
8.2. Treatment Assignment 
All enrolled subjects will be programmed to conventional CRT from the point of enrollment 
visit to the 6 Month Visit. At the 6 Month Visit, the clinical composite score (CCS) will be 
calculated for each subject to determine the subject’s responder status to conventional CRT. 
Subjects who are responders will be in the Responder Group and complete the study at the 6 
Month Visit, as shown in Figure 8.2-1.   
Subjects who are non-responders to conventional CRT based on the CCS calculation belong 
to the Non-Responder Group. The LV MSP feature will be enabled for these subjects from 
the 6 Month Visit through the 12 Month Visit. Those subjects who are able to receive the LV 
MSP therapy and achieve at least 93% of LV pacing are classified in the LV MSP Group, 
which is defined as meeting all of the following criteria: 
• Subjects who have achieved at least 2 viable LV pacing vectors  
• Subjects who have the LV MSP feature enabled 
• Subjects who have achieved at least 93% of the LV MSP pacing  
To determine whether an LV pacing vector is considered viable, the following criteria are 
recommended: 
• The pacing impedance is not out-of-range per physician’s programmed value 
• No presence of PNS - the pacing capture threshold (PCT) plus 3V of safety margin 
should be less than PNS threshold 
• LV PCT at ≤ 4.5V or demonstrated capture at ≤ 4.5V 
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Figure 8.2-1: Study Design Flowchart 
 
 
8.3. Justification for the Study Design 
This study is designed to evaluate the therapy benefit provided by multisite pacing to those 
patients who are non-responders to CRT with single site LV pacing based on a clinical 
evaluation using the CCS. The study’s primary endpoint of the Clinical Composite Endpoint 
(CCS) measures multiple components related to the improvement of patient’s clinical status, 
including Patient Global Assessment, NYHA class change, heart failure event, and mortality 
rate. See Section 11.5.1 for the definition and calculation used in the study. These measures 
are well-understood and widely accepted by the medical community. 
9. Subject Selection  
9.1. Study Population and Eligibility  
Subjects included in the SMART MSP Study should be selected from the investigator’s 
general patient population who received BSC Resonate family of CRT-D devices, and were 
indicated for CRT-D implantation per BSC labeled indication provided in Section 9.1.1. 
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. 
9.1.1. BSC Labeled Indication for CRT-D Implantation 
The BSC’s CRT-Ds are indicated for patients with heart failure who receive stable optimal 
pharmacologic therapy (OPT) for heart failure and who meet any one of the following 
classifications: 
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• Moderate to severe heart failure (NYHA Class III-IV) with EF ≤ 35% and QRS 
duration ≥ 120 ms 
• Left bundle branch block (LBBB) with QRS duration ≥ 130 ms, EF ≤ 30%, and mild 
(NYHA Class II) ischemic or non-ischemic heart failure or asymptomatic (NYHA 
Class I) ischemic heart failure    
9.2. Inclusion Criteria 
Subjects who meet all of the following criteria (see Table 9.2-1) may be given consideration 
for inclusion in this clinical investigation, provided no exclusion criterion (see Section 9.3) is 
met. 
Table 9.2-1: Inclusion Criteria 
Inclusion 
Criteria 
1. Subjects who received de novo implantation of BSC’s Resonate 
family of CRT-D devices with the LV MSP feature4 and BSC’s 
ACUITYTM X4 LV Quadripolar leads. A Resonate family of CRT-D 
device upgrade from previous single or dual chamber pacemaker or 
ICD implantation is allowed.  
2. Subjects must meet BSC labeled indication for CRT-D implantation.  
3. Subjects must have a functional RA lead and RV lead implanted  
4. Subjects who are willing and capable of providing informed consent 
5. Subjects who are willing and capable of participating in all 
testing/visits associated with this clinical study at an approved clinical 
study center and at the intervals defined by this protocol 
6. Subjects who are age 18 and above, or of legal age to give informed 
consent specific to state and national law 
 
9.3. Exclusion Criteria 
Subjects who meet any one of the following criteria in Table 9.3-1 will be excluded from 
this clinical study. 
                                                
4 Resonate refers to all trademarked devices in this family of pulse generators, including RESONATE HF, 
RESONATE, VIGILANT, and MOMENTUM. 
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Table 9.3-1: Exclusion Criteria 
Exclusion 
Criteria 
1. Subjects who received LV pacing prior to receiving the Resonate 
family of CRT-D system implantation. 
2. Subjects who received the LV MSP therapy post CRT-D implantation 
but prior to enrollment 
3. Subjects with documented history of permanent AF 
4. Subjects with documented permanent complete AV block  
5. Subjects who are expected to receive a heart transplant during the 12 
months course of the study 
6. Subjects with documented life expectancy of less than 12 months 
7. Women of childbearing potential who are pregnant or plan to become 
pregnant over the course of the clinical trial.  Note: For patients with 
uncertain pregnancy status, pregnancy tests should have been 
performed per site’s standard clinical practice prior to CRT-D device 
implant. 
8. Subjects who enrolled in any other concurrent study or registry, with 
the exception of mandatory national or governmental registry, without 
prior written approval from BSC 
 
10. Subject Accountability 
10.1. Point of Enrollment 
Subjects who meet all study eligibility criteria will be considered enrolled in the SMART 
MSP Study at the time of signing the informed consent form. All enrolled subjects meeting 
the eligibility criteria will be counted against the enrollment ceiling for the study. Any 
adverse event (AE) experienced post-enrollment by an actively enrolled subject that meets 
the protocol requirement for reporting must be recorded in the electronic case report form 
(eCRF) or alternative methods, if necessary. See Section 20 for information on protocol 
requirements of AE reporting. 
10.2. Point of Study Exit 
All subjects enrolled in the clinical study shall be accounted for. An End of Study form is 
required for all study subjects and is completed following occurrence of any of these events: 
• Subject completion of study participation 
o For subjects classified in the Responder Group, this is upon the completion of 
the 6 Month Visit.  
o For subjects classified in the Non-Responder Group, this is upon the 
completion of the 12 Month Visit. 
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• Subject withdrawal 
• Subject death 
10.3. Study Withdrawal 
If a subject withdraws from the clinical study, the reason(s) shall be reported. If such 
withdrawal is due to problems related to the device safety or performance, the investigator 
shall ask for the subject’s permission to follow the subject outside of the study.   
Reasons for withdrawal may include but are not limited to: 
• physician discretion 
• subject choice to withdraw consent 
• CRT-D device or LV lead explant 
• lost to follow-up 
• uncorrected LV lead dislodgment or undiscovered LV lead dislodgment until the 6 
Month Visit 
• LV lead revision prior to the 6 Month Visit   
While study withdrawal is discouraged, subjects may withdraw from the study at any time, 
with or without reason, and without prejudice to further treatment. All applicable eCRFs up 
to the point of subject withdrawal and an “End of Study” eCRF must be completed. For 
subjects who are “lost-to-follow-up”, the investigator/center staff must have at least three 
documented attempts to contact the subject prior to completion of the “End of Study” eCRF. 
Additional data can no longer be collected after the point at which a subject has been 
withdrawn from the study or withdraws his/her consent, regardless of the reason. All data 
queries should be resolved and all open adverse events should be closed or documented as 
chronic. Data collected up to the point of subject withdrawal may be used. 
10.4. Subject Status and Classification 
All patients who meet all study eligibility criteria, and sign and date an informed consent 
form are considered enrolled in the study. 
Enrolled subjects will be classified as follows: 
• Active enrolled - subject who completes the Informed Consent process, signs and 
dates the ICF and meets the eligibility criteria. Active enrolled subjects will be 
counted towards the enrollment ceiling. 
• Consented and ineligible – subject who signs Informed Consent but does not meet the 
eligibility criteria. 
10.5. Enrollment Controls 
Approximately 586 subjects will be enrolled in the study. Study sites will be notified when 
the enrollment ceiling is close to being reached and once enrollment is complete. No single 
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site shall enroll more than 20% of the study subjects without the prior written approval from 
BSC. 
11. Study Methods 
11.1. Data Collection 
The data collection schedule is shown in Table 11.1-1
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Table 11.1-1: Data Collection Schedule 
Procedure/Assessment 
Enrollment Visit  
(between 1 day and 21 
days post-CRT-D 
implantation) 
Follow-up Visits 
6 Month  
Office Visit 
(183 days post- 
enrollment  
-30 days/+0 day ) 
12 Month  
Office Visit 
(183 days post- 
6 Month Visit  
-0 day/+30 days) 
Additional Visit 
Informed consent process, including informed 
consent signature and date 
X 
-- 
-- 
-- 
Inclusion and exclusion 
X 
-- 
-- 
-- 
Demographics 
X 
-- 
-- 
-- 
Medical history and medication 
X 
-- 
-- 
-- 
NYHA Class  
X 
X 
X 
-- 
Patient Global Assessment (PGA), Physician 
Global Assessment (PhGA) 
-- 
X 
X 
-- 
Adverse Events Assessment 
X 
X 
X 
X 
HeartLogic Alert (required if the feature is 
enabled) 
X 
X 
X 
-- 
Echo measurement, required only if performed 
by standard of care 
X 
X 
X 
-- 
Device settings and status 
X 
X 
X 
X 
Lead measurements (RA, RV, and LV*) 
X 
X 
X 
O 
SmartDelay test and value, ECG/EGM 
X 
X  
X 
-- 
LV VectorGuide test and value 
X** 
X*** 
X**** 
-- 
RVp-LVs interval test, ECG/EGM 
X 
X 
X 
-- 
SmartVector test and value 
-- 
X (Non-Responder Group 
with LV MSP on) 
X (Non-Responder Group 
with LV MSP on) 
-- 
SmartOffset test and value 
-- 
X (Non-Responder Group 
with LV MSP on) 
X (Non-Responder Group 
with LV MSP on) 
-- 
Battery Consumption 
X 
X  
X 
-- 
LV lead location 
X***** 
-- 
-- 
-- 
Sleep Incline Trend calibration  
X****** 
-- 
-- 
-- 
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Procedure/Assessment 
Enrollment Visit  
(between 1 day and 21 
days post-CRT-D 
implantation) 
Follow-up Visits 
6 Month  
Office Visit 
(183 days post- 
enrollment  
-30 days/+0 day ) 
12 Month  
Office Visit 
(183 days post- 
6 Month Visit  
-0 day/+30 days) 
Additional Visit 
“Save all” device data 
-- 
X******* 
X******* 
-- 
X = Required; -- = Not required/ Not applicable; O = Optional.  
* The LV pacing configuration for lead measurements is per investigator discretion 
** It is required to start the LV VectorGuide test at Enrollment Visit in order to measure the RV-LV intervals; however, it is not required to complete the LV VectorGuide test. 
*** For subjects in the Responder Group, it is required to start the LV VectorGuide test at the 6 Month Visit in order to measure the RV-LV intervals; however, it is not required to 
complete the LV VectorGuide test. For subjects in the Non-Responder Group, LV VectorGuide test is required. 
**** For subjects in the Non-Responder Group who did not receive LV MSP therapy, it is required to start the LV VectorGuide test at the 12 Month Visit in order to measure the 
RV-LV intervals; however, it is not required to complete the LV VectorGuide test. For subjects who received LV MSP therapy, LV VectorGuide test is required. 
***** Required if the LV lead location information is available through imaging or patient’s medical record.  
****** Sleep Incline Trend calibration is not required if the Sleep Incline Sensor is initializing or if the trend is already calibrated prior to this visit. 
******* “Save All” device data collection is only required for subjects not enrolled on LATITUDE Remote Monitoring System. 
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11.2. Study Candidate Screening 
The investigator or designee is responsible for screening potential patients and selecting 
those who meet all inclusion criteria and do not meet any of exclusion criteria. 
11.3. Informed Consent 
Subjects who meet all of the inclusion criteria, none of the exclusion criteria, and sign and 
date the informed consent form are considered enrolled in the study.  
11.4. Enrollment Visit 
The Enrollment Visit may occur at the pre-discharge visit, and must be between 1 day and 21 
days after the CRT-D implantation procedure. Enrollment cannot occur on the same day of 
the implantation procedure. A list of the data to be collected at the Enrollment Visit is 
provided below, with further details included in the sections below.   
• CRT-D indication verification 
• Echo measurement 
• Subject demographics 
• Medical history and medications 
• NYHA class assessment 
• Device and lead information 
• Current device settings and status 
• Lead measurements 
• SmartDelay test and value 
• Asense to Vsense and Apace to Vsense intervals  
• LV VectorGuide test and value 
• RVp-LVs interval test 
• LV lead location (if available) 
• Battery consumption 
• Sleep Incline Trend calibration 
• Final device settings and status 
• Adverse event assessment 
11.4.1. CRT-D Indication Verification 
The following values from the subject’s medical record are required to demonstrate that each 
subject met BSC’s labeled indications prior to their CRT-D implantation: 
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• Most recent Echo measurement of LVEF and date of measurement 
o It is required that the LVEF value be measured no more than 6 months prior to 
the CRT-D implantation. 
o The following measurement will be collected per site’s standard of care 
practice: LVESV, LVEDV, Aortic VTI, and Mitral valve regurgitation.  
• QRS duration 
• Bundle Branch Block morphology (LBBB or non-LBBB) 
• Heart failure etiology (ischemic or non-ischemic) 
• NYHA class value 
• Cardiovascular medications 
11.4.2. Subject Demographics 
Subject’s age, sex, and race/ethnicity are required. 
11.4.3. Medical History and Medication 
Subject’s history of cardiovascular diseases and current cardiovascular medications use are 
required to be collected. 
11.4.4. NYHA Class Assessment 
Obtain the subject’s most recent NYHA Class assessment prior to the CRT-D implantation 
per the definition shown in Table 11.4-1. 
Table 11.4-1: NYHA Classifications5 
 
