Precision Event Monitoring for Patients With Heart Failure Using HeartLogic: PREEMPT-HF
Conditions: Heart Failure, Defibrillators, Implantable, Monitoring, Physiologic, Cardiac Resynchronization Therapy, Cardiovascular Disease, Heart Disease
Sponsor: Boston Scientific Corporation

92120219_Global Form Clinical Study Protocol Template (Post-Market)_Rev/Ver AA 
 PREEMPT-HF Protocol, 92216931, Rev/Ver B 
Page 1 of 71 
 
 
PREcision Event Monitoring of PatienTs with Heart Failure using 
HeartLogicTM 
 
PREEMPT-HF 
C1926 
CLINICAL INVESTIGATION PLAN 
 
 
 
Sponsored By 
Boston Scientific Corporation 
4100 Hamline Avenue North 
St. Paul, MN 55112 
 
 
 
 
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                                                     PREEMPT-HF Protocol, 92216931, Rev/Ver B  
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Contact Information 
Role 
Contact  
Clinical Contacts 
Stephen Ruble, PhD 
Clinical Fellow 
Boston Scientific, Inc. 
Rhythm Management 
4100 Hamline Ave N. 
St. Paul, MN 55112, United States 
Phone +1 651.582.4397 
e-mail: Stephen.Ruble@bsci.com 
 
Maria Paz López-Chicharro Alvarez 
Senior Clinical Trial Manager 
Guidant Europe, a Boston Scientific Company 
Rhythm Management 
Green Square, Lambroekstraat 5D 
1831 Diegem, Belgium 
Phone Tel. +34 686076599 
e-mail: Maria.Lopez-Chicharro@bsci.com 
 
Karen Reidt 
Senior Clinical Trial Manager 
Boston Scientific, Inc. 
Rhythm Management 
4100 Hamline Ave N. 
St. Paul, MN 55112, United States 
Phone: +1.651.202.8033 
e-mail: karen.reidt@bsci.com 
 
Guidant Europe NV 
Lambroekstraat 5D 
1831 Diegem 
Belgium 
 
Boston Scientific Pty. Ltd. 
Level 5 
247 Coward Street 
Mascot 
NSW 
Australia 2020 
 
 
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92120219_Global Form Clinical Study Protocol Template (Post-Market)_Rev/Ver AA 
Confidential                                                     PREEMPT-HF Protocol, 92216931, Rev/Ver B  
Page 3 of 71 
  
 
Original Release: 14-Mar-2018 
Current Version: 10-Apr-2018 
 
Revision 
Version 
Protocol 
Date 
Template 
number 
and 
version 
Protocol 
Section 
Modified 
Existing Text 
as Written in 
Protocol, 
Version  
Revised/New 
Text as Written 
in 
Protocol, 
Version  
Justification 
for 
Modification 
A 
14-Mar-
2018 
92120219 
AA 
NA 
Ver A 
Ver A  
NA 
B 
06-Apr-
2018 
92120219 
AA 
Synopsis; 
1; 3.1; 4;. 
Figure 2;  
4.2; Figure 
3; 5.2; 
Figure 4; 
6.4; 7.3; 
8.2; 8.4; 
9.5; 9.5.1; 
9.6; 9.7; 
9.8; 9.11; 
Table 9; 
10.1.2; 
10.1.3; 
10.3; 
10.5.1; 
10.5.2; 
10.7; 11.2; 
14.6; 17.1; 
Table 17.2; 
17.5; 17.7; 
17.8; 18; 
20.3; 21;   
Ver A 
Punctuation, 
grammatical and 
formatting 
corrections 
NA 
B 
06-Apr-
2018 
92120219 
AA 
3.1 
Removed: If 
feasible, the 
linked data set 
will be used 
to compare 
claims-based 
inpatient 
events with 
study 
collected 
hospitalizatio
ns, assess the 
accuracy of 
claims-based 
algorithms to 
identify 
NA 
Redudant 
information  
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92120219_Global Form Clinical Study Protocol Template (Post-Market)_Rev/Ver AA 
Confidential                                                     PREEMPT-HF Protocol, 92216931, Rev/Ver B  
Page 4 of 71 
  
Revision 
Version 
Protocol 
Date 
Template 
number 
and 
version 
Protocol 
Section 
Modified 
Existing Text 
as Written in 
Protocol, 
Version  
Revised/New 
Text as Written 
in 
Protocol, 
Version  
Justification 
for 
Modification 
sensor 
detected 
events, and 
estimate the 
cost savings 
from 
avoidable 
hospitalizatio
ns. 
B 
06-Apr-
2018 
92120219 
AA 
5.2, 3.; 10.3 
Removed: 
non-study  
Replaced: third-
party 
Clarification 
B 
06-Apr-
2018 
92120219 
AA 
8.2 
Removed: If 
the patient 
opts in for 
data linkage 
in the 
informed 
consent, then 
additional 
device data 
may be used 
for data 
linkage 
beyondthe 
point of 
withdrawal as 
specified in 
section 9.5 
NA 
Consistency 
with informed 
consent  
B 
06-Apr-
2018 
92120219 
AA 
9.5.1 
Removed: 
investigate the 
feasibility of 
linking study 
data to non 
study data. 
Therefore the 
informed 
consent will 
contain a 
specific 
provision for 
patients to opt 
in for the use 
of their study 
for future 
research 
conducted by 
Boston 
Scientific 
also link study 
data to third-
party data 
sources 
Consistency 
with informed 
consent 
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92120219_Global Form Clinical Study Protocol Template (Post-Market)_Rev/Ver AA 
Confidential                                                     PREEMPT-HF Protocol, 92216931, Rev/Ver B  
Page 5 of 71 
  
Revision 
Version 
Protocol 
Date 
Template 
number 
and 
version 
Protocol 
Section 
Modified 
Existing Text 
as Written in 
Protocol, 
Version  
Revised/New 
Text as Written 
in 
Protocol, 
Version  
Justification 
for 
Modification 
related to data 
linkage. 
B 
06-Apr-
2018 
92120219 
AA 
9.5.1 
N/A 
Added: Data 
linkage will 
focus on disease 
states and 
comorbidities 
common in 
device patients 
such as heart 
failure, 
hypertension, 
cardiac 
arrhythmias, 
acute coronary 
syndrome, heart 
valve disorders, 
respiratory 
disease, renal 
disease, 
gastrointestinal 
disease, sleep 
apnea, 
infectious 
disease etc. 
 
Added 
additional detail 
regarding 
purpose of data 
linkage.   
B 
06-Apr-
2018 
92120219 
AA 
9.5.1 
Removed: 
The non-study 
data  
Replaced: The 
PREEMPT-HF 
study data  
Clarification 
B 
06-Apr-
2018 
92120219 
AA 
9.5.1 
N/A 
Added: 
PREEMPT-HF 
study data will 
be used in 
combination 
with internal 
BSC databases 
(e.g., device 
tracking 
database) to 
obtain, use and 
disclose certain 
protected health 
information to 
third parties. 
This may 
include device 
serial and model 
Clarification 
regarding data 
linkage  
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92120219_Global Form Clinical Study Protocol Template (Post-Market)_Rev/Ver AA 
Confidential                                                     PREEMPT-HF Protocol, 92216931, Rev/Ver B  
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Revision 
Version 
Protocol 
Date 
Template 
number 
and 
version 
Protocol 
Section 
Modified 
Existing Text 
as Written in 
Protocol, 
Version  
Revised/New 
Text as Written 
in 
Protocol, 
Version  
Justification 
for 
Modification 
number, last 
name, date of 
birth, address, 
zip code, the last 
four digits of the 
subject’s social 
security number, 
implant date, 
and the hospital 
where the 
implant 
procedure was 
performed.  
B 
06-Apr-
2018 
92120219 
AA 
9.5.1 
N/A 
Added: 
(wording in 
red): The third-
party data 
sources include 
but are not 
limited to payer 
administrative 
claims and 
health analytics 
(e.g., Medicare, 
Medicaid. 
Truven, Optum) 
Clarification 
B 
06-Apr-
2018 
92120219 
AA 
9.5.1 
Removed: In 
patients who 
opt in, study 
data (such as 
device and 
lead serial and 
model 
number) will 
be used with 
internal BSC 
databases 
(e.g., device 
tracking 
database) to 
obtain, use 
and disclose 
certain 
protected 
health 
information to 
third parties to 
enable 
database 
Added: The 
subject may 
withdraw 
permission for 
the use and 
sharing of 
personal health 
information at 
any time if 
provided in 
writing to the 
study doctor. 
Please notify 
Boston 
Scientific of any 
subjects that 
submit in 
writing their 
request to 
withdraw their 
permission for 
the use of 
personal health 
Added details 
regarding 
personal health 
information; 
added details on 
how a patient 
can withdraw 
consent for the 
use of personal 
information.  
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92120219_Global Form Clinical Study Protocol Template (Post-Market)_Rev/Ver AA 
Confidential                                                     PREEMPT-HF Protocol, 92216931, Rev/Ver B  
Page 7 of 71 
  
Revision 
Version 
Protocol 
Date 
Template 
number 
and 
version 
Protocol 
Section 
Modified 
Existing Text 
as Written in 
Protocol, 
Version  
Revised/New 
Text as Written 
in 
Protocol, 
Version  
Justification 
for 
Modification 
linkage. 
Device sensor 
data available 
through 
LATITUDE 
and the 
information 
from the 
aforementione
d data sources 
may be linked 
for up to 
seven (7) ears 
after study 
completion.  
information.  
B 
06-Apr-
2018 
92120219 
AA 
9.8 
 
If this review 
coincides with 
an in-clinic visit, 
the subject must 
be asked 
whether he or 
she had any 
reviewable 
clinical events 
(RCEs) since 
the baseline 
visit. As defined 
in section 5.1, 
an RCE is 
defined as either 
an all-cause 
hospitalization, 
or HF outpatient 
visit. If the 
subject reports 
having an RCE 
at a center not 
participating in 
the study, every 
effort  should be 
made to obtain 
medical records 
from the center. 
Clarification 
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Confidential                                                     PREEMPT-HF Protocol, 92216931, Rev/Ver B  
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1 
Protocol Synopsis 
PREcision Event Monitoring of PatienTs with Heart Failure using HeartLogicTM     
(PREEMPT-HF) 
Study 
Objective(s) 
The goal of the PREEMPT-HF study is to collect device and clinical 
event data to evaluate extended applications of the HeartLogicTM Heart 
Failure Diagnostic (HeartLogic) in a broad spectrum of heart failure (HF) 
patients with an implantable cardioverter defibrillator (ICD) or cardiac 
resynchronization therapy defibrillator (CRT-D). There are no primary 
safety and/or efficacy endpoints for this study. 
 
Subjects will be followed for approximately 12 months after the baseline 
visit to collect the required number of clinical events to support the study 
objectives. These events are called Reviewable Clinical Events (RCEs), 
and include all-cause hospitalizations and HF outpatient visits.  
 
Clinical event definitions are as follows:  
• Hospitalization (all-cause): the subject is admitted to inpatient 
hospital care and discharged on a different calendar date. 
• HF Hospitalization: the subject is admitted with 
signs/symptoms of congestive heart failure (CHF) and receives 
unscheduled augmented HF therapy with oral or intravenous 
medications, ultrafiltration therapy or other parenteral therapy.  
• HF Readmission (30-day): the subject is admitted for an 
unplanned hospitalization for any cause within 30 days post 
discharge from a HF hospitalization. 
• HF Outpatient Visit: the subject has signs/symptoms of CHF, 
and receives unscheduled intravenous decongestive therapy 
(e.g., IV diuretics, IV inotropes, IV vasoactive drugs, 
ultrafiltration) in a setting that does not involve a hospitalization 
(e.g., emergency room, HF clinic, primary care clinic, etc.). 
 