                                                
5 NYHA Heart Failure Classification by American Heart Association, updated September 28, 2016. 
http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-Heart-
Failure_UCM_306328_Article.jsp#.WLWhqlUrKpo 
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11.4.5. Device Information 
The following are required for the implanted CRT-D device, RA lead, RV lead, and LV lead: 
• Manufacturer 
• Model and serial number 
• Implant date 
11.4.6. Current Device Settings and Status 
Print a copy of the Quick Notes Report from the PRM to document current device settings 
and status prior to conducting any test and changing the programming settings. 
11.4.7. Lead Measurements 
The following lead measurements are required to be collected for the RA lead, RV lead, and 
LV lead: 
• Intrinsic amplitude (mV) 
• Pacing capture threshold (PCT in V; the recommended pulse width is 0.4 ms) 
• Pacing lead impedance (Ω)  
• Shocking lead impedance (Ω, RV lead). 
The following document is required for the RA lead, RV lead, and LV lead measurements: 
• Print a copy of the Quick Notes Report from the PRM 
Lead measurement testing is required unless a rationale is provided. For example, the 
measurement is prohibited by a subject’s condition.  
It is recommended that the PCT measurements be collected in the following fashion:  
• At least 3 cardiac cycles at a given voltage level are obtained before stepping down to 
the next voltage level.  
• A count of two non-capture beats at a given voltage level is reached before declaring 
a loss of capture (LOC) for any of these tests.  
• The pacing configurations used in the LV lead measurement testing are per the 
investigator discretion. At least one configuration must be tested for the LV lead, and 
it is recommended that the tested configuration be the configuration planned for final 
programming.  
It is recommended that the threshold be defined as one voltage level above the level where 
two non-captured beats are observed. If multiple PCT tests were performed, only the final 
measurement is required to be entered on the CRF. 
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11.4.8. SmartDelay Test 
It is required to perform the SmartDelay test for all subjects to obtain programming 
recommendations for the AV Delay and Pacing Chamber. It is per the investigator discretion 
whether to follow the programming recommendations. However, the Pacing Chamber that is 
selected for a subject at the Enrollment Visit must be used for that subject through the 6 
Month Visit (for all subjects) and through the 12 Month Visit (for non-responders). 
The LV offset is required to be set at 0 ms prior to running the SmartDelay test.  
The SmartDelay test nominal Temporary Paced Lower Rate Limit (LRL) is set at 80 bpm. It 
is recommended to set the LRL at 10 to 15 bpm above the subject’s intrinsic heart rate before 
conducting the SmartDelay test.  
The following values from the SmartDelay test are required to be collected: 
• SAV (sensed AV delay) and PAV (paced AV delay), both the recommended and final 
programmed values. 
• Pacing Chamber (BiV or LV Only), both the recommended and final programmed 
values. 
• Rationale if the SmartDelay recommendations are not followed. 
The following documents from the SmartDelay test are required: 
• Set EGM channels to RA, RV, and LV. Obtain ECG/EGM strips at the paper speed of 
100 mm/s for approximately 3-5 representative beats during the Atrial Sense test and 
Atrial Pace test, respectively. The following values are required to be measured from 
the ECG/EGM strips: 
o Asense-RVsense, Asense-LVsense, Apace-RVsense, and Apace-LVsense 
intervals for each of the representative beats 
o Calculate the mean value for each of the 4 intervals from these representative 
beats 
Record the Subject ID and visit information (Enrollment, 6 Month, or 12 Month) on 
each ECG/EGM strip. Copies of all ECG/EGM strip should be submitted to BSC 
quarterly or more frequently, and before study ends. The data collected in this test 
will be used for future product feature enhancement or development, and are not 
associated with the primary and ancillary objectives. A deviation is not required if the 
ECG/EGM strips are not sent to BSC. 
• Print a copy of the Settings Changes Report from the PRM immediately after running 
the SmartDelay test and before any other changes in settings are made and 
programmed. This report will display the recommended changes to the SAV, PAV, 
and Pacing Chamber at pending status. 
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 SmartDelay will display the 
nominal value as the recommended value. The SmartDelay test should be limited to two 
attempts in total. 
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11.4.9. LV VectorGuide Test 
It is required that the RV-LV interval value be measured from all 4 electrodes as cathode 
(LVTip1, LVRing2, LVRing3, and LVRing4) by starting the LV VectorGuide Test; 
however, it is not required to complete all steps of the LV VectorGuide test once the RV-LV 
intervals are collected. If the LV VectorGuide test is completed, provide the number of viable 
pacing vectors (See Section 8.2 for definition of viable pacing vectors). 
Subjects must have RV and LV sensed beats for test to be successful. If the subject does not 
tolerate a low intrinsic heart rate, stop the test and provide the rationale for not completing 
the required test (e.g. subject needs RV pacing support). 
The following values are required to be collected: 
• Select the unipolar vectors and run the RV-LV Delay test for all 4 unipolar vectors to 
obtain RV-LV delay values. 
The following values are required to be collected only if the LV VectorGuide test is 
completed: 
• Number of viable pacing vectors (See definition in Section 8.2) 
The following document is required: 
• Print a copy of the LV VectorGuide Report from the PRM. 
11.4.10. RVp-LVs Interval Test 
The data collected in this section will be used for future product feature enhancement or 
development, and are not associated with the primary and ancillary objectives. A deviation is 
not required if the test is not performed or the ECG/EGM strips are not sent to BSC. 
Set the EGM channels to RA, RV and LV, pacing mode to VVI, LRL to 10 to 15 beats above 
the subject’s intrinsic rate and ventricular pacing chamber to RV Only. Obtain the 
ECG/EGM strips at the paper speed of 100 mm/s for approximately 3-5 representative beats 
in two LV sense vector configurations: LVTip1 to Can and LVRing2 to Can, respectively. 
Record the Subject ID, visit information (Enrollment, 6 Month, or 12 Month), and the 
cathode of the LV sensing configuration (LVTip1 or LVRing2) on each ECG/EGM strip. 
Copies of all ECG/EGM strip should be submitted to BSC quarterly or more frequently, and 
before study ends.  
11.4.11. LV Lead Location 
The coronary venous LV lead location is required to be collected if the location information 
is available; such information would typically be available by reviewing lead imaging 
documents including in-procedure fluoroscopy or pre-discharge chest X-rays, or obtained 
from the subject’s medical record.  
The LV lead location is required to be classified and recorded in the eCRF as follows: 
• Anterior, anterolateral, lateral, posterolateral, or posterior 
and 
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• Basal, Middle, or Apical 
11.4.12. Battery Consumption 
The following values are required to be collected: 
• Time to explant 
• Charge Remaining 
11.4.13. Sleep Incline Trend Calibration 
The Sleep Incline Trend of the CRT-D device will be calibrated at Enrollment Visit. 
Calibration is not required if the Sleep Incline Sensor is initializing or if the trend is already 
calibrated prior to this visit. The data collected in this section will be used for future product 
feature enhancement or development, and are not associated with the primary and ancillary 
objectives. A deviation is not required if the calibration is not performed.  
11.4.14. Final Device Settings and Status 
Print a copy of the Device Settings Report from the PRM for all subjects at the Enrollment 
Visit and clear the device counters as the final step. Record whether the HeartLogic feature 
(Heart Failure Sensor Suite) is enabled in the CRT-D device and whether the HeartLogic 
Alert is programmed ON via the LATITUDE system. All subjects at the Enrollment Visit are 
required to receive conventional CRT therapy and have the LV MSP feature programmed 
off. All other programming settings are per investigator discretion. 
11.4.15. Adverse Event Assessment 
Study required adverse event data will be collected and assessed for each subject after 
signing of the informed consent. See Section 20 for Adverse Event collection and reporting 
requirements. 
A summary of the source documentation required at the Enrollment Visit is described in 
Table 11.4-2.  
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Table 11.4-2: Source Documentation Required at Enrollment Visit 
Source Documentation Requirement 
Disposition 
Informed consent form and process, including informed 
consent signature and date 
Retain at study site 
Inclusion and exclusion criteria 
Cardiovascular disease history and medication 
NYHA class assessment 
Device and lead information 
Adverse event assessment 
Device Settings Report, Quick Notes Report, LV 
VectorGuide Report, Settings Changes Report 
Echo measurement, if performed per standard of care 
Manually recorded Charge Remaining 
ECG/EGM Strips from the SmartDelay test 
Retain at study site 
Submit 1 copy to BSC 
ECG/EGM Strips from the RVp-LVs interval  test 
 
11.5. 6 Month Visit 
The 6 Month Visit must be performed in office at 183 -30 days/+0 day post-Enrollment Visit. 
A list of the data to be collected at the 6 Month Visit is provided below, with further details 
included in the sections below.   
• NYHA class assessment 
• Patient Global Assessment 
• Physician Global Assessment 
• HF event 
• Response status determination 
• Echo measurement 
• Current device setting and status 
• Lead measurements 
• LV VectorGuide test and value 
• RVp-LVs interval test 
• SmartDelay test and value 
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• Asense to Vsense and Apace to Vsense intervals 
• SmartVector and SmartOffset value 
• Battery consumption 
• Final device settings and status 
• Adverse event assessment 
• HeartLogic Alert  
• “Save All” device data 
11.5.1. Definition and Components of the Clinical Composite Score 
The CCS will be calculated for all subjects at the 6 Month Visit. The CCS consists of the 
following components: 
• All-cause mortality 
• Heart Failure (HF) event 
• Patient Global Assessment (PGA) 
• NYHA class 
11.5.1.1. HF Event Definition 
For the purpose of the CCS calculation, HF event is defined as an adverse event with a 
primary cause of HF and either of the conditions below is met: 
• Subject is admitted and discharged with a calendar date change. 
• Subject is not hospitalized but received one or more IV medications including 
diuretics, inotropes, vasodilators, other parenteral therapy, or aquapheresis. 
11.5.1.2. PGA Classification  
Interpretation of no change status in PGA is defined as the following: 
• A little better, no change, and a little worse.  
Per CCS definition, a little better and a little worse are considered placebo effect and are 
treated as no change in PGA status.  
The investigator will use the subject’s response to the PGA and classify response of “a little 
better”, “no change”, or “a little worse” to the category of “no change”. Subsequently, the 
investigator will use “very much better”, “much better”, “no change”, “much worse”, and 
“very much worse” to determine the status of PGA changes. 
See Table 11.5-1 for a detailed description of the PGA assessment tool. 
11.5.1.3. NYHA Class Assessment 
See Section 11.4.4 for a detailed description of performing NYHA Class assessment.  
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11.5.1.4. CCS Status Classification 
Subjects will be classified as improved, unchanged, or worsened by comparing their clinical 
response in the current visit to their last visit. At the 6 Month Visit, subjects’ status will be 
compared to their status immediately prior to receiving the CRT-D implantation. The 
following criteria will be used:  
• Improved: Subjects are considered improved if they experienced a favorable change 
in at least one NYHA functional class or in the PGA (or both) while remaining alive 
and free of HF event comparing to their status in the Enrollment Visit. See Table 
11.5-1 on selecting improved PGA status. 
• Worsened: Subjects are considered worsened if any of the followings occurs: 
o died (from any cause) or  
o experienced an HF event or  
o reported worsening of at least one NYHA functional class or  
o reported worsening of the PGA comparing to their status immediately prior to 
receiving the CRT-D implantation. See Table 11.5-1 on selecting worsened 
PGA status. 
• Unchanged: Subjects are considered unchanged if they are neither improved nor 
worsened. 
11.5.2. NYHA Class 
NYHA Class assessment shall be performed by a site staff who is blinded to the study 
design, subject’s clinical status in the study, and the programmed device settings. The 
subject’s current NYHA Class must be determined based on Table 11.4-1.  
11.5.3. Patient Global Assessment 
The current PGA must be filled out by the subject, as specified in the assessment tool in 
Table 11.5-1. 
11.5.4. Physician Global Assessment 
The current Physician Global Assessment (PhGA) will be filled out by the 
investigator/delegated site staff based on the evaluation of the subject’s status from multiple 
clinical aspects. A comparison of the assessment tool for the PGA and PhGA is shown in 
Table 11.5-1. 
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Table 11.5-1: Comparison of the Global Assessment Tool: Patient Global Assessment 
(PGA) and Physician Global Assessment (PhGA) 
 
11.5.5. Response Status Determination 
Based on subject’s vital status, NYHA class, PGA, and occurrence of HF event, the 
investigator/delegated site staff will classify each subject to either responder or non-
responder per the following criteria: 
• Responder: subjects with an Improved CCS score 
• Non-Responder: subjects with a Worsened or unchanged CCS score 
The PhGA will not be used in classifying the subject response status. Responders will 
complete the study at the end of their 6 Month Visit based on the CCS status collected on the 
6 Month Visit eCRF.  
All reported hospitalizations and events that meet the definition of HF events will be 
adjudicated by the Clinical Events Committee (CEC) for relatedness to the heart failure. A 
subject with any hospitalization or IV therapy reported in the first 6 months will continue to 
be followed as a non-responder, regardless of the CCS. If the CEC determines that the event 
is not an HF event and the subject belongs to the Responder Group, the subject will be exited 
prior to the 12 Month Visit and excluded from the analysis for the non-responders.  
Non-responders will continue to be followed in the study via the Non-Responder Group. 
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11.5.6. Echocardiography Measurement 
If an echocardiography was performed by the standard of care since last visit, collect the 
subject’s most recently obtained echo values and the date of measurement. 
• LVEF 
• LVESV 
• LVEDV 
• Aortic VTI 
• Mitral Valve Regurgitation 
11.5.7. Current Device Settings and Status 
Print a copy of the Quick Notes Report from the PRM to document current device settings 
and status prior to conducting any test and changing the programming settings. A list of 
settings and status, including but not limited to the SmartDelay settings, percent of pacing 
(%RA paced, % RV paced, %LV paced), and percent of AT/AF (%AT/AF) are required to 
be collected. 
11.5.8. Lead Measurements 
The following lead measurements are required to be collected for the RA lead, RV lead, and 
LV lead: 
• Intrinsic amplitude (mV) 
• Pacing capture threshold (PCT in V; the recommended pulse width is 0.4 ms) 
• Pacing lead impedance (Ω)  
• Shocking lead impedance (Ω, RV lead) 
The following document is required for the RA lead, RV lead, and LV lead measurements: 
• Print a copy of the Quick Notes Report from the PRM. 
Lead measurement testing is required unless a rationale is provided. For example, the 
measurement is prohibited by a subject’s condition.  
It is recommended that the PCT measurements be collected in the following fashion:  
• At least 3 cardiac cycles at a given voltage level are obtained before stepping down to 
the next voltage level.  
• A count of two non-capture beats at a given voltage level is reached before declaring 
a loss of capture (LOC) for any of these tests.  
It is recommended that the threshold be defined as one voltage level above the level where 
two non-captured beats are observed. If multiple PCT tests were performed, only the final 
measurement is required to be entered on the CRF. 
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11.5.9. LV VectorGuide Test 
At the 6 Month Visit, the VectorGuide test should be performed prior to performing the 
SmartDelay test by selecting the VectorGuide test under the Test tab from the main 
programmer screen. 
Responder Group 
For subjects classified in the Responder Group, it is required that the RV-LV interval value 
be measured from all 4 electrodes as cathode (LVTip1, LVRing2, LVRing3, and LVRing4) 
by starting the LV VectorGuide test; however, it is not required to complete all steps of the 
LV VectorGuide test once the RV-LV intervals are collected. If the LV VectorGuide test is 
completed, also provide the number of viable pacing vectors. 
Subjects must have RV and LV sensed beats for the test to be successful. If the subject does 
not tolerate a low intrinsic heart rate, stop the test and provide the rationale for not 
completing the required test (e.g. subject needs RV pacing support). 
The following values are required to be collected in the Responder Group: 
• Select the unipolar vectors and run the RV-LV Delay test for all 4 unipolar vectors to 
obtain RV-LV delay values. 
The following values are required to be collected only if the LV VectorGuide test is 
completed: 
• Number of viable pacing vectors (See definition in Section 8.2) 
The following document is required in the Responder Group: 
• Print a copy of the LV VectorGuide Report from the PRM.  
Non-Responder Group 
For subjects classified in the Non-Responder Group, it is required to use the LV VectorGuide 
to assess viable LV pacing vectors from all 17 pacing vectors.  
For all 17 pacing vectors, the following values are required to be collected for subjects in the 
Non-Responder Group: 
• RV-LV delay  
• LV pacing impedance  
• PNS test results 
• LV Quick Capture threshold test 
• Number of viable pacing vectors (See definition in Section 8.2) 
The following document is required for subjects in the Non-Responder Group: 
• Print a copy of the LV VectorGuide Report from the PRM. 
For subjects classified in the Non-Responder Group, the LV pacing vectors will be 
recommended by the required SmartVector test; however, since it is not required to follow 
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the recommendation from the SmartVector, final pacing vectors are per the investigator 
discretion. 
LV MSP Status in Non-Responder Group 
Subjects who have at least 2 viable pacing vectors identified using the LV VectorGuide test 
or determined by the investigator will have the LV MSP feature turned on.  
Subjects who do not have at least 2 viable pacing vectors identified will continue to be 
followed in the study but will not have the LV MSP feature turned on due to lacking of 2 
viable pacing vectors. 
11.5.10. RVp-LVs Interval Test 
The data collected in this section will be used for future product feature enhancement or 
development, and are not associated with the primary and ancillary objectives. A deviation is 
not required if the test is not performed or the ECG/EGM strips are not sent to BSC. 
Set the EGM channels to RA, RV and LV, pacing mode to VVI, LRL to 10 to 15 beats above 
the subject’s intrinsic rate and ventricular pacing chamber to RV Only. Obtain the 
ECG/EGM strips at the paper speed of 100 mm/s for approximately 3-5 representative beats 
in two LV sense vector configurations: LVTip1 to Can and LVRing2 to Can, respectively. 
Record the Subject ID, visit information (Enrollment, 6 Month, or 12 Month), and the 
cathode of the LV sensing configuration (LVTip1 or LVRing2) on each ECG/EGM strip. 
Copies of all ECG/EGM strip should be submitted to BSC quarterly or more frequently, and 
before study ends.  
11.5.11. SmartDelay Test 
It is required to perform the SmartDelay test for all subjects to obtain programming 
recommendations for the AV Delay and Pacing Chamber. It is per the investigator discretion 
whether to follow the programming recommendations. However, the Pacing Chamber that is 
selected for a subject at the Enrollment Visit must be used for that subject through the 6 
Month Visit (all subjects) or through the 12 Month Visits (for non-responders). For subjects 
in the Responder Group, there is no requirement to keep the same Pacing Chamber as these 
subjects are completing the study at the end of the 6 Month Visit. 
The LV offset is required to be set at 0 ms prior to running the SmartDelay test. For non-
responders, it is recommended that the LV pacing vector is set to a viable vector (from the 
LV VectorGuide test) with the longest RV-LV delay before running the SmartDelay test.   
The SmartDelay test nominal Temporary Paced Lower Rate Limit (LRL) is set at 80 bpm. It 
is recommended to set the LRL at 10 to 15 bpm above the subject’s intrinsic heart rate before 
conducting the SmartDelay test.  
The following values from the SmartDelay test are required to be collected: 
• SAV and PAV, both the recommended and final programmed values. 
• Pacing Chamber (BiV or LV Only), both the recommended and final programmed 
values. 
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• Rationale if the SmartDelay recommendations are not followed. 
The following documents from the SmartDelay test are required: 
• Set EGM channels to RA, RV, and LV. Obtain ECG/EGM strips at the paper speed of 
100 mm/s for approximately 3-5 representative beats during the Atrial Sense test and 
Atrial Pace test, respectively. The following values are required to be measured from 
the ECG/EGM strips: 
o Asense-RVsense, Asense-LVsense, Apace-RVsense, and Apace-LVsense 
intervals for each of the representative beats 
o Calculate the mean value for each of the 4 intervals from these representative 
beats  
Record the Subject ID and visit information (Enrollment, 6 Month, or 12 Month) on 
each ECG/EGM strip. Copies of all ECG/EGM strip should be submitted to BSC 
quarterly or more frequently, and before study ends. The data collected in this test 
will be used for future product feature enhancement or development, and are not 
associated with the primary and ancillary objectives. A deviation is not required if the 
ECG/EGM strips are not sent to BSC. 
• Print a copy of the Settings Changes Report from the PRM immediately after running 
the SmartDelay test and before any other setting changes are made and programmed. 
This report will display the recommended changes to the SAV, PAV, and Pacing 
Chamber at pending status. 
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. The SmartDelay test should be limited to two attempts in 
total.  
11.5.12. SmartVector Operation (Non-Responders with LV MSP on) 
For subjects who will receive the LV MSP therapy, it is required to use SmartVector to 
obtain recommendations for LVa and LVb pacing vectors after performing the LV 
VectorGuide tests. It is recommended to use the pacing vectors recommended by the 
SmartVector test; however, final selection of the 2 pacing vectors is per investigator 
discretion. 
The following values are required to be collected for subjects who have the LV MSP turned 
on: 
• The pacing configuration of LVa and LVb, both the recommended and final 
programmed vectors. 
• Rationale if the SmartVector recommendations are not followed. 
The following document is required for subjects who have the LV MSP on: 
• Print a copy of the Settings Changes Report from the PRM before setting changes are 
made and programmed to show the recommended changes to the LVa and LVb 
vectors. 
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11.5.13. SmartOffset Operation (Non-Responders with LV MSP on) 
For subjects who will receive the LV MSP therapy, it is required to use SmartOffset to obtain 
recommendations for the offset value between LVa, LVb, and RV. It is recommended to use 
the offset provided by the SmartVector operation; however, the final programmed offset is 
per investigator’s discretion.  
The following values are required to be collected for Non-Responders with the LV MSP 
turned on: 
• Offset from LVa to LVb to RV, both recommended and final programmed. 
• Offset from LVa to LVb if LV only pacing is programmed, both recommended and 
final programmed. 
• Rationale if the SmartOffset recommendations are not followed. 
The following document is required to be collected for Non-Responders with the LV MSP 
turned on: 
• Print a copy of the Settings Changes Report from the PRM before setting changes are 
made and programmed to show the recommended changes to the offset. 
11.5.14. LV MSP Settings Programming 
Complete the programming of the LV MSP settings for subjects in the Non-Responder 
Group who have the LV MSP on. It is required that the LV MSP feature be turned on from 
the 6 Month Visit to the 12 Month Visit. The investigator may consider turning off the LV 
MSP feature if a subject experiences worsening symptoms. The subject may continue to 
receive conventional CRT. A rationale and study deviation are required if the LV MSP 
feature is turned off. 
11.5.15. Battery Consumption 
The following values are required to be collected: 
• Time to explant 
• Charge Remaining 
11.5.16. Final device settings and status 
Print a copy of the Device Settings Report from the PRM for all subjects at the 6 Month Visit 
and clear the device counters as the final step. For non-responder subjects with at least 2 
viable LV pacing vectors, it is required to turn on the LV MSP feature. The pacing chamber 
(BiV or LV only) is required to be the same as determined at the Enrollment Visit. All other 
programming settings are per investigator discretion. 
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11.5.17. Adverse Event Assessment 
Study required adverse event data will be collected and assessed for each subject. 
Hospitalization records are required to be sent to BSC. See Section 20 for Adverse Event 
collection and reporting requirements.  
11.5.18. HeartLogic Alert  
The HeartLogic Alert feature is newly available in the Resonate family of devices. If the 
HeartLogic Alert feature is turned on, then the HeartLogic Alert(s) that resulted in a change 
in the subject’s medical treatment will be collected. 
11.5.19. “Save All” Device Data 
Device data is required to be downloaded on a USB disk using “Save All” method if the 
subject is not enrolled in the LATITUDE Remote Monitoring System. Downloading the data 
requires ending the PRM session with the device. Hence, it is recommended to complete all 
other study activities that require PRM-device communication prior to this step. For subjects 
enrolled in the LATITUDE Remote Monitoring System, device data will be transmitted to 
BSC automatically on a regular basis and do not require manual download. 
The original USB disk will be retained at the site and a copy of the disk should be submitted 
to BSC quarterly or more frequently. Label the Subject ID and visit information (6 Month or 
12 Month) on both USB disks. The data collected in this section will be used for future 
product feature enhancement or development, and are not associated with the primary and 
ancillary objectives. A deviation is not required if the “Save All” USB disk is not performed 
or submitted to BSC. 
A summary of the source documentation required at the 6 Month Visit is described in Table 
11.5-2.  
Table 11.5-2: Source Documentation Requirement at the 6 Month Visit 
Source Documentation Requirement 
Disposition 
NYHA class assessment 
Retain at study site 
Patient Global Assessment 
Physician Global Assessment 
Adverse event assessment 
Device Settings Report, Settings Changes Report, Quick 
Notes Report, LV VectorGuide Report 
Hospitalization record 
Echo measurement, if performed per standard of care 
Manually recorded Charge Remaining 
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Source Documentation Requirement 
Disposition 
ECG/EGM Strips from the SmartDelay test 
Retain at study site 
Submit 1 copy to BSC 
ECG/EGM Strips from the RVp-LVs interval test 
“Save All” device data on USB disk, if applicable 
 