Primary Objective 
The primary objective of the PREEMPT-HF study is to investigate the 
association between HF sensor data and 30-day HF readmissions.  
 
Additional Objectives 
1. Characterize HF sensor data for: 
o Association with risk for device VT/VF therapy 
o Phenomapping of HF events  
o Association with non-HF hospitalizations including 
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Confidential                                                     PREEMPT-HF Protocol, 92216931, Rev/Ver B  
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PREcision Event Monitoring of PatienTs with Heart Failure using HeartLogicTM     
(PREEMPT-HF) 
cardiac non-HF events and non-cardiac events 
2. Collect subject Sleep Incline Sensor data prior to and following 
reviewable clinical events 
3. Link study data to third-party data, such as Center for Medicare 
and Medicaid Services (CMS) administrative claims (US only). 
Association of clinical study events and sensor data with other 
data sources will be investigated. Any study data linkage will 
abide by all applicable laws, regulations, and data use agreements, 
and patients will be consented accordingly.  
Indication(s) for 
Use  
The study will use commercially approved Boston Scientific CRT-D and 
ICD devices that contain the HeartLogic feature. Only subjects that meet 
the eligibility criteria will be enrolled in the study.  
Commercial 
Device/System 
The LATITUDETM system, ICD and CRT-D devices with the HeartLogic 
feature, and programmed as follows: 
Feature/Sensor 
Programmed 
Heart Failure Sensors 
ON 
Respiratory Sensor 
ON 
Sleep Incline Sensor 
ON 
HeartLogic 
Disabled on LATITUDE 
 
 
 
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Study Design 
The PREEMPT-HF study is a global, multi-center, post-market 
prospective, non-randomized study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Planned 
Number of 
Subjects 
Up to 3750 subjects will be enrolled. An interim analysis is planned to 
determine final sample size. 
Planned 
Number of Sites 
/ Countries 
Up to 200 sites in the United States, Canada, Europe and Asia Pacific. 
Primary Safety 
Endpoint 
This is a post-market study with no primary safety endpoint. 
Primary 
Effectiveness 
Endpoint 
This is a post-market study with no primary effectiveness endpoints. 
Additional 
Endpoints 
This is a post-market study with no secondary endpoints. 
Subject Consent 
and Enrollment 
Visit  
(post implant) 
enrollment 
Baseline Visit 
(Must occur ≥7 days post 
implant and ≤ 30 days 
post enrollment) 
Interim Medical 
Record Review 
[NO subject visit 
required] 
 
6 Month 
Final Clinic Visit 
 
12 Month  
Study Exit 
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Method of 
Assigning 
Patients to 
Treatment 
There is no randomization as all subjects are assigned to a single group 
and are followed with HeartLogic disabled. The investigator will have 
access to an electronic database which will be used to generate the patient 
ID and all eCRFs for subjects enrolled in the clinical study. 
Follow-up 
Schedule 
The required protocol study visits and medical record reviews are as 
follows: 
• Enrollment visit  
• Baseline visit 
• Interim medical record review (6 month, does not require a 
clinic visit) 
• Final clinic visit (12 month, or at the point of withdrawal) 
 
Subjects will exit the study following their final clinic visit.  
Study Duration The study duration is estimated to be 6 years from first patient enrollment 
to study closure. 
Participant 
Duration 
The study duration for each subject is expected to be approximately 12 
months from enrollment to the final clinic visit. A patient can be in the 
study for up to 460 days (15 months) if the maximum visit windows are 
taken in to account. 
Inclusion 
Criteria 
• Subject is age 18 or above, or of legal age to give informed consent 
specific to each country and national laws. 
• Subject has a documented diagnosis of heart failure. 
• Subject has a Boston Scientific CRT-D or ICD device implant that 
has HeartLogic, with Heart Failure Sensors turned ON, Respiratory 
Sensor turned ON, and Sleep Incline Sensor turned ON.  
• Subject has an active bipolar RV lead implant. 
• Subject is enrolled in LATITUDE (NXT 5.0 or future version), and is 
willing to be remotely monitored from the baseline visit for 
approximately 12 months with HeartLogic disabled.  
Exclusion 
Criteria 
• Subject has received or is scheduled to receive a heart transplant or 
ventricular assist device (VAD). 
• Subject is enrolled in any concurrent clinical study without prior 
Boston Scientific written approval (excluding registries). 
• Subject has a life expectancy of less than 12 months. 
• Subject has a history of non-compliance to medical care or known 
inability to comply with requirements of the clinical study protocol.  
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Statistical Methods  
Primary 
Statistical 
Hypothesis 
There is no statistical hypothesis. The primary objective of the 
PREEMPT-HF study is to investigate association between HF sensor data 
and 30-day HF readmissions.  
Statistical Test 
Method 
The following statistical analyses will be used to evaluate the objectives 
of the study: 
 
Primary Objective  
The difference in sensor trends pre-admission and post-discharge will be 
compared between subjects with and without a 30-day HF readmission. 
The comparison will be evaluated using a two-sample t-test for each HF 
sensor measurement. 
 
Additional Objectives 
1. Association with risk for device VT/VF: will be evaluated using 
an odds ratio. 
2. Phenomapping of HF events: will be evaluated using cluster 
analysis. 
3. Association with non-HF hospitalizations including cardiac non-
HF events and non-cardiac events: will be evaluated using a 
paired t-test for each HF Sensor. 
Sample Size 
Parameters 
Up to 3750 enrolled subjects are necessary to evaluate the primary 
objective. An index HF hospitalization refers to the first HF 
hospitalization during the study follow-up period. A HF hospitalization is 
deemed usable if sensor data is available during the event and sufficient 
follow up time is recorded to determine if a readmission occurs. 
 
A total of 215 usable index HF hospitalizations are required to have at 
least 80% power to detect a standardized difference of 0.5 in the mean 
sensor change (admission – discharge) between the groups with and 
without a 30-day HF readmission. It is expected that of the 215-usable 
index (first during the study) HF hospitalizations, 43 will be followed by 
a 30-day readmission (20%). 
 
Based on the following assumptions, a total of 215 usable index HF 
hospitalizations are required: 
• 80% Power to detect a standardized mean difference of 0.5 
between groups 
• Two-sided Type I error (alpha) of 0.05 
• 3:1 ratio of group sizes (no-readmission:30-day HF readmission), 
where the no-readmission group will exclude index HF 
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hospitalizations with 31 to 60-day readmissions 
 
Assuming a 20% loss of usable HF events due to proximity to study start 
and exit (completion or withdrawal), a total of 270 index HF 
hospitalizations are required to obtain 215 usable HF hospitalizations. 
 
Based on the following assumptions, up to 3750 subject enrollments are 
required to obtain the 270 required HF hospitalizations: 
• 9 % index HF hospitalization rate 
• 20% death/withdrawal over entire length of the study 
• Average of 12 months of sensor data per patient 
 
 
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2 
Table of Contents 
1 
PROTOCOL SYNOPSIS .......................................................................................................... 8 
2 
TABLE OF CONTENTS ........................................................................................................ 14 
2.1 
Table of Figures ...................................................................................................... 18 
2.2 
Table of Tables ....................................................................................................... 18 
3 
INTRODUCTION ................................................................................................................. 19 
3.1 
Study Rationale and Background ......................................................................... 19 
4 
COMMERCIAL DEVICE DESCRIPTION .............................................................................. 21 
4.1 
Device Description .................................................................................................. 21 
4.2 
Medical Equipment Description ........................................................................... 22 
5 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................... 24 
5.1 
Primary Objective .................................................................................................. 24 
5.2 
Study Endpoints ..................................................................................................... 26 
6 
STUDY DESIGN .................................................................................................................. 26 
6.1 
Scale and Duration ................................................................................................. 28 
6.2 
Treatment Assignment .......................................................................................... 28 
6.3 
Treatment and Control .......................................................................................... 28 
6.4 
Justification for the Study Design ......................................................................... 28 
7 
SUBJECT SELECTION ......................................................................................................... 29 
7.1 
Study Population and Eligibility ........................................................................... 29 
7.2 
Inclusion Criteria ................................................................................................... 29 
7.3 
Exclusion Criteria .................................................................................................. 29 
8 
SUBJECT ACCOUNTABILITY .............................................................................................. 29 
8.1 
Point of Enrollment ................................................................................................ 29 
8.2 
Withdrawal ............................................................................................................. 30 
8.3 
Lost to Follow-Up ................................................................................................... 30 
8.4 
Subject Status and Classification .......................................................................... 30 
8.5 
End-of-Study Definition ........................................................................................ 31 
9 
STUDY METHODS .............................................................................................................. 31 
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9.1 
Data Collection ....................................................................................................... 31 
9.2 
Device Interrogation / Collection of Programming data .................................... 32 
9.3 
Study Candidate Screening ................................................................................... 33 
9.4 
Strategies for Recruitment and Retention ........................................................... 33 
9.5 
Informed Consent .................................................................................................. 33 
9.5.1 
Data Linkage .............................................................................................. 33 
9.6 
Enrollment Visit ..................................................................................................... 34 
9.7 
Baseline Visit [Day 0] ............................................................................................. 34 
9.8 
Interim Medical Record Review [150-210 days] ................................................. 36 
9.9 
Final Clinic Visit  [350-430 days] .......................................................................... 37 
9.10 Study Completion ................................................................................................... 38 
9.11 Source Documents .................................................................................................. 38 
9.11.1 
Enrollment Visit ......................................................................................... 38 
9.11.2 
Baseline Visit ............................................................................................. 38 
9.11.3 
Interim Medical Record Review ................................................................ 39 
9.11.4 
Final Clinic Visit ........................................................................................ 39 
9.11.5 
Reviewable Clinical Events ....................................................................... 39 
10 STATISTICAL CONSIDERATIONS ....................................................................................... 41 
10.1 Primary Endpoint .................................................................................................. 41 
10.1.1 
Hypotheses ................................................................................................. 41 
10.1.2 
Sample Size ............................................................................................... 41 
10.1.3 
Statistical Methods ..................................................................................... 42 
10.2 Secondary Endpoints ............................................................................................. 42 
10.3 Other Objectives/Measurements .......................................................................... 42 
10.4 General Statistical Methods .................................................................................. 43 
10.5 Analysis Sets ........................................................................................................... 43 
10.5.1 
Primary analysis ......................................................................................... 43 
10.5.2 
Additional analyses .................................................................................... 43 
10.6 Control of Systematic Error/Bias ......................................................................... 43 
10.7 Number of Subjects per Investigational Site ....................................................... 43 
10.8 Other Endpoints/Measurements ........................................................................... 43 
10.9 Interim Analyses .................................................................................................... 43 
10.10 Subgroup Analyses ................................................................................................. 44 
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10.11 Justification of Pooling .......................................................................................... 44 
10.12 Multivariable Analyses .......................................................................................... 44 
10.13 Changes to Planned Analyses ................................................................................ 44 
11 DATA MANAGEMENT ........................................................................................................ 44 
11.1 Data Collection, Processing, and Review ............................................................. 44 
11.2 Data Retention ........................................................................................................ 45 
12 DEVIATIONS ...................................................................................................................... 45 
13 DEVICE/EQUIPMENT ACCOUNTABILITY .......................................................................... 46 
14 COMPLIANCE ..................................................................................................................... 46 
14.1 Statement of Compliance ....................................................................................... 46 
14.2 Investigator Responsibilities ................................................................................. 46 
14.3 Delegation of Responsibility .................................................................................. 48 
14.4 Institutional Review Board/ Research Ethics Board / Ethics Committee ......... 48 
14.5 Sponsor Responsibilities ........................................................................................ 48 
14.6 Role of Boston Scientific Representatives ............................................................ 49 
14.7 Insurance ................................................................................................................. 50 
15 MONITORING ..................................................................................................................... 50 
16 POTENTIAL RISKS AND BENEFITS .................................................................................... 50 
16.1 Directions for Use ................................................................................................... 50 
16.2 Risks Associated with Participation in the Clinical Study ................................. 51 
16.3 Possible Interactions with Concomitant Medical Treatments, if Applicable ... 51 
16.4 Risk Minimization Actions .................................................................................... 51 
16.5 Anticipated Benefits ............................................................................................... 51 
17 SAFETY REPORTING .......................................................................................................... 51 
17.1 Reportable Events by Investigational Site to Boston Scientific ......................... 51 
17.2 Definitions and Classification ............................................................................... 52 
17.3 Relationship to Device(s) ....................................................................................... 54 
17.4 Investigator Reporting Requirements .................................................................. 55 
17.5 Safety definitions .................................................................................................... 57 
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17.6 Boston Scientific Device Deficiencies .................................................................... 59 
17.7 Reporting to Regulatory Authorities / IRBs / ECs / REBs/ Investigators ........ 59 
17.8 Subject Death Reporting ....................................................................................... 59 
18 INFORMED CONSENT ......................................................................................................... 60 
19 COMMITTEES .................................................................................................................... 61 
19.1 Safety Monitoring Process ..................................................................................... 61 
19.2 BSC Internal Medical Record Review ................................................................. 62 
20 SUSPENSION OR TERMINATION ......................................................................................... 62 
20.1 Premature Termination of the Study ................................................................... 62 
20.2 Criteria for Premature Termination of the Study .............................................. 62 
20.3 Termination of Study Participation by the Investigator or Withdrawal of 
IRB/ EC/REB Approval ........................................................................................ 62 
20.4 Requirements for Documentation and Subject Follow-up ................................. 62 
20.5 Criteria for Suspending/Terminating a Study Site ............................................. 63 
21 PUBLICATION POLICY ....................................................................................................... 63 
22 REIMBURSEMENT AND COMPENSATION FOR SUBJECTS .................................................. 64 
22.1 Subject Reimbursement ........................................................................................ 64 
22.2 Compensation for Subject’s Health Injury ......................................................... 64 
23 BIBLIOGRAPHY .................................................................................................................. 64 
24 ABBREVIATIONS AND DEFINITIONS .................................................................................. 67 
24.1 Abbreviations ......................................................................................................... 67 
24.2 Definitions ............................................................................................................... 69 
25 APPENDIX .......................................................................................................................... 70 
25.1 Data Collection Requirements for Demographics, Cardiac Disease History, 
Physical Assessment and Blood Labs ................................................................... 70 
25.2 PI Classification of Primary Organ Cause .......................................................... 71 
 
 
 
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2.1 Table of Figures 
Figure 1: Example of Implantable Devices Used in PREEMPT-HF Study ........................... 21 
Figure 2: LATITUDE NXT 5.0 System ................................................................................. 22 
Figure 3:  Reviewable Clinical Events Data Requirements in relation to AE reporting ........ 25 
Figure 4: PREEMPT-HF Study Design .................................................................................. 27 
 
2.2 Table of Tables 
Table 4-1 Device Models ........................................................................................................ 22 
Table 6-1: Visit and Review Schedule .................................................................................... 27 
Table 7-1: Inclusion Criteria ................................................................................................... 29 
Table 7-2: Exclusion Criteria .................................................................................................. 29 
Table 9-1 Data Collection Schedule ....................................................................................... 32 
Table 9-2 Source Documentation Requirements for Reviewable Clinical Events ................. 40 
Table 17-1: Safety Definitions ................................................................................................ 52 
Table 17-2: Criteria for Assessing Relationship of Study Device or Procedure to Adverse 
Event .................................................................................................................... 54 
Table 17-3: Communication Requirements for Adverse Events ............................................ 56 
Table 17-4 Safety Definitions ................................................................................................. 57 
Table 24-1: Abbreviations ...................................................................................................... 67 
Table 24-2: Definitions ........................................................................................................... 69 
 
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3 
Introduction 
3.1 Study Rationale and Background 
Heart failure (HF) is a complex clinical syndrome with high morbidity, mortality, and 
economic burden1, 2. Chronic HF is persistent, gradually progressive, and punctuated by 
episodes of acute worsening leading to hospitalizations3. Therefore, there remains an unmet 
clinical need to slow the progression of HF and prevent hospitalizations. HeartLogicTM, 
available in Boston Scientific cardiac resynchronization therapy devices and defibrillators 
(CRT-Ds and ICDs), combines novel sensor parameters such as heart sounds and respiration 
with other measurements like thoracic impedance, heart rate, and activity into a HeartLogic 
Index for the early detection of worsening HF4, 5. However, there is limited data on the 
association of HeartLogic with the risk of HF readmissions and tachyarrhythmias, or for 
phenotyping the broad spectrum of HF patients.   
Thus, the goal of the PREEMPT-HF study is to collect data aimed at extending HeartLogic 
applications. Specific study objectives are listed below.  
(1) Associate HF sensor data with HF 30-day readmission: Hospitalizations due to 
worsening HF are associated with high post-acute re-hospitalization and mortality, 
which in turn has led payers to impose financial penalties targeted at reducing 
readmissions while improving care quality6. Recent data from fee-for-service 
Medicare beneficiaries indicate that these incentives have reduced readmission rate; 
but, the magnitude of readmission reduction has been modest (from 23.5% in 2008 to 
21.4% in 2014), the rate of decline has slowed, and the mortality has not improved7. 
Readmission risk stratification algorithms developed to date have utilized clinical and 
patient data8, 9. The ability to further reduce readmissions will require new 
approaches. For example, implantable device diagnostics have been used to risk 
stratify HF patients for readmissions10, and pulmonary artery pressure guided HF 
management has been associated with a 59% reduction in 30-day HF readmissions11. 
The PREEMPT-HF study will evaluate the novel HF sensor parameters for 
readmission detection and patient risk stratification. In order to evaluate the 
incremental benefit of sensor data for readmissions, only patients with HeartLogic 
disabled will be included in the study. 
(2) Characterize HF sensor data for association with risk of tachyarrhythmias and 
device therapy: Acute HF exacerbations are presumed to trigger atrial and ventricular 
tachyarrhythmias through a number of mechanisms including increased cardiac filling 
pressure and neurohormonal activation12-15; however patient risk assessment for 
malignant arrhythmias is subjective and device sensor based algorithms for risk 
stratification using traditional device sensors have had only modest accuracy16-19. 
Similarly, a new onset or worsening of atrial or ventricular tachyarrhythmia may 
itself be a trigger for worsening of HF. The PREEMPT-HF study will investigate the 
association between the HeartLogic Index and patient risk for device ventricular 
tachycardia/fibrillation (VT/VF) therapy. 
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(3) Characterize HF sensor data for phenomapping of HF events: Clinical practitioners 
have recognized that HF is comprised of multiple heterogeneous entities including 
HF with reduced, preserved, and mid-range ejection fraction (HFrEF, HFpEF, and 
HFmEF)20. Similarly, acute worsening HF has been classified by hemodynamic 
profiles incorporating congestion (wet/dry) and perfusion (warm/cold). However, 
physiological measurements underlying clinical classifications exhibit significant 
variation. For example, even though the majority (>80%) of patients admitted for 
worsening HF show clinical signs or symptoms of volume overload, there is a wide 
distribution of body fluid and its composition21. Data driven approaches such as 
cluster analysis has been applied to phenotype HFrEF22 and HFpEF23, but continuous 
data collected by implanted devices have not been utilized. The PREEMPT-HF study 
will collect data to investigate machine learning and clustering approaches for event 
classification using HF sensor data and baseline clinical variables. This type of 
unbiased dense phenotype mapping is known as phenomapping.  
(4) Characterize association of HF sensor data with non-HF hospitalizations: Due to 
aging and the convergence of cardiac disease and other comorbid conditions, 
approximately 3 out of 4 hospitalizations in HF patients are classified as unrelated to 
HF by event adjudication committees24, 25. Therefore, strategies to reduce 
hospitalizations should consider both cardiac and non-cardiac conditions. Preliminary 
data from the MultiSENSE showed that non-cardiac hospitalizations were associated 
with sensor changes including impedance, heart rate, heart rate variability and the 
first heart sound; however additional data are needed in more specific event 
subgroups26. The interrelationship of HF with other disease states is underscored by 
the observation that pulmonary artery pressure driven HF management is associated 
with a reduction in hospitalizations related to respiratory disease27. Data from the 
PREEMPT-HF study will be used to further investigate the relation between diverse 
HF Sensor measurements and non-HF related events. 
(5) Collect data on patient sleep incline leading up to and following clinical events: 
Because orthopnea and paroxysmal nocturnal dyspnea are hallmarks of worsening 
HF, devices with HeartLogic are equipped with a Sleep Incline Sensor to measure the 
subject’s night-time elevation angle. A cross-sectional analysis of data from the 
MultiSENSE study (N=46 patients in 65 visits) showed that orthopnea symptoms 
were associated with increased sleep incline angle (mean±SEM of 23.2±2.8 degrees 
vs. 10.7±1.7 degrees)28. The PREEMPT-HF study will extend this analysis to a 
longitudinal assessment of sensor measurements in the vicinity of hospitalization 
events. 
(6) Investigate feasibility of linking study data to administrative claims: The capability to 
cost-effectively develop and test future device diagnostics may be dependent on the 
ability to link broad data sets, and validate knowledge obtained from multiple sources 
using data driven approaches, while ensuring the protection of patient privacy and 
data confidentiality29, 30. The utilization of claims data linked to remote monitoring 
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data offer a glimpse into how device features can be evaluated without expensive 
clinical trials31-33. The PREEMPT-HF study aims to assess the feasibility of linking 
claims data with comprehensive device and other study data in applicable 
geographies. For example, in the United States the Centers for Medicare and 
Medicaid Services (CMS) has instituted an Innovator Research Program to allow 
access to claims data for research34.  
4 
Commercial Device Description  
4.1 Device Description 
The PREEMPT-HF study will use Implanted Cardioverter Defibrillator (ICD) or Cardiac 
Resynchronization Therapy Defibrillator (CRT-D) device models that are commercially 
approved and contain the HeartLogic HF diagnostic feature (Figure 1). For a full description 
of the HeartLogic feature, please refer to the labeling. 
 