11.6. 12 Month Visit 
The 12 Month Visit must be performed in office at 183 -0 day/+30 days post-6 Month Visit 
for subjects who were classified in the Non-Responder Group at the 6 Month Visit. A list of 
the data to be collected at the 12 Month Visit is provided below, with further details included 
in the sections below.   
• NYHA class assessment 
• Patient Global Assessment 
• Physician Global Assessment 
• HF Event 
• Response status determination 
• Echo measurement 
• Current device setting and status 
• Lead measurements 
• SmartDelay test and value 
• Asense to Vsense and Apace to Vsense intervals 
• LV VectorGuide test and value 
• RVp-LVs interval test 
• SmartVector and SmartOffset value 
• Battery consumption 
• Final device settings and status 
• Adverse event assessment 
• HeartLogic Alert  
•  “Save All” device data 
11.6.1. Definition and Components of the Clinical Composite Score 
The CCS will be calculated for all subjects at the 12 Month Visit. The CCS consists of the 
following components: 
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• All-cause mortality 
• Heart Failure (HF) event 
• Patient Global Assessment (PGA) 
• NYHA class 
11.6.1.1. HF Event Definition 
For the purpose of the CCS calculation, HF event is defined as an adverse event with a 
primary cause of HF and either of the conditions below is met: 
• Subject is admitted and discharged with a calendar date change. 
• Subject is not hospitalized but received one or more IV medications including 
diuretics, inotropes, vasodilators, other parenteral therapy, or aquapheresis. 
11.6.1.2. PGA Classification  
Interpretation of no change status in PGA is defined as the following: 
• A little better, no change, and a little worse.  
Per CCS definition, a little better and a little worse are considered as placebo effect and are 
treated as no change. 
The investigator will use the subject’s response to the PGA and classify response of “a little 
better”, “no change”, or “a little worse” to the category of “no change”. Subsequently, the 
investigator will use “very much better”, “much better”, “no change”, “much worse”, and 
“very much worse” to determine the status of PGA changes. 
11.6.1.3. NYHA Class Assessment 
See Section 11.4.4 for a detailed description of performing NYHA Class assessment.  
11.6.1.4. CCS Status Classification 
Subjects will be classified as improved, unchanged, or worsened by comparing their clinical 
response in the current visit to their last visit. At the 12 Month Visit, subjects’ status will be 
compared to their status at the 6 Month Visit. The following criteria will be used:  
• Improved: Subjects are considered improved if they experienced a favorable change 
in at least one NYHA functional class or in the PGA (or both) while remaining alive 
and free of HF event comparing to their status in the 6 Month Visit. See Table 11.5-1 
on selecting improved PGA status. 
• Worsened: Subjects are considered worsened if any of the followings occurs: 
o died (from any cause) or  
o experienced a HF event or  
o reported worsening of at least one NYHA functional class or  
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o reported worsening of the PGA comparing to their status in the 6 Month Visit. 
See Table 11.5-1 on selecting worsened PGA status. 
• Unchanged: Subjects are considered unchanged if they are neither improved nor 
worsened. 
11.6.2. NYHA Class 
NYHA Class assessment shall be performed by a site staff who is blinded to the study 
design, subject’s clinical status in the study, and the programmed device settings. The 
subject’s current NYHA Class must be determined based on Table 11.4-1.  
11.6.3. Patient Global Assessment 
The current PGA must be filled out by the subject, as specified in the assessment tool in 
Table 11.5-1. 
11.6.4. Physician Global Assessment 
The current Physician Global Assessment (PhGA) will be filled out by the 
investigator/delegated site staff based on the evaluation of the subject’s status from multiple 
clinical aspects. A comparison of the assessment tool for the PGA and PhGA is shown in 
Table 11.5-1. 
11.6.5. Response Status Determination 
Based on the subject’s vital status, NYHA class, PGA, and occurrence of HF event, the 
investigator/delegated site staff will classify each subject in the Non-Responder Group to be 
either a responder or a non-responder per the following criteria: 
• Responder: subjects with an Improved CCS score 
• Non-Responder: subjects with a Worsened or unchanged CCS score 
The PhGA will not be used in classifying the subject response status. All subjects in the Non-
Responder Group will complete the study at the end of their 12 Month Visit.  
All reported hospitalization and events that meet the definition of HF event will be 
adjudicated by the Clinical Events Committee (CEC) for relatedness to the heart failure. 
11.6.6. Echocardiography Measurement 
If an echocardiography was performed by the standard of care since last visit, collect the 
subject’s most recently obtained echo values and the date of measurement. 
• LVEF 
• LVESV 
• LVEDV 
• Aortic VTI 
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• Mitral Valve Regurgitation 
11.6.7. Current Device Settings and Status 
Print a copy of the Quick Notes Report from the PRM to document current device settings 
and status prior to conducting any test and changing the programming settings. A list of 
settings and status, including but not limited to the SmartDelay settings, percent of pacing 
(%RA paced, % RV paced, %LVa paced, and %LVb paced), and percent of AT/AF 
(%AT/AF) are required to be collected. 
The investigator may have turned off the LV MSP feature if a subject experienced worsening 
symptoms prior to the 12 Month Visit. A rationale and study deviation are required if the LV 
MSP feature is turned off prior to the 12 Month Visit. 
11.6.8. Lead Measurements 
The following lead measurements are required to be collected for the RA lead, RV lead, and 
LV lead: 
• Intrinsic amplitude (mV) 
• Pacing capture threshold (PCT in V; the recommended pulse width is 0.4 ms) 
• Pacing lead impedance (Ω)  
• Shocking lead impedance (Ω, RV lead) 
The following document is required for the RA lead, RV lead, and LV lead measurements: 
• Print a copy of the Quick Notes Report from the PRM. 
Lead measurement testing is required unless a rationale is provided. For example, the 
measurement is prohibited by a subject’s condition.  
It is recommended that the PCT measurements be collected in the following fashion:  
• At least 3 cardiac cycles at a given voltage level are obtained before stepping down to 
the next voltage level.  
• A count of two non-capture beats at a given voltage level is reached before declaring 
a loss of capture (LOC) for any of these tests.  
It is recommended that the threshold be defined as one voltage level above the level where 
two non-captured beats are observed. If multiple PCT tests were performed, only the final 
measurement is required to be entered on the CRF. 
11.6.9. SmartDelay Test 
It is required to perform the SmartDelay test for all subjects to obtain programming 
recommendations for the AV Delay and Pacing Chamber. It is per the investigator discretion 
whether to follow the programming recommendations. The pacing chamber is selected for 
the subject at the Enrollment Visit. There is no requirement to keep the same pacing chamber 
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at the end of the 12 Month Visit as all subjects in the Non-Responder Group will complete 
the study at their 12 Month Visit. 
The LV offset is required to be set at 0 ms prior to running the SmartDelay test.  
The SmartDelay test nominal Temporary Paced Lower Rate Limit (LRL) is set at 80 bpm. It 
is recommended to set the LRL at 10 to 15 bpm above the subject’s intrinsic heart rate before 
conducting the SmartDelay test.  
The following values from the SmartDelay test are required to be collected: 
• SAV and PAV, both the recommended and final programmed values. 
• Pacing Chamber (BiV or LV Only), both the recommended and final programmed 
values. 
• Rationale if the SmartDelay recommendations are not followed 
The following documents from the SmartDelay test are required: 
• Set EGM channels to RA, RV, and LV. Obtain ECG/EGM strips at the paper speed of 
100 mm/s for approximately 3-5 representative beats during the Atrial Sense test and 
Atrial Pace test, respectively. The following values are required to be measured from 
the ECG/EGM strips: 
o Asense-RVsense, Asense-LVsense, Apace-RVsense, and Apace-LVsense 
intervals for each of the representative beats 
o Calculate the mean value for each of the 4 intervals from these representative 
beats  
Record the Subject ID and visit information (Enrollment, 6 Month, or 12 Month) on 
each ECG/EGM strip. Copies of all ECG/EGM strip should be submitted to BSC 
quarterly or more frequently, and before study ends. The data collected in this test 
will be used for future product feature enhancement or development, and are not 
associated with the primary and ancillary objectives. A deviation is not required if the 
ECG/EGM strips are not sent to BSC. 
• Print a copy of the Settings Changes Report from the PRM immediately after running 
the SmartDelay test and before any other setting changes are made and programmed. 
This report will display the recommended changes to the SAV, PAV, and Pacing 
Chamber at pending status. 
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. The SmartDelay test should be limited to two attempts in 
total.  
11.6.10. LV VectorGuide Test 
Non-Responder Group with No LV MSP  
For Non-Responder Group subjects who did not receive the LV MSP therapy, it is required 
that the RV-LV interval value be measured from all 4 electrodes as cathode (LVTip1, 
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LVRing2, LVRing3, and LVRing4) by starting the LV VectorGuide test; however, it is not 
required to complete all steps of the LV VectorGuide test once the RV-LV intervals are 
collected. If the LV VectorGuide test is completed, also provide the number of viable pacing 
vectors. 
Subjects must have RV and LV sensed beats for the test to be successful. If the subject does 
not tolerate a low intrinsic heart rate, stop the test and provide the rationale for not 
completing the required test (e.g. subject needs RV pacing support). 
The following values are required to be collected in the Non-Responder Group: 
• Select the unipolar vectors and run the RV-LV Delay test for all 4 unipolar vectors to 
obtain RV-LV delay values. 
The following values are required to be collected only if the LV VectorGuide test is 
completed: 
• Number of viable pacing vectors (See definition in Section 8.2) 
The following document is required in the Non-Responder Group: 
• Print a copy of the LV VectorGuide Report from the PRM.  
Non-Responder Group with LV MSP on 
For subjects with the LV MSP turned on, it is required to use the LV VectorGuide test to 
assess viable LV pacing vectors from all 17 pacing vectors.  
For all 17 pacing vectors, the following values are required to be collected for subjects in the 
Non-Responder Group: 
• RV-LV delay  
• LV pacing impedance  
• PNS test results 
• LV Quick Capture threshold test 
• Number of viable pacing vectors (See definition in Section 8.2) 
The following document is required for subjects with the LV MSP on: 
• Print a copy of the LV VectorGuide Report from the PRM. 
11.6.11. RVp-LVs Interval Test 
The data collected in this section will be used for future product feature enhancement or 
development, and are not associated with the primary and ancillary objectives. A deviation is 
not required if the test is not performed or the ECG/EGM strips are not sent to BSC. 
Set the EGM channels to RA, RV and LV, pacing mode to VVI, LRL to 10 to 15 beats above 
the subject’s intrinsic rate and ventricular pacing chamber to RV Only. Obtain the 
ECG/EGM strips at the paper speed of 100 mm/s for approximately 3-5 representative beats 
in two LV sense vector configurations: LVTip1 to Can and LVRing2 to Can, respectively. 
Record the Subject ID, visit information (Enrollment, 6 Month, or 12 Month), and the 
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cathode of the LV sensing configuration (LVTip1 or LVRing2) on each ECG/EGM strip. 
Copies of all ECG/EGM strip should be submitted to BSC quarterly or more frequently, and 
before study ends.  
11.6.12. SmartVector Operation 
For subjects who receive the LV MSP therapy, it is required to use SmartVector to obtain 
recommendations for the LVa and the LVb pacing vectors after performing the LV 
VectorGuide tests. It is recommended to use the pacing vectors recommended by 
SmartVector test; however, final selection of the 2 pacing vectors is per investigator 
discretion.  
The following values are required to be collected for subjects who have the LV MSP turned 
on: 
• The pacing configuration of LVa and LVb, both recommended and final programmed 
vectors. 
• Rationale if the SmartVector recommendations are not followed 
The following document is required to be collected for subjects who have the LV MSP 
turned on: 
• Print a copy of the Settings Changes Report from the PRM before setting changes are 
made and programmed to show the recommended changes to the LVa and LVb 
vector. 
11.6.13. SmartOffset Operation 
For subjects who receive the LV MSP therapy, it is required to use SmartOffset to obtain 
recommendations for the offset value between LVa, LVb, and RV. It is recommended to use 
the offset recommended by the SmartVector operation; however, the final programmed offset 
is per investigator discretion.  
The following values are required to be collected for subjects who have the LV MSP turned 
on: 
• Offset from LVa to LVb to RV, both recommended and final programmed. 
• Offset from LVa to LVb if LV only pacing is programmed, both recommended and 
final programmed. 
• Rationale if the SmartOffset recommendations are not followed 
The following document is required to be collected for subjects who have the LV MSP 
turned on: 
• Print a copy of the Settings Changes Report from the PRM before setting changes are 
made and programmed to show the recommended changes to the offset. 
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11.6.14. LV MSP Settings Programming 
At the end of the 12 Month Visit, programming the device to the LV MSP feature for all 
subjects is per investigator discretion. 
11.6.15. Battery Consumption 
The following values are required to be collected: 
• Time to explant 
• Charge Remaining 
11.6.16. Final device settings and status 
Print a copy of the Device Settings Report from the PRM for all subjects at the 12 Month 
Visit. Final programming at the 12 Month Visit is per investigator discretion. 
11.6.17. Adverse Event Assessment 
Study required adverse event data will be collected and assessed for each subject. 
Hospitalization records are required to be sent to BSC. See Section 20 for Adverse Event 
collection and reporting requirements. 
11.6.18. HeartLogic Alert  
The HeartLogic Alert feature is newly available in the Resonate family of devices. If the 
HeartLogic Alert feature is turned on, then the HeartLogic Alert(s) that resulted in a change 
in the subject’s medical treatment will be collected. 
11.6.19. “Save All” Device Data 
Device data is required to be downloaded on a USB disk using “Save All” method if the 
subject is not enrolled in the LATITUDE Remote Monitoring System. Downloading the data 
requires ending the PRM session with the device. Hence, it is recommended to complete all 
other study activities that require PRM-device communication prior to this step. For subjects 
enrolled in the LATITUDE Remote Monitoring System, device data will be transmitted to 
BSC automatically on a regular basis and do not require manual download. 
The original USB disk will be retained at the site and a copy of the disk should be submitted 
to BSC quarterly or more frequently. Label the Subject ID and visit information (6 Month or 
12 Month) on both USB disks. The data collected in this section will be used for future 
product feature enhancement or development, and are not associated with the primary and 
ancillary objectives. A deviation is not required if the “Save All” USB disk is not performed 
or submitted to BSC. 
A summary of the source documentation required at the 12 Month Visit is described in Table 
11.6-1.  
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Table 11.6-1: Source Documentation Requirement at the 12 Month Visit 
Source Documentation Requirement 
Disposition 
NYHA class assessment 
Retain at study site 
Patient Global Assessment 
Physician Global Assessment 
Adverse event assessment 
Device Settings Report, Settings Changes Report, Quick 
Notes Report, LV VectorGuide Report  
Hospitalization record 
Echo measurement, if performed per standard of care 
Manually recorded Charge Remaining 
ECG/EGM Strips from the SmartDelay test 
Retain at study site 
Submit 1 copy to BSC 
ECG/EGM Strips from the RVp-LVs interval test 
“Save All” device data USB disk, if applicable 
 