The implanted portion of the study system includes the CRT-D or ICD pulse generator (PG), 
along with its associated commercially available leads. For the PREEMPT-HF study, BSC 
CRT-D and ICDs can be associated with leads from any manufacturer. The models being 
used are shown in Table 4-1, but future device models with the HeartLogic feature may also 
be included as they become commercially available. In addition, a Programmer Recorder 
Monitor (PRM) with appropriate software must be used to interrogate the device (Model 
2868 Application Software, v4.04 or other compatible version).  
Figure 1: Example of Implantable Devices Used in PREEMPT-HF Study 
 
 
 
 
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Table 4-1 Device Models 
Device Trade Names* 
 
RESONATE™ X4 CRT-D Models – G447 
RESONATE™ EL ICD Models – D432, D433 
 
MOMENTUM™ CRT-D Models – G124, G125, G126 
MOMENTUM™ X4 CRT-D Models – G138  
MOMENTUM™ EL ICD Models – D120, D121 
 
VIGILIANT™ X4 CRT-D Models – G247 
VIGILIANT™ EL ICD Models – D232, D233 
 
PERCIVA™ ICD Models – D400, D401, D412, D413 
 
Model 2868 Application Software, v4.04 (or future equivalents) 
*Future models that are compatible with the study may also be used.  
4.2 Medical Equipment Description 
The external portion of the system includes the commercially available LATITUDE NXT 5.0 
patient management system (or future versions) and the PRM. LATITUDE is a remote 
monitoring system (Figure 2) that gathers data from the PG and external sensors (blood 
pressure monitor and weight scale) and transmits it to a web server. LATITUDE enables 
physicians to remotely monitor both device and patient status. The LATITUDE 
communicator uses wireless telemetry to transfer data from the implanted device and external 
sensors to the web server, which can be accessed by the study doctor and Boston Scientific. 
Figure 2: LATITUDE NXT 5.0 System 
 
 
 
 
 
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The primary means of device data collection for the PREEMPT-HF study is through the 
LATITUDE patient management system. Therefore, LATITUDE enrollment is required for 
subject participation in the study, and data transmission via LATITUDE (i.e., referred to as 
“monitored on LATITUDE”) must be confirmed at the baseline visit. During the course of 
the study if the subject is away from the communicator, sensor data storage to PG memory 
will continue; however, the next data upload will not occur until the subject is within range 
of the communicator. To ensure timely data transmission, LATITUDE must be programmed 
for scheduled follow-ups to occur every 3 months or sooner. At the final study visit, the 
investigational site must interrogate the subject’s device using the PRM. This will trigger a 
remote data upload to LATITUDE when the subject returns within range of the 
communicator. 
 
For the PREEMPT-HF study, Heart Failure Sensors must be turned ON. This must be done 
via the PRM. The Heart Failure Sensors consists of heart sounds (S3 and S3/S1), respiration 
(respiratory rate and rapid shallow breathing index), impedance, heart rate and activity.  
 
Only subjects with Heart Failure Sensors turned On, Respiratory Sensor turned ON, and 
HeartLogic disabled are eligible to participate in the study. The state where HeartLogic is not 
enabled on LATITUDE is referred to as HeartLogic disabled. In this state, the device will 
continue to collect sensor data, but the HeartLogic Index and Heart Sounds sensor trends will 
not be displayed on the LATITUDE system, and clinicians will not receive HeartLogic alerts. 
Sensor data will be stored in the PG for 365 days after which the earliest data are overwritten. 
The subject must be withdrawn from the study if Heart Failure Sensors will be turned OFF, 
or if HeartLogic will be enabled. Subjects may remain in the study if the Respiratory Sensor 
or Sleep Incline Sensor are turned OFF; however, this will be considered as a protocol 
deviation. The Sleep Incline Sensor measures the subject’s average elevation angle over the 
programmed sleep schedule. Sleep schedule can be programmed using the PRM.  
 
Following device implant, the Sleep Incline Sensor requires a minimum of seven (7) days for 
initialization, after which sensor calibration must be performed. Initialization may take 
longer if subject lacks diversity in his/her body orientations during this period. Calibration 
can be performed using a single-position method with the subject in upright posture, or a 
two-position method using both upright and supine postures. A two-position calibration is 
recommended when possible. During calibration, the subject must be fully vertical or 
horizontal when the PRM captures the upright and supine postures respectively.  
 
The impedance and sleep incline trends will be visible on LATITUDE even when 
HeartLogic is disabled. Therefore, information about the subject’s participation in a remote 
monitoring program using these sensors will be collected at the end of the study and will be 
used for analysis.  
 
Boston Scientific has performed safety risk management activities, design verification and 
design validation testing to demonstrate that devices with HeartLogic function safely and 
effectively per the design intent. The products conform to user needs and intended use, all 
system-level requirements have been tested with no uncorrected failures, and the risk is 
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acceptable for normal product use in accordance with product labeling. A copy of the 
Instructions for Use and device labelling can be provided in local language(s) as required per 
national regulations. 
5 
Study Objectives and Endpoints 
The PREEMPT-HF study is designed to collect device and clinical event data to evaluate 
extended applications of HeartLogic in a broad sample of HF subjects with an implantable 
ICD or CRT-D.  
5.1 Primary Objective 
The primary objective of the PREEMPT-HF study is to investigate the association between 
HF Sensor data and 30-day HF readmissions.  
 
Subjects will be followed for approximately 12 months to collect the required number of 
clinical events to support the study objectives. These events are called Reviewable Clinical 
Events (RCEs), and include all-cause hospitalizations and HF outpatient visits (as defined 
below).  
 
RCEs require the investigational site to review the subject’s medical records and complete 
the appropriate eCRF (Figure 3). 
 
Clinical events for the purposes of data analysis are defined as follows:  
• Hospitalization (all-cause): the subject is admitted to inpatient hospital care and 
discharged on a different calendar date. 
• HF Hospitalization: the subject is admitted with signs/symptoms of congestive 
heart failure (CHF) and receives unscheduled augmented HF therapy with oral or 
intravenous medications, ultrafiltration therapy or other parenteral therapy.  
• HF Readmission (30-day): the subject is admitted for an unplanned hospitalization 
for any cause within 30 days post discharge from a HF hospitalization. 
• HF Outpatient Visit: the subject has signs/symptoms of congestive HF, and 
receives unscheduled intravenous decongestive therapy (e.g., IV diuretics, IV 
inotropes, IV vasoactive drugs, ultrafiltration), in a setting that does not involve a 
hospitalization (e.g.: emergency room, HF clinic, primary care clinic, etc.).  
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Figure 3:  Reviewable Clinical Events Data Requirements in relation to AE reporting 
All cause hospitalization
Heart failure outpatient visit  
PI Classification is cardiac 
hospitalization?
Has one of the following reviewable 
clinical events (RCEs) occurred? 
 
•
All-cause hospitalization
•
Heart failure outpatient visit with IV 
decongestive therapy
•
PI review of medical record
•
PI classification of primary cause 
that led to the admission
Was one of the following 
conditions associated with 
the hospitalization?
•
Primary cause of renal?
•
Primary cause of pulmonary?
•
Secondary cause of worsening 
heart failure or inpatient 
worsening of heart failure?
•
90-day re-admission following a 
heart failure hospitalization?
Submit the 
following:
•
Discharge 
summary
Submit the following:
•
Admission/presentation record
•
Discharge summary
•
Medications
•
Physician progress notes 
•
Blood labs (kidney function, 
natuiretic peptides, basic 
metabolic panel)
•
Other diagnostics (ECG, Chest x-
ray, echocardiography summary 
report)
YES
YES
NO
AE reporting per 
Section 17
AE reporting per Section 17 
and source data per 
Reviewable Clinical Events 
requirements Section 9.11.5 
Submit the following:
•
Physician notes
•
Medications
•
Blood labs
NO
YES
NO
 
 
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5.2 Additional Objectives 
Additional objectives of the PREEMPT-HF study are intended to:  
 
1. Characterize HF Sensor data for: 
o Association with risk for device VT/VF therapy 
o Phenomapping of HF events  
o Association with non-HF hospitalizations including cardiac non-HF events 
and non-cardiac events 
2. Collect subject Sleep Incline Sensor data prior to and following reviewable clinical 
events 
3. Link study data to third-party data, such as Center for Medicare and Medicaid 
Services (CMS) administrative claims (US only). Association of reviewable clinical 
study events with other sources will be investigated. Any study data linkage will 
abide by all applicable laws, regulations, and data use agreements, and patients will 
be consented accordingly. 
5.3 Study Endpoints 
PREEMPT-HF is a non-mandated post-market study. Data will be collected in subjects 
treated per usual standard of care procedures. However, the device needs to be programmed 
with Heart Failure Sensors ON and HeartLogic disabled. There are no pre-defined endpoints, 
and there are no special clinical evaluations or tests that are not a part of standard of care. 
6 
Study Design 
PREEMPT-HF study is a global, multi-center, prospective, non-randomized study. The study 
objective is to evaluate extended applications of HF sensor measurements in relation to RCEs 
(i.e., all-cause hospitalizations and HF outpatient visits). Device data will be collected using 
the LATITUDE remote monitoring system. However, it is critical to report RCEs via the 
eCRFs as defined in the study protocol.  
Prior to enrollment, patients who meet the eligibility criteria (Sections 7.2 and 7.3) and agree 
to participate in the study will be asked to sign a Subject Informed Consent document 
approved by an Institutional Review Board/Ethics Committee, or Competent Authority (as 
applicable per local regulations). The follow-up schedule for subjects is shown in Table 6-1, 
and the overall study flow is shown in Figure 4.  
 
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Table 6-1: Visit and Review Schedule 
Visit 
Window 
Enrollment Visit 
The subject may be enrolled at any time following 
device implant  
Baseline Visit 
The baseline visit must be conducted at least 7 days 
following implant, and within 30 days of subject consent  
Interim Medical Record Review 
(6 month) 
150 to 210 days from baseline visit 
Final Clinic Visit 
(12 month) 
350 to 430 days from baseline visit (or at the point of 
withdrawal) 
 
Figure 4: PREEMPT-HF Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All subjects will be evaluated at the baseline visit and will be followed until the final in-clinic 
visit (approximately 12 months). Study visits should be scheduled, if possible, to coincide 
with standard of care visits. At the baseline visit the subject should be provided with a study 
ID card containing contact numbers for site research staff. The subject should be informed to 
contact site research staff if hospitalized or treated with IV HF therapy, including events that 
occur at a non-study hospital or physician’s office.  
Subject Consent and 
Enrollment Visit 
(post implant) 
enrollment 
Baseline Visit 
(Must occur ≥7 days post 
implant and ≤ 30 days post 
enrollment) 
Interim Medical 
Record Review [NO 
subject visit required] 
 