11.7. Additional Visit 
An Additional Visit is required to be completed when the device is interrogated and any of 
the following programming settings have been permanently changed: 
• Any time the device counter is reset 
o Date the counter is reset 
o Percent of LV pacing prior to resetting the counter in subjects receiving either 
conventional CRT or LV MSP pacing. 
• AV delay 
• Pacing chamber (BiV pacing or LV only pacing) 
• LV Offsets 
• The LV pacing configuration selected at the Enrollment Visit 
• The 2 pacing vectors selected for the LV MSP at the 6 Month Visit  
• SmartOffset  
• Pacing mode (e.g. DDD, VVI) 
• LRL 
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• LV MSP programming change (On or Off) 
A rationale for the setting changes is required. A deviation is required if the changes in 
programming settings are not per the protocol requirement. 
The following documents are required: 
• Print a copy of the Settings Changes Report from the PRM. 
• Print a copy of the Device Settings Report from the PRM. 
Lead measurement is optional at this visit. 
11.7.1. Adverse Event Assessment 
Study required adverse event data will be collected and assessed for each subject. 
Hospitalization records are required to be sent to BSC. See Section 20 for Adverse Event 
collection and reporting requirements. 
A summary of the source documentation required at the Additional Visit is described in 
Table 11.7-1.  
Table 11.7-1: Source Documentation Requirement at Additional Visit 
Source Documentation Requirement 
Disposition 
Settings Changes Report, Device Settings Report 
Retain at study site 
Adverse event assessment 
 
11.8. Study Completion 
All subjects will be followed until the completion of their required last visit, death, or 
withdrawal if it occurs prior to the last required visit. For subjects in the Responder Group, 
their last visit is the 6 Month Visit; for subjects in the Non-Responder Group, their last visit 
is the 12 Month Visit, regardless if the LV MSP feature was turned on or not. Upon 
completion of participation in the study, subjects will be followed per normal standard of 
care. 
12. Statistical Considerations 
12.1. SMART MSP Study Endpoints 
12.1.1. Primary Safety Endpoint: LV MSP feature-related complication-free rate 
The primary safety endpoint will be assessed for all non-responder subjects with the LV MSP 
on for any duration between the 6 Month Visit and the 12 Month Visit. 
Safety will be confirmed by evaluating the LV MSP feature-related complication-free rate 
(CFR) between the 6 Month Visit and 12 Month Visit. For the purpose of this endpoint, an 
LV MSP feature-related complication will be defined as those complications that are 
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determined as “yes, related” or “possibly related” to the LV MSP feature and will count 
against this endpoint. These may include but are not limited to: 
• Ventricular Tachyarrhythmia/Ventricular Fibrillation (VT/VF) 
• Loss of Capture (LOC)  
• Phrenic Nerve Stimulation (PNS) 
• Worsening HF 
12.1.1.1. Hypotheses 
The following hypotheses will be used to evaluate the Primary Safety Endpoint: 
H0: LV MSP feature-related complication-free rate between 6 Month Visit and 12 
Month Visit ≤ 90%  
HA: LV MSP feature-related complication-free rate between 6 Month Visit and 12 
Month Visit > 90%. 
The performance goal is set at 90%, which is consistent with other product features 
undergoing FDA evaluation6. 
12.1.1.2. Sample Size  
The overall study sample size of 586 subjects is driven by the primary effectiveness 
endpoint. For further details on overall sample size and attrition see Section 12.3. The 
sample size of 61 subjects is required to evaluate the Primary Safety Endpoint. Since a power 
calculation cannot be directly calculated for a one group Kaplan-Meier analysis, an exact test 
was used. A power calculation using a sample size of 61 subjects as the non-responders with 
the LV MSP on was calculated based on a one-sided exact test for a single binomial 
proportion, using SAS Version 9.4 with the following assumptions: 
• Performance goal = 90% 
• Expected LV MSP feature-related CFR rate between 6 and 12 Month Visit = 98% 
• Significance level = 5% 
• Power = 80% 
12.1.1.3. Statistical Methods 
Data from subjects who are deemed as a non-responder at the 6 Month Visit with LV MSP 
turned on for any duration of time from 6 Month Visit onward will be eligible for inclusion 
in the endpoint analysis. The LV MSP feature-related CFR between the 6 Month Visit and 
the 12 Month Visit will be calculated using Kaplan-Meier methodology. The evaluation 
period for each subject will begin at the time LV MSP was turned on (at or after the 6 Month 
Visit) and will continue through 180 days post-LV MSP being turned on.   
                                                
6 BSC’s Enable MRI Clinical Study (IDE # G150181); performance goal for MR Scan related complication-free 
rate. 
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The 95% one-sided lower pointwise confidence limit of the LV MSP feature-related 
complication-free rate will be calculated via log-log methodology and compared to the 
performance goal of 90%. If the lower confidence limit exceeds 90%, the null hypothesis will 
be rejected. 
Each subject’s exact follow-up time in the period between the 6 Month Visit when the LV 
MSP is turned on through 180 days after the LV MSP is turned on will be included in the 
analysis due to the rate being calculated via Kaplan-Meier methodology. The subjects that 
reach the 6 Month Visit and have the LV MSP turned on but fail to reach 180 days of follow-
up after the LV MSP was turned on (without experiencing an endpoint event prior to their 
end of follow-up in the period) will be censored at the time of their end of follow-up in the 
period. Because non-informative censoring cannot be assumed for these subjects, a tipping 
point analysis will be performed to determine the potential effects these censored subjects 
could have on the results if full information on each subject was present. The tipping point 
analysis will assign each subject that was censored between the 6 and 12 Month Visit as 
either having or not having an LV MSP feature-related complication. The tipping point will 
be determined by the point at which the endpoint results turn from passing (null hypothesis) 
to failing (null hypothesis rejected). An exact binomial test will be performed for the tipping 
point analysis. 
In addition, a sensitivity analysis on the impact of “Unknown” related to the LV MSP feature 
will be performed. Subjects with a complication determined as “yes, related”, “possibly 
related” or “Unknown” related to the LV MSP feature will be included as a LV MSP feature-
related complication. 
12.1.2. Primary Effectiveness Endpoints: Proportion of LV MSP Group with an 
Improved CCS 
The effectiveness endpoint for SMART MSP PAS is the proportion of the LV MSP Group 
with an Improved CCS. Details regarding the CCS are provided in Section 11.5.1. For this 
endpoint, those subjects in the LV MSP Group that become responders will be defined as 
having an Improved CCS as discussed in Section 11.5.1. This endpoint will be evaluated at 
the 12 Month Visit to determine if the LV MSP Group subjects improved from their 6 Month 
Visit. 
12.1.2.1. Hypotheses 
The following hypotheses will be used to evaluate the Primary Effectiveness Endpoint: 
H0: Proportion of LV MSP Group subjects with Improved CCS from 6 Month Visit 
through 12 Month Visit ≤ 5% 
HA: Proportion of LV MSP Group subjects with Improved CCS from 6 Month Visit 
through 12 Month Visit > 5% 
12.1.2.2. Sample Size  
The sample size of 110 subjects with paired CCS calculation from the 6 Month Visit through 
12 Month Visit is required to evaluate the Primary Effectiveness Endpoint. For further details 
on overall sample size and attrition see Figure 12.3-1. The overall study sample size is 
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driven by the primary effectiveness endpoint. This sample size was calculated based on a 
one-sided exact test for a single binomial proportion, using SAS Version 9.4 with the 
following assumptions:  
• Performance goal = 5% 
• Expected performance = 15% 
• One-sided significance level = 5% 
• Power = 95% 
The performance goal was established based on the evaluation of clinical response data 
previously reported for similar features under investigation, and based on clinical input from 
the study’s National Principal Investigator and the Steering Committee that an improvement 
of at least 5% would be clinically meaningful given the subject’s non-responder status as 
determined after 6 months of conventional CRT with single-site LV pacing.  
12.1.2.3. Statistical Methods 
The SMART MSP PAS study’s Primary Effectiveness Endpoint will be analyzed when the 
last 12 Month Visit is completed by the subjects in the LV MSP Group. Subjects eligible for 
this analysis include all non-responder subjects who meet the definition of the LV MSP 
Group. The LV MSP Group subjects’ CCS data (NYHA class, HF event, all-cause mortality, 
and patient global assessment) will be collected at the 6 and 12 Month Visit and contribute to 
the endpoint analysis. The LV MSP Group subjects with the LV MSP on for less than 6 
month duration will be included in the analysis. 
The 95% one-sided lower pointwise confidence limit of the response rate will be calculated 
using the one-sided exact methodology for a single binomial proportion and compared to the 
performance goal of 5%. If the lower confidence limit exceeds the performance goal, then the 
null hypothesis will be rejected.  
Subjects that do not have complete paired CCS data regarding NYHA class, HF event, all-
cause mortality, and patient global assessment collected at the 6 and 12 month follow-up visit 
will be considered to have missing data. A tipping point analysis will be used to determine 
the potential effects subjects with missing data could have had on the results. The tipping 
point analysis will consider a range of possible responder rates in the subjects with missing 
data. The tipping point will be determined by the point at which the endpoint results turn 
from passing (null hypothesis rejected) to failing (null hypothesis not rejected). 
12.2. Ancillary Assessments 
The ancillary assessments are not formal endpoints and are not statistically powered.   
12.2.1. Assessment of Echocardiographic Measurements and CCS Response Status 
Outcomes in Non-responders 
Subjects with echo measurements (such as LVEF and LVESV) at Enrollment, 6, and 12 
Month Visit will be reported. In addition, data available (response outcome of CCS and echo 
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measurements) for these subjects will be reported with summary descriptive statistics and 
listings. Additional analyses may be explored. 
12.2.2. Assessment of Effectiveness of LV MSP in the SMART MSP PAS and SMART 
Registry 
A supplemental analysis of the primary effectiveness endpoint and subgroups will be 
performed and include a subset of data collected from the SMART Registry, a post market 
study assessing the LV MSP feature in a similar patient population to fulfill the requirement 
of an European regulatory body. 
12.2.3. Assessment of Worsened LV MSP Group 
The percentage of subjects in the LV MSP Group that worsened from the 6 Month Visit 
through 12 Month Visit will be reported. For this assessment, the CCS will define worsened 
as “Worsened” only and will not include subjects with a CCS of “No change.” 
12.2.4. Assessment of RV-LV Electrical Delay and Response 
Available data on RV-LV electrical delay will be collected to determine whether an electrical 
delay is a predictor of responder status in the overall population.  
12.2.5. Assessment of Battery Consumption 
In order to understand the impact of MSP on battery longevity, the following time durations 
will be summarized using descriptive statistics: 
• BiV related battery consumption from enrollment to 6 months 
• LV MSP related battery consumption from 6 to 12 months 
• The average battery life in years for subjects with the LV MSP On at 12 Month Visit 
12.2.6. Assessment of SmartDelay and SmartVector Usage 
In order to understand the usage of features such as SmartVector and SmartDelay, the 
following will be summarized using descriptive statistics:  
• Percent success using the SmartVector 
• Percent use of SmartDelay  
• Percent of subjects with SmartDelay value (AV delay and paced chamber) changed 
between Enrollment  Visit and 6 Month Visit and 6 to 12 Month Visit 
12.2.7. Assessment of Percentage of Pacing  
The following data on percentage of pacing will be summarized using descriptive statistics: 
• Percent of BiV pacing at 6 Month Visit 
• Percent of LV only pacing (if programmed) at 6 Month Visit 
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• Percent of LVa and LVb for LV MSP pacing at 12 Month Visit 
12.2.8. Assessment of Additional Data Collection  
Additional data collection and descriptive statistics will be collected and reported but is not 
limited to the following data:  
• Overall response rate at 6 Month Visit 
• Percent of the LV MSP Group subjects with furthest apart two viable vectors  
12.3. Sample Size Summary and Attrition 
The overall sample size of 586 subjects for the required LV MSP Group is based on the 
Primary Effectiveness endpoint. This sample size accounts for the overall study attrition. 
Below are the sources of attrition at different stages of this study: 
• LV pacing less than 93%7: 10% 
• Subject exiting the study prior to the 6 Month Visit8: 10% 
• Responder rate 9: 70% 
• Percent of subjects who cannot achieve 2 viable pacing vectors10: 15% 
• Subject exiting the study between the 6 and 12 Month Visit11: 8% 
Figure 12.3-1 indicates the sample size at different time points throughout the study. The 
overall attrition for this study is 81%. 
                                                