6 Month 
Final Clinic Visit 
 
12 Month  
Study Exit 
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An interim medical record review is required at 6 months to capture study clinical events (see 
section 6). No subject visit is required. Accurate and comprehensive capture of RCEs is 
critical for the success of the study. When possible, this medical record review should 
coincide with an in-clinic standard of care visit so that the investigator can ask the subject 
about any RCEs that may have occurred since the last visit.  
During the final clinic visit (12 months or at the point of withdrawal), a device interrogation 
using the PRM must be performed. This ensures that the device data will be uploaded the 
next time the subject is in contact with their LATITUDE system at home. Once the site has 
confirmed device data transfer via LATITUDE, the end of study eCRF must be completed. 
There will be no further data collection for that subject. Individual subjects are then exited 
from the study, and the Heart Failure Sensors and feature can be programmed per clinician 
discretion. 
6.1 Scale and Duration 
Up to 3750 subjects will be enrolled in United States, Canada, Europe, and Asia Pacific. 
Sites may continue to enroll subjects until notified of enrollment completion. The maximum 
enrollment ceiling per site is 375 subjects. Enrollments are expected to occur over a period of 
approximately 60 months. Subjects enrolled in the study will be followed for approximately 
12 months. A patient can be in the study for up to 460 days (15 months) if the maximum visit 
windows are taken in to account. The study will be conducted at up to 200 sites globally and 
the study is expected to be completed in approximately 6 years. 
6.2 Treatment Assignment 
There is no treatment assignment in this study.  
6.3 Treatment and Control 
This is an observational study with no treatment or control groups. All enrolled subjects will 
already be implanted with a commercially available Boston Scientific CRT-D or ICD device. 
For the specific model numbers see Table 4-1. Devices will have Heart Failure Sensors 
turned ON, Respiratory Sensor turned ON, Sleep Incline Sensor turned ON, and HeartLogic 
disabled. 
6.4 Justification for the Study Design 
The results of the MultiSENSE study4 were based upon 400 subjects followed for 12 months 
(test cohort). While this provided sufficient sample size to evaluate HeartLogic performance 
to predict the initial (index) HF event, it was not sufficient for analyzing HF readmissions. 
Thus, a much larger sample size is needed to obtain sufficient numbers of subjects with HF 
readmissions. To evaluate HeartLogic for HF readmissions, subjects cannot be treated by 
using the feature, and clinicians must be blinded to HeartLogic Index and alerts. Therefore, 
this study will only enroll subjects who have HeartLogic disabled. Data from this study will 
be used to evaluate the association of HF sensor measurements with 30-day HF readmissions.  
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7 
Subject Selection  
7.1 Study Population and Eligibility  
Eligibility for study enrollment is determined by specific eligibility criteria as described in 
Table 7-1 and Table 7-2. 
7.2 Inclusion Criteria 
Subjects who meet all of the following inclusion criteria (Table 7-1) may be given 
consideration for enrollment in this clinical study, provided no exclusion criterion (Table 
7-2) is met. 
Table 7-1: Inclusion Criteria 
Inclusion 
Criteria 
• 
Subject is age 18 or above, or of legal age to give informed consent specific to each 
country and national laws 
• 
Subject has a documented diagnosis of heart failure  
• 
Subject has a Boston Scientific CRT-D or ICD device implant that has HeartLogic, 
with Heart Failure Sensors turned ON, Respiratory Sensor turned ON, and Sleep 
Incline Sensor turned ON 
• 
Subject has an active bipolar RV lead implant. 
• 
Subject is enrolled in LATITUDE (NXT 5.0 or future version), and is willing to be 
remotely monitored from the baseline visit for approximately 12 months with 
HeartLogic disabled  
7.3 Exclusion Criteria 
Subjects who meet any of the following criteria (Table 7-2) cannot be included in this study 
or will be excluded from this clinical study. 
Table 7-2: Exclusion Criteria 
Exclusion 
Criteria 
• 
Subject has received or is scheduled to receive a heart transplant or ventricular 
assist device (VAD) 
• 
Subject is enrolled in any concurrent clinical study without prior Boston Scientific 
written approval (excluding registries) 
• 
Subject has a life expectancy of less than 12 months 
• 
Subject has a history of non-compliance to medical care or known inability to 
comply with requirements of the clinical study protocol  
8 
Subject Accountability 
8.1 Point of Enrollment 
Subjects are considered enrolled at the point when they sign and date the informed consent 
form. The consent may be obtained at any point in time following the calendar day of 
implantation of the device. There is no limitation on the time from post-implantation to 
consent. However, the baseline visit must occur within 30 days of consent. The eligibility 
criteria must be confirmed prior to consenting the patient. 
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8.2 Withdrawal 
All subjects enrolled in the clinical study (including those withdrawn from the clinical study 
or lost to follow-up) shall be accounted for and documented. If a subject withdraws from the 
clinical study, an “End of Study” eCRF must be completed, with the subject status as 
“withdrawn”.  
Subjects will be classified as “withdrawn” if at least one of the following conditions are met:  
• subject lost to follow-up (Section 8.3)  
• subject classification of ineligible or attempt (Section 8.4)  
• clinician recommendation 
• subject choice  
• device explant, device revision, or lead revision  
All applicable eCRFs up to the point of withdrawal (including the Final Clinic Visit if 
possible) and the “End of Study” eCRF must be completed.  
After a subject has been withdrawn from the study, additional study data will no longer be 
collected after the point of withdrawal. All open adverse events should be closed or 
documented as chronic. Data collected up to the point of subject withdrawal may be used for 
analysis. 
8.3 Lost to Follow-Up 
A subject will be considered lost to follow-up if he or she fails to return for the final clinic 
visit and is unable to be contacted by the study site staff. 
The following actions need to be taken if a subject fails to return to the clinic for the final 
clinic visit:  
• The site will attempt to contact the subject and reschedule the missed visit and 
ascertain if the subject wishes to continue in the study. 
• Before a subject is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the subject (3 documented attempts with a 
minimum of one certified letter sent to the subject). These contact attempts should be 
documented in the subject’s medical record or study file. 
• Should the subject continue to be unreachable, he or she must be withdrawn from the 
study with a primary reason of lost to follow-up. 
8.4 Subject Status and Classification 
Subjects will be classified as follows:  
• Consent ineligible 
o Refers to a subject that signs the Informed Consent but does not meet 
eligibility criteria 
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• Attempt 
o Refers to a subject that signs the Informed Consent and meets the eligibility 
criteria, but does NOT meet AT LEAST ONE of the conditions below: 
 Subject is monitored on LATITUDE as of the baseline visit 
 HeartLogic is disabled in LATITUDE as of the baseline visit 
 The frequency of scheduled remote follow-ups in the LATITUDE 
system is 3 months or less 
• Monitored on LATITUDE 
o Refers to a subject that signs the Informed Consent, meets the eligibility 
criteria, and meets ALL the conditions below: 
 Subject is monitored on LATITUDE as of the baseline visit 
 HeartLogic is disabled in LATITUDE as of the baseline visit 
 The frequency of scheduled remote follow-ups in the LATITUDE 
system is 3 months or less 
8.5 End-of-Study Definition  
The PREEMPT-HF study is considered completed when participants are no longer being 
actively followed and/or the last participant’s final clinic visit has occurred.  
9 
Study Methods 
9.1 Data Collection 
The details of the data collection and the study follow up schedule are shown in Table 9-1. 
All required data elements must be entered into the PREEMPT-HF study eCRFs.  
 
 
 
 
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Table 9-1 Data Collection Schedule  
Procedure/ 
Assessment 
Enrollment 
Visit 
Baseline 
Visit 
(Day 0) 
 
Interim Medical 
Record Review1 
(150-210 days) 
Final Clinic 
Visit2 
(350-430 days) 
 
Informed Consent Process, including 
Signature and Date  
X 
-- 
-- 
-- 
Inclusion/Exclusion Criteria Assessed 
X 
-- 
-- 
-- 
Confirmation LATITUDE Transmission 
-- 
X 
-- 
X 
Device Information 
-- 
X 
X (changes only) 
X (changes 
only) 
Distribute Subject ID Card with Site 
Contact Information 
-- 
X 
-- 
-- 
Sleep Incline Calibration 
-- 
X 
-- 
-- 
Demographics 
-- 
X 
-- 
-- 
Physical Assessment 
-- 
X 
-- 
X 
Medical History 
-- 
X 
-- 
-- 
Blood Labs 
-- 
O 
-- 
O 
Cardiac Medications Reviewed 
-- 
X 
-- 
-- 
Assessment of Adverse Events and 
Reviewable Clinical Events 
-- 
X 
X 
X 
Supplementary Diagnostics Data 
Collection 
-- 
-- 
O 
O 
1 The interim medical record review does not require an in-clinic visit.   
2*Please complete the final clinic visit form for subjects withdrawn prior to 350 days 
An “X” indicates a mandatory data requirement. Failure to complete will result in a protocol deviation.  
An “O” indicates optional but recommended data. 
9.2 Device Interrogation / Collection of Programming Data 
The device must be interrogated with a PRM at enrollment, baseline and during the final 
clinic visit. These interrogations are required to confirm the appropriate programming of the 
device, including Heart Failure Sensors ON, Sleep Incline Sensor ON, and Respiratory 
Sensor ON. All other device settings can be programmed per clinician discretion. The PRM 
must also be used to calibrate the Sleep Incline Sensor.   
 
HF Sensor data and Sleep Incline data will be collected via the LATITUDE patient 
communicator.  
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9.3 Study Candidate Screening 
Subjects will be recruited from the investigator’s pool of patients that have an ICD or CRT-D 
implant with the HeartLogic feature. The investigator has the responsibility of screening 
potential subjects and selecting only those who meet the eligibility criteria. For the purpose 
of this clinical study no screening logs are required, and the site is not required to report 
screen failures.  
9.4 Strategies for Recruitment and Retention 
Study recruitment will rely upon the general pool of patients that meet the eligibility criteria 
and have an ICD or CRT-D implant.  
9.5   Informed Consent  
Eligible subjects can be consented for the study any time after the calendar day of the ICD or 
CRT-D implant. Participants who meet all the inclusion criteria and none of the exclusion 
criteria, and sign and date the informed consent form are considered enrolled in the study. No 
procedures or data will be collected prior to signing the informed consent form. Legal 
Authorized Representatives (LAR) must not be used for this study.  
9.5.1 Data Linkage 
The PREEMPT-HF study will also link study data to third-party data sources. The purpose of 
data linkage is to conduct research to improve clinical applications such as patient 
management and therapy (both device and non-device), algorithms for patient risk 
stratification and prognostic evaluation, health economic evaluation, and clinical trial 
methodologies. Data linkage will focus on disease states and comorbidities common in 
device patients such as heart failure, hypertension, cardiac arrhythmias, acute coronary 
syndrome, heart valve disorders, respiratory disease, renal disease, gastrointestinal disease, 
sleep apnea, infectious disease, etc. 
PREEMPT-HF study data will be used in combination with internal BSC databases (e.g., 
device tracking database) to obtain, use, and disclose certain protected health information to 
third-parties.  This may include device serial and model number, implant date, the hospital 
where the implant procedure was performed, subject last name, date of birth, address zip 
code, and the last four digits of the subject’s social security number.   
The third-party data sources include but are not limited to payer administrative claims and 
health analytics (e.g., Centers for Medicare and Medicaid Services, Truven, Optum), 
provider electronic health records (EHRs), pharmacy benefit management (or other third-
party administration of prescription drug programs), clinical registries (used for post market 
surveillance or quality improvement), biobanks, and government databases (such as census 
data, or social security death index).  
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The subject may withdraw permission for the use and sharing of personal health information 
at any time if provided in writing to the study doctor.  Please notify Boston Scientific of any 
subjects that submit in writing their request to withdraw their permission for the use of 
personal health information.   
Boston Scientific will abide by all applicable laws, regulations, and data use agreements 
associated with data linkage to third-party data sources. This research could not practicably 
be conducted without access to and use of the protected health information. Additionally, 
Boston Scientific will employ reasonable administrative, physical and technical safeguards 
that are designed to protect against data loss, misuse of data, unauthorized access or 
disclosure of data, and alteration or destruction of data. This includes implementation of 
adequate plans to use only minimum identifiable data needed in a finder file to enable 
linkage, and the removal and destruction of the finder file after each linkage is complete at 
the earliest opportunity consistent with conduct of research.   
9.6 Enrollment Visit 
Enrollment cannot occur on the same calendar day of the implant procedure, but may occur 
before the patient is discharged from the hospital where the implant occurred.  
At the enrollment visit the following activities are required:  
• Confirmation of subject consent 
• Confirmation that the subject meets all the inclusion and none of the exclusion 
criteria (Sections 7.2 and 7.3) 
9.7 Baseline Visit [Day 0] 
The baseline visit must be conducted no sooner than seven (7) days post-device implant to 
allow for automatic initialization of the Sleep Incline Sensor. Enrollment and baseline visits 
can be completed on the same day provided the device has been implanted for at least seven 
(7) days with the Sleep Incline Sensor turned ON. However, the baseline visit must be 
conducted no later than 30 days following enrollment.  
The following information must be gathered and entered into the eCRFs in a timely manner. 
• Subject device information 
o Manufacturer, model and serial number of pulse generator and active leads 
o Implant date for all active devices 
o Anatomical locations of pulse generator and leads 
• LATITUDE monitoring 
o Confirm that the subject is monitored in LATITUDE 
o Review in LATITUDE at the patient level that HeartLogic is disabled  
o Confirm scheduled remote patient monitoring follow-ups are programmed to 
occur at a frequency no less often than once every three (3) months.  
 
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• Sleep Incline Sensor calibration and data collection: 
*Important: The device will NOT collect any Sleep Incline data until a body 
calibration has been performed. Calibration is a required step to ensure the PG is 
collecting sleep incline data.* 
o Sleep Incline Sensor calibrations are performed by the clinician using the 
PRM. Calibration should be performed using the two-position method for 
increased accuracy. This requires the patient to sit and to lie down, so the 
calibration must be conducted in a room with adequate facilities. Care must be 
taken to ensure that the subject is fully vertical or horizontal when the PRM 
captures the upright and supine postures. Once the patient is in position, the 
clinician will run the software on the PRM for the data collection. It takes 
approximately 10 seconds of data collection for each position. The entire 
procedure should take about 1-2 minutes. For patients unable to perform the 
two-position calibration, a single position may be performed. 
o Regardless of whether the Sleep Incline Sensor has been calibrated prior to the 
PREEMPT-HF Study baseline visit, please re-calibrate. Document the 
calibration in the patient medical record.  
o If the Sleep Incline Sensor is turned ON, but the Sensor initialization is 
incomplete seven (7) days after implant, then calibration cannot be performed. 
Please document in the eCRF if initialization failure resulted in the inability to 
calibrate the sensor. If initialization failure occurs, calibration may be 
performed at a subsequent standard of care office visit. 
o Record the details of the sleep incline calibration in the patient medical record 
as source documentation.   
• Provide subject with an ID card containing PREEMPT-HF study site contact 
information. Subjects should be instructed to inform the study coordinator or any 
other study site personnel if they are hospitalized for any reason, or receive IV HF 
treatment) 
• Subject demographics (see Appendix for details) 
• Physical assessment (Appendix) 
• Medical history (Appendix) 
• Enter all cardiac medications 
• Blood labs: If available in the medical records, enter the most recent blood lab values 
collected for the following: 
o Natriuretic peptides (BNP or NT-proBNP) and date of collection 
o Creatinine and date of collection 
• Indicate if the subject is implanted and monitored using a commercial pulmonary 
artery pressure sensor, or if the subject is monitored using serial natriuretic peptides.  
• Review subject medical records since the enrollment and assess for Reviewable 
Clinical Events (RCEs) and reportable AEs (See Figure 3).  
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In addition, subjects located in the United States (US) who own a smart phone may be 
provided with the option to use a geo-location tracking app to ensure timely reporting of 
hospitalizations. The app contains the location of all hospitals in the US. If a subject exceeds 
the pre-specified and programmable amount of time at a hospital, the app will prompt the 
patient to confirm a hospitalization. In addition, the investigational site will get a notification 
that the patient may be hospitalized. To protect patient privacy, Boston Scientific will not 
receive these notifications.  
9.8 Interim Medical Record Review [150-210 days] 
The interim medical record review must be conducted 150 to 210 days following the baseline 
visit. It is encouraged to perform the interim medical record review at the time of an in-clinic 
standard of care visit. If this review coincides with an in-clinic visit, the subject must be 
asked whether he or she had any reviewable clinical events (RCEs) since the baseline visit. 
As defined in section 5.1, an RCE is defined as either an all-cause hospitalization, or HF 
outpatient visit. If the subject reports having an RCE at a center not participating in the study, 
every effort  should be made to obtain medical records from the center. An overview of the 
activities and data to be collected is provided below. 
• Review subject medical records since the date of the baseline visit and assess for 
RCEs and reportable AEs   
• If RCEs are identified during the medical record review (see Figure 3 for details), 
complete the “Reviewable Clinical Event” eCRF.  
o Each newly identified RCE must have a unique eCRF. For example, if the 
subject had two HF outpatient visits for an on-going AE it must be 
captured in two separate “Reviewable Clinical Event” eCRFs. 
o If a single RCE is associated with multiple AEs, only the primary AE (i.e., 
the chief complaint leading to the clinic/hospital visit) should be 
associated with an “Reviewable Clinical Event” eCRF. For example, if a 
subject was admitted due to symptoms of gastrointestinal bleeding but 
developed worsening HF during the course of hospitalization, the 
gastrointestinal bleeding would be the primary AE, and therefore it would 
be associated with the “Reviewable Clinical Event” eCRF. A separate 
“Reviewable Clinical Event” eCRF is not required for the in-patient 
worsening of HF even if it is reported as a separate AE. 
• For hospitalizations, the Principal Investigator must review the patient’s medical 
records and classify the primary organ cause in the “Reviewable Clinical Event” 
eCRF (see Appendix for details). Appropriate classification is important for event 
subgroup analysis. Classification also triggers the request for medical record 
documentation to be sent to BSC. 
• Supplementary diagnostics data collection: This eCRF sub-folder is created only 
if the investigational site confirms that the subject is routinely monitored using 
pulmonary artery (PA) pressure data from an implanted commercially-approved 
device, or using serial natriuretic peptides (BNP or NT-proBNP). If the site 
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confirms the use of supplementary diagnostic data, the following should be 
entered in the corresponding eCRF: 
o PA pressure readings 
o Serial natriuretic peptide values  
o Volume status of the subject (hypervolemic, hypovolemic, euvolemic)  
o Treatments initiated in response to the diagnostic data  
 
**The sponsor retains the right to restrict the total amount of supplemental data that 
would be collected during the course of the study.  In this event, sites would be 
notified to stop reporting supplemental data, and the data base eCRF may be locked 
for further data entry.** 
9.9 Final Clinic Visit  [350-430 days] 
The final visit must be performed in-clinic 350 to 430 days following the baseline visit. If 
the patient is withdrawn prior to the window for the final clinic visit, please complete the 
final clinic visit at the point of withdrawal.  An overview of the data to be collected at this 
visit is provided below. 
• Review subject medical records since the date of the baseline visit and assess for 
RCEs and reportable adverse events.  
o Collect and report using the same process used in the interim medical record 
review (See section 9.8).  
• Physical assessment (See Appendix) 
• Blood labs: Enter the most recent blood lab values since the baseline visit for the 
following.  
o Natriuretic peptides (BNP or NT-proBNP) and date of collection. If serial 
natriuretic peptide data has already been entered in the supplementary 
diagnostics form, the same values need not be entered in the final visit eCRF. 
o Creatinine and date of collection 
• Supplementary diagnostics data collection:  
o Collect using the same process as in the interim medical record review (See 
section 9.8). 
• Interrogate the device with a PRM. This ensures that the device data will be uploaded 
when the patient returns to within range of the communicator. 
• Confirm that a LATITUDE transmission occurred in the previous 90 days. If 
transmission has not occurred instruct patient to do a patient initiated interrogation 
when they are in range of their communicator. 
• Remote monitoring usage:  
 
o Provide information about the frequency and use of remote monitoring to 
manage the patient’s HF condition over the past 12 months (e.g. sleep incline, 
weight, blood pressure, arrhythmia burden). 
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9.10  Study Completion 
An “End of Study” eCRF must be completed when the subject’s participation concludes for 
one of the following reasons:  
• The subject completes the final in-clinic visit after 350 days (minimum final clinic 
visit window). At this point, the subject will exit the study, and device settings can be 
configured per clinician discretion. The subject status will be “completed study.” 
• The subject withdraws from the study. At this point, the subject will exit the study, 
and device settings can be configured per clinician discretion, and the subject status 
will be “withdrawn”.   All applicable eCRFs (including the Final Clinic Visit if 
possible) and the “End of Study” eCRF must be completed with information up to the 
point of withdrawal. Complete a review of the medical records for RCEs to the point 
of withdrawal, and interrogate the PG (See section 9.9 for visit details). PG 
interrogation ensures that the device data will be uploaded when the patient returns to 
within range of the communicator. 
• The study is terminated by Boston Scientific. At this point, the subject will exit the 
study, and device settings can be configured per clinician discretion. The subject 
status will be “withdrawn.” 
9.11  Source Documents 
The following tables detail the data collection and the required source documentation.  
9.11.1 
Enrollment Visit 
Data Collection 
Source Documentation 
Informed Consent 
Study Center 
Inclusion/Exclusion Criteria 
Study center 
Confirmation of LATITUDE Enrollment 
LATITUDE printout at the Study Center 
Confirmation of Heart Failure Sensors 
ON, Sleep Incline Sensor ON, and 
Respiratory Sensor ON 
Study Center (documented in the patient 
medical record) 
9.11.2 
Baseline Visit 
Data Collection 
Source Documentation 
Confirmation of LATITUDE transmission 
and HeartLogic is disabled 
LATITUDE printout at the Study 
Center 
LATITUDE Remote Scheduled Follow-up 
Programming 
LATITUDE printout at the Study 
Center 
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Sleep Incline Sensor calibration 
Study Center (documented in the 
patient medical record) 
Demographics, Medical History, Physical 
Assessment, Blood Labs 
Study Center 
Assess for RCEs and reportable AEs 
Retain original at study center and 
submit a copy to Boston Scientific (see 
Section 9.11.5 for additional details 
regarding RCEs) 
9.11.3 
Interim Medical Record Review 
Data Collection 
Source Documentation 
Assess for RCEs and reportable AEs 
Retain original at study center and submit 
a copy to Boston Scientific (see Section 
9.11.5 for additional details regarding 
RCEs) 
Supplementary Diagnostics Data 
Study Center 
9.11.4 
Final Clinic Visit 
Data Collection 
Source Documentation 
Assess for RCEs and reportable AEs 
Retain original at study center and submit 
a copy to Boston Scientific (see Section 
9.11.5 for additional details regarding 
RCEs) 
Physical Assessment 
Study Center 
Blood Labs 
Study Center 
Supplemental Diagnostics 
Study Center 
Remote Monitoring Usage 
Study Center 
9.11.5 
 Reviewable Clinical Events 
Table 9-2 summarizes specific source data requirements for the RCEs, along with the 
additional required reporting of all SAEs. It is preferable that original source documents are 
maintained on site. In lieu of original source documents, copies are required to be 
maintained.  
 