7 Koplan BA, Kaplan AJ, Weiner S, Jones PW, Seth M, Christman SA. Heart failure decompensation and all-
cause mortality in relation to percent biventricular pacing in patients with heart failure: is a goal of 100% 
biventricular pacing necessary? J Am Coll Cardiol. 2009 Jan 27;53(4):355-60. 
8 Based on an estimate from BSC SMART AV Clinical Study and NAVIGATE X4 Clinical Study. 
9 Based on an evaluation of a set of previous clinical studies reporting clinical response rate to conventional 
CRT therapy and feedback from the physicians of the study’s Steering Committee. 
10 Based on an estimate from BSC NAVIGATE X4 Clinical Study and Rally X4 Clinical Study. 
11 Based on an estimate from BSC SMART AV Clinical Study and NAVIGATE X4 Clinical Study. 
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Figure 12.3-1: Subject Flowchart with Estimated Attrition 
 
12.4. General Statistical Methods 
12.4.1. Study Success Criteria 
The study will be considered successful if all primary endpoints (safety and effectiveness) 
are passed. 
12.4.2. Analysis Sets 
The analysis sets that will be used for each endpoint is shown in Table 12.4-1. 
Table 12.4-1: Analysis Sets for Each Primary Endpoint 
Endpoint 
Analysis Sets 
SMART MSP PAS Primary Safety 
Endpoint 
All  subjects who are non-responders with the LV MSP on for 
any duration from the 6 to the 12 month visit 
SMART MSP PAS Primary Effectiveness 
Endpoint 
All subjects who meet the LV MSP group criteria 
12.4.3. Control of Systematic Error/Bias 
Selection of patients will be made from the Investigator’s usual patient population. All 
patients meeting the eligibility criteria and having signed the ICF will be enrolled in the 
study. To control for inter-observer variability among sites, an independent Clinical Events 
Committee (CEC) will adjudicate the reported HF event to be used as the component of the 
CCS to assess the Primary Effectiveness Endpoint.  
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12.4.4. Control of Type I Error 
Each primary endpoint can be tested at the significance level of 5% while still maintaining 
the overall type I error level at no greater than 5%. This follows the methodology of the 
Intersection-Union Test (IUT). 
12.4.5. Number of Subjects per Investigative Site 
To avoid any center effect and bias, one center will not be authorized to enroll more than 
20% of the study subjects. 
12.5. Data Analyses 
In addition to the study endpoint analysis discussed in Section 12.1 and Section 12.2, the 
following data analyses are planned for the SMART MSP Study. 
12.5.1. Interim Analyses  
No formal interim analyses are planned for the purpose of stopping the study early for 
declaring effectiveness or for futility. Analysis of each endpoint will be performed when all 
applicable data for that endpoint has been collected.  
12.5.2. Pooling Analysis 
Assessment of Pooling Across Investigational Centers 
The poolability of data by center will be tested. This analysis will be performed to determine 
whether there are differences from center-to-center. 
Center-to-center heterogeneity will be assessed by performing random effects logistic 
regression analysis. 
Investigational center will be added into the model as a random effect. Centers will be 
deemed to be heterogeneous if the variance of the random center effect is found to 
significantly differ from zero. A significance level of 15% will be used for each test. 
12.5.3. Subgroup Analyses 
Analyses will be performed for the primary effectiveness endpoint to determine whether 
significant differences exist in endpoint results between subgroups of the LV MSP Group. 
The list of baseline covariates (with applicable subgroups in parentheses) includes, but is not 
necessarily limited to: 
Categorical variables: 
• Ischemic Etiology (Ischemic vs Non-Ischemic) 
• Bundle Branch Block morphology (LBBB vs Non-LBBB) 
• NYHA class (I/II vs III/IV) 
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• LV MSP Pacing chamber (BiV MSP vs. LV ONLY MSP)12  
• Presence of atrial fibrillation (Yes or No ) 
• Diabetes (Yes vs. No) 
• Sex (Male vs. Female) 
• Spiral LV lead length (Short vs. Long) 
• LV lead shape (Spiral vs. Straight) 
Continuous Variables:  
• RV-LV electrical delay 
• Electrode spacing between the two LV pacing vectors13 
• QRS width  
For categorical variables, the subgroup variable will be added to a logistic univariate 
regression model. In addition, continuous variables will be determined as binary or 
continuous by linearity characteristics and/or clinical determination. If deemed as continuous, 
the subgroup variable will be added to a logistic univariate regression model.  
In addition to subgroup analyses, descriptive statistics of patient demographic and baseline 
characteristics will be presented for each subgroup listed in this section. Descriptive statistics 
will also be presented for the overall study population. 
12.5.4. Multivariable Analyses 
As stated in the subgroup analysis in Section 12.5.3, the number of events in the LV MSP 
Group is limited. Therefore, multivariate analyses will be deemed exploratory. The various 
baseline covariates and their relationship to effectiveness endpoint are outlined in Section 
12.5.3. For the effectiveness endpoint and subgroup analyses, all baseline characteristics 
found to be significantly associated with the response status will be included as covariates, in 
a multivariate regression model. The impact of each baseline characteristic’s subgroups will 
be presented along with the multivariate model results. 
12.5.5. Changes to Planned Analyses 
Any changes to the planned statistical analyses made prior to performing the analyses will be 
documented in a 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 deviation. 
                                                
12 LV MSP pacing chamber is only collected at the 6 Month Visit when the LV MSP feature is turned on. 
13 Electrode spacing between the two LV pacing vectors is only collected at the 6 Month Visit when the LV 
MSP feature is turned on. 
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13. Data Management 
13.1. Data Collection, Processing, and Review 
Subject data will be recorded in a limited access secure electronic data capture (EDC) 
system.  
The clinical database will reside on a production server hosted by EDC System. All changes 
made to the clinical data will be captured in an electronic audit trail and available for review 
by the sponsor or its representative. The associated RAVE software and database have been 
designed to meet regulatory compliance for deployment as part of a validated system 
compliant with laws and regulations applicable to the conduct of clinical studies pertaining to 
the use of electronic records and signatures. Database backups are performed regularly. 
The Investigator provides his/her electronic signature on the appropriate electronic case 
report forms (eCRFs) in compliance with local regulations. A written signature on printouts 
of the eCRFs must also be provided if required by local regulation. Changes to data 
previously submitted to the sponsor require a new electronic signature by the Investigator 
acknowledging and approving the changes. 
Visual and/or electronic data review will be performed to identify possible data 
discrepancies. Manual and/or automatic queries will be created in the EDC system and will 
be issued to the site for appropriate response. Site staff will be responsible for resolving all 
queries in the database. 
13.2. Data Retention 
The Investigator or his/her designee or the 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 study has been formally closed. These 
documents will be retained in compliance with other local regulations. The Investigator will 
take measures to ensure that these essential documents are not accidentally damaged or 
destroyed. If for any reason the Investigator withdraws responsibility for maintaining these 
essential documents, custody must be transferred to an individual who will assume 
responsibility and BSC must receive written notification of this custodial change.  
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/FDA) 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 
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sponsor and the reviewing IRB per local reporting guidelines 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 EDC eCRF system. 
Sites may also be required to report deviations to the IRB, per local guidelines and 
government regulations.  
Deviations will be reviewed and evaluated on an ongoing basis and, as necessary, appropriate 
corrective and preventive actions notification, site re-training, or site discontinuation 
/termination will be put into place by the sponsor. 
16. Device/Equipment Accountability 
Devices used within the SMART MSP Study are commercially available and are not 
investigational.  
17. Compliance 
17.1. Statement of Compliance 
This study will be conducted in accordance with post market clinical follow up guidelines 
and will follow the 21 CFR part 56 and part 50, ethical principles that have their origins in 
the Declaration of Helsinki, and pertinent local laws and regulations. The study shall not 
begin until the required approval/favorable opinion from the IRB and/or the regulatory 
authority has been obtained, if appropriate. Any additional requirements imposed by the IRB 
or the regulatory authority shall be followed, if appropriate. 
17.2. 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, ethical principles that have their origins in the Declaration of Helsinki, any conditions 
of approval imposed by the reviewing IRB, 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.   
• 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 
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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 per Section 
20. 
• Report to sponsor, per the protocol requirements, all SAEs and device deficiencies that 
could have led to a SADE and potential USADE or UADE. 
• Report to the IRB 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, and supply BSC with any additional requested 
information related to the safety reporting of a particular event. 
• Allow the sponsor or sponsor representatives 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 when performing auditing 
activities. 
• Ensure that informed consent is obtained in accordance with applicable laws, this 
protocol and local IRB 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. 
• 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 
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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. 
17.2.1. Delegation of Responsibility 
When specific tasks are delegated by an investigator, including but not limited to conducting 
the informed consent process, the Principal Investigator is responsible for providing 
appropriate training and adequate supervision of those to whom tasks are delegated. No study 
related tasks can be performed prior to completing the appropriate study training. The 
investigator is accountable for regulatory violations resulting from failure to adequately 
supervise the conduct of the clinical study.  
17.3. Institutional Review Board 
Prior to gaining Approval-to-Enroll status, the investigational site will provide to the sponsor 
documentation verifying that their IRB 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 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. Prior approval must also be obtained for other 
materials related to subject recruitment or which will be provided to the subject. 
Annual IRB approval and renewals will be obtained throughout the duration of the study as 
required by local/country or IRB requirements. Copies of the Investigator’s reports and the 
IRB continuance of approval must be provided to the sponsor.  
17.4. 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 
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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.  
17.4.1. Role of Boston Scientific Representatives 
Boston Scientific personnel can provide technical support to the investigator and other health 
care personnel (collectively HCP) as needed during implant, testing required by the protocol, 
and follow-ups. Support may include HCP training, addressing HCP questions, or providing 
clarifications to HCPs concerning the operation of BSC equipment/devices (including 
programmers, analyzers, and other support equipment). 
At the request of the investigator and while under investigator supervision, BSC personnel 
may operate equipment during implant or follow-up, assist with the conduct of testing 
specified in the protocol, and interact with the subject to accomplish requested activities. 
Typical tasks may include the following. 
• Interrogating the device or programming device parameters to investigator-requested 
settings. 
• 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 technical source form. 
• Print out programming reports directly from the 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. 
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• 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. 
18. Monitoring 
Monitoring will be performed during the study to assess continued compliance with the 
protocol and applicable regulations. In addition, the clinical research monitor from BSC or 
BSC designees 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 and/or their institution guarantee 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. 
19. Potential Risks and Benefits 
19.1. Anticipated Adverse Events 
Subjects participating in this study are subject to the same risks shared by all patients 
undergoing implantation of a CRT-D system. Based on the literature and on pulse generator 
and/or lead implant experience, an alphabetical list of the possible adverse events is provided 
in the Resonate family of CRT-D physician’s technical manual as follows:  
• Air embolism  
• Allergic reaction  
• Bleeding  
• Bradycardia 
• Cardiac tamponade  
• Chronic nerve damage  
• Component failure  
• Conductor coil fracture 
• Death  
• Electrolyte imbalance/ dehydration  
• Elevated thresholds  
• Erosion  
• Excessive fibrotic tissue growth  
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• Extracardiac stimulation (muscle/ nerve stimulation) 
• Failure to convert an induced arrhythmia 
• Fluid accumulation  
• Foreign body rejection phenomena  
• Formation of hematomas or seromas  
• Heart block  
• Inability to defibrillate or pace 
• Inappropriate therapy (e.g., shocks, and antitachycardia pacing [ATP] where 
applicable, pacing) 
• Incisional pain  
• Incomplete lead connection with pulse generator  
• Infection including endocarditis 
• Insulating myocardium during defibrillation with internal or external paddles 
• Lead dislodgment  
• Lead fracture  
• Lead insulation breakage or abrasion  
• Lead perforation 
• Lead tip deformation and / or breakage  
• Local tissue reaction 
• Loss of capture 
• Myocardial infarction (MI) 
• Myocardial necrosis 
• Myocardial trauma (e.g., tissue damage, valve damage) 
• Myopotential sensing  
• Oversensing / undersensing  
• Pacemaker-mediated tachycardia (PMT) 
• Pericardial rub, effusion  
• Pneumothorax 
• Pulse generator migration 
• Shunting current during defibrillation with internal or external paddles 
• Syncope 
• Tachyarrhythmias, which include acceleration of arrhythmias and early, recurrent 
atrial fibrillation  
• Thrombus, thromboemboli 
• Valve damage  
• Vasovagal response 
• Venous occlusion  
• Venous trauma (e.g. perforation, dissection, erosion) 
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• Worsening heart failure 
Subjects 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 
Additionally, potential adverse events associated with the implantation of a coronary venous 
lead system include: 
• Allergic reaction to contrast media 
• Breakage/failure of implant instruments 
• Prolonged exposure to fluoroscopic radiation 
• Renal failure from contract media used to visualize coronary veins.  
19.2. Risks Associated with the Study Device(s)  
There are no additional risks associated with the study devices beyond those already 
described for BSC commercially approved and market available CRT-D devices with the LV 
MSP feature. 
19.3. Risks associated with Participation in the Clinical Study 
All subjects have previously received a CRT-D device implantation as part of standard of 
care treatment. The study procedure starts at the Enrollment Visit, which is after device 
implant, and at the regularly scheduled standard of care follow-up visits.  
In the SMART MSP study, a subset of the subjects in the Non-Responder Group 
(approximately 110 subjects) will receive the LV MSP therapy from the 6 Month Visit to the 
12 Month Visit. The LV MSP feature may increase the device battery consumption. It is 
anticipated that the impact to the battery consumption during the study may average 6 weeks 
but may be as long as 4.8 months.  
Additionally, there may be a temporary increase in the subject’s heart rate and loss of AV 
synchrony due to VVI pacing during the Smart Delay test and RVp-LVs interval test. In rare 
cases, subjects may experience temporary symptoms of fatigue, chest discomfort, dyspnea, 
cough, confusion, presyncope, or syncope during these tests. The investigator may stop the 
test if the subject does not tolerate the testing procedure. 
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19.4. Risk Minimization Actions 
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. 
19.5. Anticipated Benefits 
There may be no benefit to the subject. However, subjects participating in clinical studies 
may have better outcomes than the general population. The subject may benefit from closer 
device follow up due to the clinical protocol schedule. Subjects may be followed more 
carefully and their status, as well as their device and lead status, is checked by various study 
personnel and systems: investigators, data coordinators, monitors and automatic warning 
systems in the clinical study database set to monitor the data as it is submitted to Boston 
Scientific. 
19.6. Risk to Benefit Rationale 
The risks involved with subject participation in this study are the same as those for patients 
not participating in the study. The LV MSP feature will only be turned on in the study for 
subjects who are determined to be non-responders to conventional CRT therapy as defined in 
the protocol and may be turned off per physician discretion. Physicians should consider 
turning the LV MSP feature off if a subject’s HF condition worsens. This study is designed 
to evaluate whether the LV MSP feature can improve clinical response to CRT in subjects 
who are not responders to conventional CRT.   
20. Safety Reporting 
20.1. Reportable Events by Investigational Site to BSC 
The communication requirements for reporting adverse events, device deficiencies, failures, 
malfunctions, and product nonconformities to BSC are listed in Table 20.4-1. Adverse 
events must always be reported through the eDC system for SMART MSP Study. However, 
in cases where the eDC is not available, report the adverse event to BSC using 
SMARTMSP.Safety@bsci.com. It is the responsibility of the investigator to assess and 
report all reportable events in the following categories: 
• All Serious Adverse Events 
• All Heart Failure and Cardiac related Adverse Events requiring IV or invasive 
therapy, including new onset of cardiac events, or worsening in severity or frequency 
of pre-existing condition(s) 
• All Adverse Device Effects 
o Events listed in the arrhythmia logbook should be reported only if determined 
to be clinically significant by the investigator and/or delegated site staff (such 
events include ATR, PMT, etc.) 
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o All arrhythmias which received inappropriate therapy (i.e. inappropriate 
shock) must be reported 
o Include adverse events related to any part of the implanted CRT-D system 
• All Device Deficiencies  
• All Adverse Events related to the protocol required testing, excluding PNS during 
lead testing. 
• Unanticipated Adverse Device Effects/Unanticipated Serious Adverse Device Effects 
Adverse event collection begins after the subject signs the informed consent. Events which 
occur prior to the signing of the informed consent form, and per the investigator/delegated 
site staff are a result of the device implant procedure should not be reported. Even if such 
event requires a treatment that is executed after the informed consent is signed. (e.g. 
hematoma that requires intervention is not an adverse event as long as it does not worsen 
after consenting; infection at the incision site is not an adverse event as long as it does not 
worsen after consenting; planned medical procedure or lead revisions are not adverse event 
as long as the event is identified prior to the consent). These are considered preexisting 
conditions and are not reportable. If the event worsens after consenting and meets criteria for 
a reportable event then they must be reported (e.g. hematoma that is worsened and requires 
intervention; a new infection at the incision site or an infection that is worsened and requires 
intervention). If the study subject is consented while still hospitalized from the initial device 
implant, and an event occurs which meets the definition of an SAE, the event must be 
reported.  
When possible, the medical diagnosis should be reported as the Event Term instead of 
individual symptoms. Multiple symptoms related to a single medical diagnosis should be 
reported within one (1) adverse event with one (1) event term (i.e. shortness of breath and 
edema are related to a diagnosis of ‘worsening heart failure’). 
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 testing procedure, it should be submitted as an adverse event 
and/or device deficiency. 
Any AE required by the protocol, experienced by the study subject after informed consent, 
and once considered enrolled in the study must be recorded in the eCRF. 
Death should not be recorded as an AE, but should only be reflected as an outcome of one (1) 
specific SAE (see Section 20.2 for AE definitions). 
Refer to Section 19 for the known risks associated with the study device(s). 
20.2. Definitions and Classification 
Adverse event definitions are provided in Table 20.2-1 Events to be reported in the clinical 
study are listed in Section 20.1. 
Table 20.2-1: Safety Term Definitions 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury, or any 
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Table 20.2-1: Safety Term Definitions 
Term 
Definition 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 -2015 
 
 
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 14155-2011 
 
Ref: MEDDEV 2.7/3 -2015 
 
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 14155-2011 
 
Ref: MEDDEV 2.7/3 -2015 
 
Note: This definition meets the reporting objectives and requirements of ISO 
14155 and MEDDEV 2.7/3. 
Adverse event that: 
a) Led to death, 
b) 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 
c) 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 -2011 
 
Ref: MEDDEV 2.7/3 -2015 
Adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event. 
 
Unanticipated Adverse Device 
Effect (UADE) 
 
Ref: 21 CFR Part 812 
 
 
Any serious adverse effect on health or safety or any life-threatening 
problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree 
of incidence in the investigational plan or application (including a 
supplementary plan or application), or any other unanticipated serious 
problem associated with a device that relates to the rights, safety, or welfare 
of subjects.   
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Table 20.2-1: Safety Term Definitions 
Term 
Definition 
Unanticipated Serious Adverse 
Device Effect (USADE) 
 
Ref: ISO 14155 -2011 
 
Ref: MEDDEV 2.7/3 -2015 
 
Serious adverse device effect which by its nature, incidence, severity, or 
outcome has not been identified in the current version of the risk analysis 
report. 
NOTE 1: Anticipated serious adverse device effect (ASADE) is an effect 
which by its nature, incidence, severity or outcome has been identified in the 
risk analysis report. 
Device Deficiency 
 
Ref: ISO 14155 -2011 
 
Ref: MEDDEV 2.7/3 -2015 
An inadequacy of an investigational medical device related to its identity, 
quality, durability, reliability, safety or performance. This may include 
malfunctions, use error, or inadequacy in the information supplied by the 
manufacturer. 
 
The following categories may be used by BSC for classification of events. 
Clinical Observation 
Ref: FDA Guidance for the 
Submission of 
Research and Marketing 
Applications for Permanent 
Pacemaker Leads and for 
Pacemaker Lead Adaptor 
510(k) Submissions 
A clinical observation is a clinical event that did not result in invasive 
intervention, injury, or death, and is not an unanticipated adverse event.  
Corrective actions were simple adjustments such as reprogramming of the 
pulse generator or antibiotic treatment of a pocket infection 
Clinical Complication 
 Ref: FDA Guidance for the 
Submission of 
Research and Marketing 
Applications for Permanent 
Pacemaker Leads and for 
Pacemaker Lead Adaptor 
510(k) Submissions 
A clinical complication is a clinical event that required an invasive 
intervention, injury, or death (e.g., surgical evacuation of a hematoma, lead 
dislodgment requiring lead repositioning, generator replacement, loss or 
abandonment of therapy). 
Type I 
 Ref: FDA Guidance for the 
Submission of 
Research and Marketing 
Applications for Permanent 
Pacemaker Leads and for 
Pacemaker Lead Adaptor 
510(k) Submissions 
Related to the investigational device or therapies.  
 
Type II 
 Ref: FDA Guidance for the 
Submission of 
Research and Marketing 
Applications for Permanent 
Pacemaker Leads and for 
Pacemaker Lead Adaptor 
510(k) Submissions 
Related to protocol or procedures.  Specifically related to protocol testing 
that is not patient standard of care.     
Type III 
 Ref: FDA Guidance for the 
Not related to the investigational device(s), system component(s), or 
labeling, but would not have occurred in the absence of the investigational 
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Table 20.2-1: Safety Term Definitions 
Term 
Definition 
Submission of 
Research and Marketing 
Applications for Permanent 
Pacemaker Leads and for 
Pacemaker Lead Adaptor 
510(k) Submissions 
device(s) and/or system component(s).  This includes clinical events related 
to commercially released devices that are used in conjunction with 
investigational device(s) or protocol procedures. 
Type IV 
 Ref: FDA Guidance for the 
Submission of 
Research and Marketing 
Applications for Permanent 
Pacemaker Leads and for 
Pacemaker Lead Adaptor 
510(k) Submissions 
Related to a change in patient’s condition. 
Type V 
 Ref: FDA Guidance for the 
Submission of 
Research and Marketing 
Applications for Permanent 
Pacemaker Leads and for 
Pacemaker Lead Adaptor 
510(k) Submissions 
Comments Only.  On occasion, comments were inadvertently entered in the 
adverse event text field of the case report form (CRF). Comments identified 
by the CRF reviewer were assigned a Type V code and not included in this 
report. 
Abbreviations: IRB=Institutional Review Board 
 
 
20.3. Relationship to Study Device(s) and/or Study Testing 
The Investigator must assess the relationship of the AE to the study device or study testing 
procedure. See criteria in Table 20.3-1.  
Table 20.3-1: Criteria for Assessing Relationship of Study Device or Procedure to 
Adverse Event 
Classification 
Description 
Not Related 
Relationship to the device or procedures can be excluded when: 
- the event is not a known side effect of the product category the device belongs to or 
of similar devices and procedures; 
- the event has no temporal relationship with the use of the investigational device or 
the procedures; 
- the serious event does not follow a known response pattern to the medical device (if 
the response pattern is previously known) and is biologically implausible; 
- the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible – and reintroduction of its use (or 
increase of the level of activation/exposure), do not impact on the serious event; 
- the event involves a body-site or an organ not expected to be affected by the device 
or procedure; the serious event can be attributed to another cause (e.g. an underlying 
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Table 20.3-1: Criteria for Assessing Relationship of Study Device or Procedure to 
Adverse Event 
Classification 
Description 
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; 
- 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. 
 