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Table 9-2 Source Documentation Requirements for Reviewable Clinical Events 
Clinical Events 
Source Document(s) 
Medical records 
Disposition 
Options 
REVIEWABLE   CLINICAL   EVENTS 
All-Cause Hospitalizations 
Cardiac 
hospitalizations 
• 
Admission/presentation record 
• 
Discharge summary 
• 
Medications 
• 
Physician progress notes 
• 
Blood labs (kidney function, 
natriuretic peptides, basic 
metabolic panel), 
• 
Other diagnostics (ECG, Chest 
x-ray, echocardiography 
summary report) 
• 
Further documentation may be 
requested by BSC 
Upload into 
RAVE 
or 
Email to 
PREEMPT.Safety
@bsci.com 
 
or 
Fax: 651-582-5847 
 
Non-cardiac 
hospitalizations within 
90 days of discharge 
from a previous HF 
Hospitalization (i.e., 
90-day readmission) 
Non-cardiac 
hospitalizations where 
HF was secondary 
contributing cause, or 
where inpatient 
worsening of HF 
occurred 
Non-cardiac 
pulmonary or renal 
events 
All other Non-cardiac 
hospitalizations 
• Discharge summary 
• Further documentation may be 
requested by BSC 
HF Outpatient Visits (with 
decongestive IV therapy) 
• 
Physician notes 
• 
Medications 
• 
Blood lab reports 
• 
Further documentation may be 
requested by BSC 
 
All Other AEs as required by 
the protocol (section 17) 
• 
Further documentation may be 
requested by BSC 
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10 Statistical Considerations 
10.1 Primary Endpoint 
There are no primary endpoints or formal hypotheses, as the purpose of this study is 
exploratory. The primary objective is to investigate the association between HF Sensor data 
and 30-day HF readmissions.  
10.1.1 
Hypotheses 
There are no formal hypotheses. The purpose of this study is exploratory. 
10.1.2 
Sample Size  
Approximately 3750 enrollments will be required for this study. The sample size was 
determined based on the estimated number of HF index hospitalizations and 30-day HF 
readmissions needed to evaluate the primary objective. Final sample size will be determined 
by an interim analysis as described in Section 10.9. An index HF hospitalization refers to the 
first HF hospitalization during the study follow-up period. A HF hospitalization is deemed 
usable if sensor data is available during the event and sufficient follow up time is recorded to 
determine if a readmission occurs. 
A total of 215 usable index HF hospitalizations are required to have at least 80% power to 
detect a standardized difference of 0.5 in the mean sensor change (admission – discharge) 
between the groups with and without a 30-day HF readmission. It is expected that of the 215 
index HF hospitalizations, 43 will be followed by a 30-day readmission (20%). 
A total of 215 usable index HF hospitalizations was determined based on the following 
assumptions: 
• 80% Power to detect a standardized mean difference of 0.5 between groups 
• Two-sided type I error (alpha) of 0.05 
• 3:1 ratio of group sizes (no-readmission : 30-day HF readmission), where the no-
readmission group will exclude index HF hospitalizations with 31 to 60-day 
readmissions 
Assuming a 20% loss of usable HF events due to proximity to study start and exit 
(completion or withdrawal), a total of 270 index HF hospitalizations are required to obtain 
215 usable HF hospitalizations.  
Approximately 3750 enrollments are required to obtain the 270 required index HF 
hospitalizations. This was determined based on the following assumptions: 
• 9 % index HF hospitalization rate per patient year 
• 20% death/withdrawal rate throughout duration of study 
• Average of 12 months of sensor data per subject 
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10.1.3 
Statistical Methods 
The primary objective will be evaluated using an independent two sample t-test. A 
comparison of mean sensor value change (admission – discharge) will be made between the 
no-readmission group and the 30-day readmission group. All subjects with a usable index HF 
hospitalization and all subjects with a 30-day HF readmission will be included in the primary 
analysis. Subjects with a 31-60-day HF hospitalization will be excluded from the analysis. A 
two-sided alpha of 0.05 will be used. 
10.2 Secondary Endpoints 
There are no secondary endpoints.  
10.3 Other Objectives/Measurements 
The additional objectives are described below along with planned statistical methods and 
analysis data to be used. 
• Characterize HF sensors for the association with risk for VT/VF therapy 
o This will be assessed using an odds ratio 
o All subjects with usable sensor and episode data will be included in the 
analysis 
• Characterize HF sensors for phenomapping of HF events  
o This will be assessed using cluster analysis 
o All subjects with a HF event and usable sensor data will be included in the 
analysis 
• Characterize HF sensors for association with non-HF hospitalizations (including 
cardiac non-HF events and non-cardiac events) 
o This will be assessed using a paired t-test 
o All subjects with a non-HF hospitalizations and usable sensor data will be 
included in the analysis 
• Collect Sleep Incline Sensor data leading up to clinical events: Subjects who were 
enrolled in a remote monitoring program using sleep incline data will be excluded 
and sensor data in the remaining patients will be analyzed using a paired t-test. 
• Link study data to third-party data sources. Data linkage will be included in the 
analysis to assess feasibility to link to claims data (see Section 9.5) and other data 
sources. The linked data set will be used to compare claims-based events with study 
RCEs, assess the accuracy of claims-based algorithms to identify sensor detected 
events, and estimate the cost savings from avoidable hospitalizations. Comparisons 
will be made using paired and un-paired t-tests and receiver operator curve (ROC) 
analyses.  
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10.4 General Statistical Methods 
All sample size calculations were performed and all statistical analyses will be done with 
SAS version 9.3 or higher. 
10.5 Analysis Sets 
10.5.1 
Primary analysis  
All subjects with a usable index HF hospitalization and all subjects with a 30-day HF 
readmission will be included in the primary analysis. Subjects with a 30-60-day HF 
hospitalization will be excluded from the analysis.  
10.5.2 
Additional analyses 
• All subjects with usable sensor and episode data will be included in the analysis of 
characterizing HF sensors for the association with risk for device VT/VF therapy 
• All subjects with a HF event and usable sensor data will be included in the analysis of 
characterizing HF sensors for phenomapping of HF events  
• All subjects with a non-HF hospitalization and usable sensor data will be included in 
the analysis of characterizing HF sensors for association with non-HF 
hospitalizations  
10.6 Control of Systematic Error/Bias 
The purpose of this study is exploratory and to characterize the association of HF sensor data 
with various clinical events. No formal tests of hypothesis are planned, no claims of safety or 
efficacy are intended, and no adjustment for multiple testing will be performed. 
10.7 Number of Subjects per Investigational Site 
A single site cannot enroll more than 375 patients. 
10.8 Other Endpoints/Measurements  
There are no endpoints or other measurements captured in this study.  
10.9 Interim Analyses  
An interim analysis is planned after 1000 subjects have been enrolled and have completed all 
required follow-up visits. The purpose of the interim analysis is to verify enrolling rates and 
HF hospitalization rate and withdrawal rate.  
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10.10 Subgroup Analyses 
Analyses may be performed to evaluate the study objectives in various subgroups. The list of 
baseline characteristics and their corresponding subgroups to be analyzed include, but are not 
limited to, the following: 
• Device – CRT-D and ICD 
• Sex – Male and Female 
• Age – < 65 and ≥ 65 years 
• NYHA Class – Class I, II, III, IV 
• LVEF – < 25% and ≥ 25% 
• Etiology – Ischemic and Non-Ischemic 
• Renal dysfunction – Yes and No 
Details of subgroup analyses will be documented in a separate Statistical Analysis Plan not 
included in this protocol. 
10.11 Justification of Pooling 
Pool-ability of data across investigational sites and geographic regions will be tested. Details 
of pooling analysis are documented in a Statistical Analysis Plan.  
10.12 Multivariable Analyses 
Multivariable exploratory analyses may be performed to determine if clinical or patient 
characteristics are associated with sensor measurements or clinical outcomes. Details of 
multivariable analyses are documented in a Statistical Analysis Plan. 
10.13 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. 
11 Data Management 
11.1 Data Collection, Processing, and Review 
Subject data will be recorded in a limited access and secure electronic data capture (EDC) 
system.  
The clinical database will reside on a production server hosted by the EDC System 
manufacturer. All changes made to the clinical data will be captured in an electronic audit 
trail and available for review by the sponsor. The associated RAVE software and database 
have been designed to meet regulatory compliance for deployment as part of a validated 
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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 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. 
11.2 Data Retention 
The Principal Investigator or his/her designee or Investigational site will maintain, at the 
investigational 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 completed. These documents 
will be retained for a longer period of time by agreement with BSC or in compliance with 
other country/regional/local regulations 
The Principal Investigator or his/her designee will take measures to ensure that these 
essential documents are not accidentally damaged or destroyed. If for any reason the 
Principal Investigator or his/her designee withdraws responsibility for maintaining these 
essential documents, custody must be transferred to an individual who will assume 
responsibility and BSC must receive written notification of this custodial change. Sites are 
required to inform Boston Scientific in writing where paper or electronic files are maintained 
in case files are stored off site and are not readily available. 
12 Deviations 
An Investigator must not make any changes or deviate from this protocol, except to protect 
the life and physical well-being of a subject in an emergency. An investigator shall notify the 
sponsor and the reviewing IRB/REB/EC of any deviation from the investigational plan to 
protect the life or physical well-being of a subject in an emergency, and those deviations 
which affect the scientific integrity of the clinical investigation. Such notice shall be given as 
soon as possible, but no later than 5 working days after the emergency occurred, or per 
prevailing local requirements, if sooner than 5 working days.  
All deviations from the investigational plan, with the reason for the deviation and the date of 
occurrence, must be documented and reported to the sponsor using the electronic database 
CRF.  Sites may also be required to report deviations to the IRB/REB/EC, per local 
guidelines and government regulations.  
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Deviations will be reviewed and evaluated on an ongoing basis and, as necessary, appropriate 
corrective and preventive actions (including IRB/REB/EC) notification, site re-training, or 
site discontinuation/termination) will be put into place by the sponsor. 
13 Device/Equipment Accountability 
The devices used in this study are commercially approved in all study geographies. Any 
device tracking and accountability will occur per the required local regulations for 
commercial devices.  
14 Compliance 
14.1 Statement of Compliance 
This study will be conducted in accordance with post market clinical follow up guidelines 
and will follow the applicable sections of ISO 14155 (Clinical Investigation of Medical 
Devices for Human Subjects – Good Clinical Practice), the relevant parts of the ICH 
Guidelines for Good Clinical Practices, ethical principles that have their origins in the 
Declaration of Helsinki, and pertinent individual country laws and regulations. The study 
shall not begin until the required approval/favorable opinion from the IRB/REB/EC and/or 
regulatory authority has been obtained, if appropriate. Any additional requirements imposed 
by the IRB/REB/EC or regulatory authority shall be followed, if appropriate. 
14.2 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, the guidance of ISO 14155, ethical principles that have their origins in the Declaration 
of Helsinki, any conditions of approval imposed by the reviewing IRB/EC/REB, 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 
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. 
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• Create and maintain source documents throughout the clinical study and ensure their 
availability with direct access during monitoring visits or audits; ensure that all clinical-
investigation-related records are retained per requirements. 
• Ensure the accuracy, completeness, legibility, and timeliness of the data reported to the 
sponsor in the CRFs and in all required reports. 
• Record, report, and assess (seriousness and relationship to the device/procedure) every 
adverse event as applicable per the protocol and observed device deficiency. 
• Report to sponsor, per the protocol requirements, all SAEs and device deficiencies that 
could have led to a SADE and potential/USADE or UADE. 
• Report to the IRB/EC/REB and regulatory authorities any SAEs and device deficiencies 
that could have led to a SADE and potential/USADE or UADE, if required by applicable 
laws or regulations or this protocol or by the IRB/EC/REB, and supply BSC with any 
additional requested information related to the safety reporting of a particular event. 
• Allow the sponsor to perform monitoring and auditing activities, and be accessible to the 
clinical research monitor or auditor and respond to questions during monitoring visits or 
audit(s). 
• Allow and support regulatory authorities and the IRB/EC/REB when performing auditing 
activities. 
• Ensure that informed consent is obtained in accordance with applicable laws, this 
protocol and local IRB/EC/REB requirements. 
• Provide adequate medical care to a subject during and after a subject’s participation in a 
clinical study in the case of adverse events, as described in the Informed Consent Form 
(ICF). 
• Inform the subject of the nature and possible cause of any adverse events experienced. 
• Inform the subject of any new significant findings occurring during the clinical 
investigation, including the need for additional medical care that may be required. 
• Provide the subject with well-defined procedures for possible emergency situations 
related to the clinical study, and make the necessary arrangements for emergency 
treatment, including decoding procedures for blinded/masked clinical investigations, as 
needed. 
• Ensure that clinical medical records are clearly marked to indicate that the subject is 
enrolled in this clinical study. 
• Ensure that, if appropriate, subjects enrolled in the clinical investigation are provided 
with some means of showing their participation in the clinical investigation, together with 
identification and compliance information for concomitant treatment measures (contact 
address and telephone numbers shall be provided). 
• Inform, with the subject’s approval or when required by national regulations, the 
subject’s personal physician about the subject’s participation in the clinical investigation. 
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• 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. 
14.3 Delegation of Responsibility 
When specific tasks are delegated, 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. Where there is a sub-
investigator at a site, the sub-investigator should not be delegated the primary supervisory 
responsibility for the site. The investigator is accountable for regulatory violations resulting 
from failure to adequately supervise the conduct of the clinical study.  
14.4 Institutional Review Board/ Research Ethics Board / Ethics Committee 
The investigational site will obtain the written and dated approval/favorable opinion of the 
IRB/EC/REB for the clinical investigation before recruiting subjects and implementing all 
subsequent amendments, if required. 
A copy of the written IRB/EC/REB 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 clinical investigation. Prior approval must 
also be obtained for other materials related to subject recruitment or which will be provided 
to the subject. 
Any amendment to the protocol will require review and approval by the IRB/REC/EC before 
the changes are implemented to the study. All changes to the ICF will be IRB/REC/EC 
approved; a determination will be made regarding whether a new ICF needs to be obtained 
from participants who provided consent, using a previously approved ICF.  
 