20.4. Investigator Reporting Requirements 
The communication requirements for reporting to BSC are as shown in Table 20.4-1. 
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Table 20.4-1: Investigator Reporting Requirement 
Event 
Classification 
Communication Method  
Communication Timeline post-market 
studies**  
Unanticipated 
Adverse Device 
Effect / 
Unanticipated 
Serious Adverse 
Device Effect  
 
Complete AE eCRF page with all 
available new and updated 
information.  
 
a) Within 1 business day of first becoming 
aware of the event. 
b) Terminating at the end of the study 
Serious Adverse 
Event  
Complete AE eCRF page with all 
available new and updated 
information.  
c) Within 10 business days after becoming 
aware of the event or as per 
local/regional regulations. Reporting 
required through end of study 
Provide all relevant source 
documentation (unidentified) for 
reported event upon request of the 
sponsor 
d) Within 60 calendar days of reported 
event 
Serious Adverse 
Device Effects 
Complete AE eCRF page with all 
available new and updated 
information. 
e) 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 complete, relevant source 
documentation (unidentified) for 
reported event 
f) Send complete source documentation 
within 60 calendar days of becoming 
aware of the event 
Device Deficiencies 
(including but not 
limited to failures, 
malfunctions, and 
product 
nonconformities) 
Complete device deficiency CRF with 
all available new and updated 
information.  
g) 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.  
h) In a timely manner (e.g. recommend 
within 30 business days) after becoming 
aware of the information. Reporting 
required through completion of study 
20.5. 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 in the eDC system 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 
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device failure or malfunction would be recorded as an adverse event on the appropriate 
eCRF. 
Any Device Deficiency that might have led to a serious adverse event if a) suitable action 
had not been taken or b) intervention had not been made or c) if circumstances had been less 
fortunate is considered a reportable event. 
20.6. Reporting to Regulatory Authorities / IRBs / 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, and regulatory authorities of 
UADE and SAE as required by local/regional regulations. 
20.7. Subject Death Reporting 
A subject death during the study should be reported to Boston Scientific as soon as possible 
and, in any event, within 3 calendar days or per local regulations (per Section 20.4) of site 
notification via eDC system. An Adverse Event eCRF, with a death outcome must be 
completed, as well as an End of Study form. The site’s IRB must be notified of any deaths in 
accordance with that site’s IRB policies and procedures. 
Boston Scientific may request additional information regarding subject deaths. These 
requests may include requests for source documentation, in order for BSC to understand the 
circumstances surrounding the death. Source documentation may include, but is not limited 
to: hospital records (H&P, consultations, diagnostics, etc.); last available device 
interrogation, last available office visit, etc. The following data should be provided: 
• Date and time of death  
• Immediate cause of death  
• Rhythm at the time of death, if known (include any available documentation) 
• Whether the death was related to the pulse generator, lead/catheter, clinical 
investigation, procedure, or patient condition  
• Whether or not the death was witnessed  
• Device status and/or activity at the time of death 
• Whether the patient 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.  
In addition, if the patient expired in the hospital:  
• A copy of the medical records for that admission (e.g., H & P, consults, test results, 
operative reports, and/or progress notes from the hospital chart)  
• Death certificate (if available)  
• Autopsy report (if applicable)  
If the patient expired outside of the hospital (e.g., home):  
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• A copy of the most recent clinic visit (if not already submitted to BSC) 
• Death certificate (if available)   
Whenever possible, the pulse generator (IPG) should be interrogated. The leads and the 
related BSC Rhythm Management system components (e.g., IPG) should be removed intact 
and returned promptly to BSC Rhythm Management for analysis. 
20.8. Source Documents for CEC Adjudication 
All post-enrollment hospitalizations except the hospitalization in which the existing device 
implant is performed will be adjudicated by the CEC per Section 22.2. Source documents 
required for adjudication include, but are not limited to: admission note, history and physical, 
consultation notes, medication lists and discharge summary. 
21. Informed Consent 
Subject participation in this clinical study is voluntary. Informed Consent is required from 
each subject. The Investigator is responsible for ensuring that Informed Consent is obtained 
prior to the study-required procedures and/or testing and data collection.  
The obtaining and documentation of Informed Consent must be in accordance with the 
principles of the Declaration of Helsinki, any applicable national regulations, and local IRB 
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, 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. 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 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, 
• 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.  
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The ICF shall always be signed and personally dated by the subject and by the investigator 
and/or an authorized designee responsible for conducting the informed consent process. The 
original signed ICF will be retained by the site and a copy of the signed and dated document 
and any other written information must be given to the person signing the form.  
Failure to obtain subject consent will be reported by BSC to the applicable regulatory body 
according to their requirements (e.g., FDA requirement is within 5 working days of learning 
of such an event). Any violations of the informed consent process must be reported as 
deviations to the sponsor and local regulatory authorities (e.g. IRB), 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. The new version of the ICF must be approved by the 
IRB. Acceptance by Boston Scientific is required if changes to the revised ICF are requested 
by the site’s IRB. The IRB will determine the subject population to be re-consented. 
22. Committees 
22.1. Safety Monitoring Process 
To promote early detection of safety issues, BSC Safety Trial Operation group will conduct 
the initial evaluations of all safety events and provide the evaluations to BSC Medical Safety 
group. 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 heart failure and CRT device/therapy and with the necessary therapeutic and 
subject matter expertise to evaluate and classify the events into the categories outlined above. 
22.2. Clinical Events Committee 
A Clinical Events Committee (CEC) is an independent group of individuals with pertinent 
expertise that reviews and adjudicates the following events, as a component used in 
determining the Primary Effectiveness Endpoint, as reported by study investigators: 
• All hospitalizations  
• Any event where a study subject is not hospitalized but received one or more IV 
medications including diuretics, inotropes, vasodilators, other parenteral therapy, or 
aquapheresis. 
• Other events at the discretion of BSC 
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The CEC will review a safety event dossier, which may include copies of subject source 
documents provided by the study sites, for all applicable events. Investigative sites are 
requested to send source documents related to the event to SMARTMSP.Safety@bsci.com. 
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 heart failure event. CEC responsibilities, qualifications, membership, 
and committee procedures are outlined in the CEC charter. 
23. Suspension or Termination 
23.1. 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. 
23.1.1 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. 
• Reaching study futility. 
23.2. Termination of Study Participation by the Investigator or Withdrawal of IRB 
Approval 
Any investigator or IRB in the SMART MSP 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. 
23.3. 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 and regulatory authorities, as applicable, will be notified. Detailed information on how 
enrolled subjects will be managed thereafter will be provided.  
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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 to 
Boston Scientific, unless this action would jeopardize the rights, safety, or welfare of the 
subjects. 
23.4. 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. The 
IRB and regulatory authorities, as applicable, will be notified. All subjects enrolled in the 
study at the site will continue to be followed per patient’s standard of care. The Principal 
Investigator at the site must make provision for these follow-up visits unless BSC notifies the 
investigational site otherwise. 
24. 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.  
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25. Abbreviations and Definitions  
25.1. Abbreviations 
Table 25.1-1: Study Abbreviation 
Abbreviation 
Term 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
Apace 
Atrial Pace Marker 
Asense 
Atrial Sense Marker 
AV 
AtrioVentricular 
BiV 
Biventricular 
BSC 
Boston Scientific Corporation 
CCS 
Clinical Composite Score (Packer CCS) 
CEC 
Clinical Events Committee 
CFR 
Complication-free rate – within the endpoint sections 
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 
CRT-P 
Cardiac Resynchronization Therapy- Pacemaker 
CS 
Coronary Sinus 
DD 
Device Deficiency 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EGM 
Electrogram 
FCS 
Field Clinical Specialist 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCP 
Healthcare Provider 
HF 
Heart Failure 
ICF  
Informed Consent Form 
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Abbreviation 
Term 
ICH 
International Conference on Harmonization 
ICD 
Implantable Cardioverter Defibrillator 
IPG 
Implantable Pulse Generator 
IQRMP 
Integrated Quality Risk Management Plan 
IRB 
Institutional Review Board 
IV 
Intravenous 
LBBB 
Left Bundle Branch Block 
LOC 
Loss of Capture 
LRL 
Lower Rate Limit 
LV 
Left Ventricle 
LVED 
Left Ventricular End Diastolic 
LVEF 
Left Ventricular Ejection Fraction 
LVESV 
Left Ventricular End Systolic Volume 
LV MSP 
Left Ventricular Multi-Site Pacing 
ms 
Millisecond 
mV 
millivolts 
NYHA 
New York Heart Association 
Ω 
Ohms 
OPT 
Optimal Pharmacologic Therapy 
PA 
Paced Atrium 
PAS 
Post Approval Study 
PAV 
Paced AV Delay 
PCT 
Pacing Capture Threshold 
PG 
Pulse Generator 
PGA 
Patient Global Assessment 
PhGA 
Physician Global Assessment 
PI 
Principal Investigator 
PNS 
Phrenic Nerve Stimulation 
PRM 
Reference to BSC Programmer 
QLV 
Q-Left Ventricular 
RA 
Right Atrium/ Atrial 
RM 
Rhythm Management 
RV 
Right Ventricle/ Ventricular 
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Abbreviation 
Term 
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 
SAS 
Statistical Analysis System 
SAV 
Sensed AV Delay 
US 
United States of America 
UADE 
Unanticipated Adverse Device Effect 
USADE 
Unanticipated Serious Adverse Device Effect 
UADE 
Unanticipated Adverse Device Effect 
V 
Volts 
VF 
Ventricular Fibrillation 
Vsense 
Ventricular Sense Marker 
VT 
Ventricular Tachycardia 
 
25.2. Definitions 
Terms are defined in Table 25.2-1.  
Table 25.2-1: Definitions 
Term 
Definition 
Clinical Composite 
Score (CCS) 
A method for evaluating heart therapies that unifies four outcomes 
of primary importance to clinicians: all-cause mortality, HF event, 
Patient Global Assessment, and New York Heart Association 
(NYHA) class.  
Resonate family of 
CRT-D devices 
As the next generation of BSC’s CRT-D devices, Resonate refers 
to all trademarked devices in this family of pulse generators, 
including RESONATE HF, RESONATE, VIGILANT, and 
MOMENTUM. 
LV MSP feature 
related Complication 
The LV MSP feature related adverse events will include, but are 
not limited to the following: 
• Ventricular Tachyarrhythmia/Ventricular Fibrillation 
(VT/VF) 
• Loss of Capture  
• Phrenic Nerve Stimulation (PNS) 
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Table 25.2-1: Definitions 
Term 
Definition 
• Worsening HF 
Conventional CRT 
CRT with single-site LV pacing 
Responder Group 
Subjects with Improved CCS score at the 6 Month Visit. 
Non-Responder Group 
Subjects with Unchanged or Worsened CCS scores at the 6 Month 
Visit. 
LV MSP Group   
Subjects who have achieved at least 2 viable LV pacing vectors, 
have the LV MSP feature enabled, and with the percent of LV 
MSP pacing threshold of at least 93% 
LV MSP Pacing 
BiV pacing with the LV MSP On 
LV MSP LV Only 
Pacing 
LV only pacing with the LV MSP On 
Viable LV Pacing 
Vector 
To determine if an LV pacing vector is considered viable, the 
following criteria are recommended: 
• The pacing impedance is not out-of-range per physician’s 
programmed value 
• No presence of PNS - the pacing capture threshold (PCT) 
plus 3V of safety margin should be less than PNS 
threshold  
• LV PCT at ≤ 4.5V or demonstrated capture at ≤ 4.5V 
 
26. References 
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. 
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. 
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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. 
Menardi E BG, Goletto C, Rossetti G, Vado A. Characterization of ventricular 
activation pattern and acute hemodynamics during multipoint left ventricular pacing. Heart 
Rhythm. 2015;12:1762-1769. 
15. 
Pappone C ĆŽ, Vicedomini G, Cuko A, McSpadden LC, Ryu K, Romano E, Saviano 
M, Baldi M, Pappone A, Ciaccio C, Giannelli L, Ionescu B, Petretta A, Vitale R, Fundaliotis 
A, Tavazzi L, Santinelli V. Multipoint left ventricular pacing improves acute hemodynamic 
response assessed with pressure-volume loops in cardiac resynchronization therapy patients. 
Heart Rhythm. 2014;11:394-401. 
16. 
Pappone C ĆŽ, Vicedomini G, Cuko A, McSpadden LC, Ryu K, Jordan CD, Romano 
E4, Baldi M, Saviano M, Pappone A, Vitale R, Catalano C, Ciaccio C, Ciannelli L, Ionescu 
B, Petretta A, Fragakis N, Fundaliotis A, Tavazzi L, Santinelli V. Improving cardiac 
resynchronization therapy response with multipoint left ventricular pacing:  Twelve-month 
follow-up study. Heart Rhythm. 2015;12:1250-1258. 
17. 
Rinaldi CA KW, Leclercq C, et al. Acute effects of multisite left ventricular pacing 
on mechanical dyssynchrony in patients receiving cardiac resynchronization therapy. Journal 
of Cardiac Failure 2013;19:731-8. 
18. 
Rinaldi CA LC, Kranig W, Kacet S, Betts T, Bordachar P, Gutleben KJ, Shetty A, 
Donal E, Keel A, Ryu K, Farazi TG, Simon M, Naqvi TZ. Improvement in acute contractility 
and hemodynamics with multipoint pacing via a left ventricular quadripolar pacing lead. J 
Interv Card Electrophysiol. 2014;40:75-80. 
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19. 
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Ryu K, Paiement P, Farazi TG. Acute haemodynamic comparison of multisite and 
biventricular pacing with a quadripolar left ventricular lead. Europace. 2013;15:984-991. 
20. 
Zanon F BE, Pastore G, Marcantoni L, Fraccaro C, Lanza D, Picariello C, Aggio S, 
Roncon L, Dell'Avvocata F, Rigatelli G, Pacetta D, Noventa F, Prinzen FW. Multipoint 
pacing by a left ventricular quadripolar lead improves the acute hemodynamic response to 
CRT compared with conventional biventricular pacing at any site. Heart Rhythm. 
2015;12:975-981. 
21. 
Zanon F ML, Baracca E, Pastore G, Lanza D, Fraccaro C, Picariello C, Conte L, 
Aggio S, Roncon L, Pacetta D, Badie N, Noventa F, Prinzen FW. Optimization of left 
ventricular pacing site plus multipoint pacing improves remodeling and clinical response to 
cardiac resynchronization therapy at 1 year. Heart Rhythm. 2016;13:1644-1651. 
22. 
Forleo GB SL, Giammaria M, Potenza D, Curnis A, Calabrese V, Ricciardi D, 
D'agostino C, Notarstefano P, Ribatti V, Morani G, Mantica M, Di Biase L, Bertaglia E, Calò 
L, Zanon F. Multipoint pacing via a quadripolar left-ventricular lead: preliminary results 
from the Italian registry on multipoint left-ventricular pacing in cardiac resynchronization 
therapy (IRON-MPP). Europace. 2016;Epub ahead of print. 
23. 
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. 
  
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