Annual IRB/EC/REB approval and renewals will be obtained throughout the duration of the 
study as required by applicable local/country laws or regulations or IRB/EC/REB 
requirements. Copies of the study reports and the IRB/EC/REB continuance of approval must 
be provided to the sponsor.  
14.5 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 this information. 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 
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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 the subject’s identifiable health information confidential in 
accordance with all applicable laws and regulations. Boston Scientific may use the subject’s 
health information to conduct this research, as well as for additional purposes, such as 
overseeing and improving the performance of its device, new medical research and proposals 
for developing new medical products or procedures, third-party data linkage 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.  
14.6 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 procedures required by the protocol, and 
required 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). 
As allowed per local regulations, at the request of the investigator and while under 
investigator supervision, BSC personnel may operate equipment during follow-up, assist with 
the conduct of testing specified in the protocol, and interact with the subject to accomplish 
requested activities.  
Typical tasks may include the following: 
• Interrogating the device or programming device parameters to investigator-requested 
settings as well as operating study equipment 
• 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 programmers, and other equipment 
• Entering technical data on technical source form provided the responsible investigator 
verifies and signs the completed worksheet  
• Print out/download programming reports/parameters directly from the clinician 
programmer and provide original printouts or electronic data reports 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 
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• Reviewing collected data and study documentation for completeness and accuracy 
 
Boston Scientific personnel will not do the following.  
• Practice medicine 
• Provide medical diagnosis or treatment to subjects 
• Discuss a subject’s condition or treatment with a subject without the approval and 
presence of the investigator 
• Independently collect critical study data (defined as primary or secondary endpoint data) 
• Enter data in eCRFs or on paper CRFs 
14.7 Insurance  
Where required by local/country regulation, proof and type of insurance coverage, by BSC 
for subjects in the study will be obtained. 
15 Monitoring 
Monitoring will be performed by Boston Scientific or its designees during the study. A 
combination of on-site, remote, or central monitoring will be used to assess continued 
compliance with the protocol and applicable regulations. This includes ensuring proper 
informed consent process, review of safety data, and adherence to protocol defined visit 
schedule. In addition, the clinical research monitor verifies that study records are adequately 
maintained, that data are reported in a satisfactory manner with respect to timeliness, 
adequacy, and accuracy, and that the Principal Investigator continues to have sufficient staff 
and IRB approved facilities to conduct the study safely and effectively. The Principal 
Investigator/institution guarantees direct access to original source documents by BSC 
personnel, their designees, and appropriate regulatory authorities. 
The study may also be subject to a quality assurance audit by BSC or its designees, as well as 
inspection by appropriate regulatory authorities. It is important that the Principal Investigator 
and relevant study personnel are available during on-site monitoring visits or audits and that 
sufficient time is devoted to the process. 
16 Potential Risks and Benefits 
16.1 Directions for Use 
Please refer to the Directions for Use for an overview of anticipated adverse (device) effects, 
and risks associated to the commercial device(s).  
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16.2 Risks Associated with Participation in the Clinical Study 
There are no required treatments or therapeutic interventions in this trial. The study involves 
the collection of sensor data and clinical event data. There are no additional risks of 
participating above those associated with standard of care.  
16.3 Possible Interactions with Concomitant Medical Treatments, if Applicable 
There are no concomitant medical treatments.  
16.4 Risk Minimization Actions 
Additional risks may exist. Risks can be minimized through compliance with this protocol, 
performing procedures in the appropriate hospital environment, adherence to subject 
selection criteria, close monitoring of the subject's physiologic status during research 
procedures and/or follow-ups and by promptly supplying BSC with all pertinent information 
required by this protocol. 
16.5 Anticipated Benefits 
There may be no benefits to a subject’s participation in the study. However, participation 
may help future patients benefit from enhanced performance of the HeartLogic algorithm.  
17 Safety Reporting 
17.1 Reportable Events by Investigational Site to Boston Scientific 
It is the responsibility of the Investigator to assess and report to BSC any event which occurs 
in any of following categories: 
• All Serious Adverse Events 
• All Device Related Adverse Events 
o Events listed in the arrhythmia logbook, should be reported only if determined 
to be clinical significant by the investigator and/or delegated site staff (e.g.: 
ATR, PMT, etc.) 
o All arrhythmias which received inappropriate shock therapy as identified by a 
study investigator must be reported 
• All Serious Adverse Device Events 
o Serious adverse device events that are a result of implant, device revision, lead 
revision, or device/lead explant are not reportable events per this protocol.  
Patients that undergo device or lead revision/explant must be withdrawn prior 
to the procedure.   
• All Device Deficiencies related to the pulse generator 
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• Unanticipated Adverse Device Effects/Unanticipated Serious Adverse Device Effects 
• HF Related Adverse Events: An adverse event is deemed as a HF Adverse Event if 
the primary cause is HF and either of following conditions is met: 
o Subject is admitted and discharged with a calendar date change. 
o Subject is not hospitalized but received one or more IV medications 
including diuretics, inotropes, vasodilators, other parenteral therapy, or 
aquapheresis. 
For event reporting the medical diagnosis must be reported. In case the diagnosis is not 
available, individual symptoms can be reported to fulfill reporting timelines. If a diagnosis 
becomes available at a later stage, it must be added to the reported event. 
If it is unclear whether or not an event fits one of the above categories, or if the event cannot 
be isolated from the device or procedure, it should be submitted as an adverse event and/or 
device deficiency. 
Any AE event required by the protocol, experienced by the study subject after informed 
consent and once considered enrolled in the study (as defined in study subject classification 
section), whether during or subsequent to the procedure, must be recorded in the eCRF. 
Underlying diseases are not reported as AEs unless there is an increase in severity or 
frequency during the course of the investigation. Death should not be recorded as an AE, but 
should only be reflected as an outcome of one (1) specific SAE (see Table 17-1 for AE 
definitions). 
Refer to Directions for Use for the known risks associated with the commercial device(s). 
17.2 Definitions and Classification 
Adverse event definitions are provided in Table 17-1. Administrative edits were made on the 
safety definitions from ISO 14155 and MEDDEV 2.7/3 for clarification purposes. 
Table 17-1: Safety Definitions 
Term 
Definition 
Adverse Event (AE) 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3  
 
 
 
 
Any untoward medical occurrence, unintended disease or injury, or 
any untoward clinical signs (including an abnormal laboratory 
finding) in subjects, users or other persons, whether or not related to 
the study medical device.  
NOTE 1: This includes events related to the study 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 
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Table 17-1: Safety Definitions 
Term 
Definition 
events related to the study medical device.  
Adverse Device Effect (ADE) 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3  
Adverse event related to the use of the study 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 study medical device. 
NOTE 2: This definition includes any event resulting from use 
error or intentional abnormal use of the study medical device. 
Serious Adverse Event (SAE) 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3  
Note: This definition meets the reporting objectives and requirements 
of ISO 14155 and MEDDEV 2.7/3. 
Adverse event that: 
a) Led to death, 
b) Led to serious deterioration in the health of the subject as defined 
by either: 
• 
a life-threatening illness or injury, or 
• 
a permanent impairment of a body structure or a body 
function, or 
• 
in-patient hospitalization or prolongation of existing 
hospitalization, or 
• 
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 
 
Ref: MEDDEV 2.7/3  
Adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event. 
 
Unanticipated Adverse Device 
Effect (UADE) 
 
Ref: 21 CFR Part 812 
 
 
Any serious adverse effect on health or safety or any life-threatening 
problem or death caused by, or associated with, a device, if that 
effect, problem, or death was not previously identified in nature, 
severity, or degree of incidence in the investigational plan or 
application (including a supplementary plan or application), or any 
other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of subjects.  
Unanticipated Serious Adverse 
Device Effect (USADE) 
Serious adverse device effect which by its nature, incidence, severity, 
or outcome has not been identified in the current version of the risk 
analysis report. 
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Table 17-1: Safety Definitions 
Term 
Definition 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3  
 
 
NOTE 1: Anticipated serious adverse device effect (ASADE) is an 
effect which by its nature, incidence, severity or outcome has been 
identified in the risk analysis report. 
Device Deficiency 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3  
An inadequacy of the study 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. 
 
17.3 Relationship to Device(s) 
The Principal Investigator must assess the relationship of the reportable AE to the device. 
See criteria in Table 17-2. 
Table 17-2: Criteria for Assessing Relationship of Study Device or Procedure to 
Adverse Event 
Classification 
Description 
Not Related 
Ref: MEDDEV 2.7/3 
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 study device or the 
procedures; 
- the serious event does not follow a known response pattern to the medical 
device (if the response pattern is previously known) and is biologically 
implausible; 
- the discontinuation of medical device application or the reduction of the level 
of activation/exposure - when clinically feasible – and reintroduction of its use 
(or increase of the level of activation/exposure), do not impact on the serious 
event; 
- the event involves a body-site or an organ not expected to be affected by the 
device or procedure;  
- the serious event can be attributed to another cause (e.g., an underlying 
or concurrent illness/ clinical condition, an effect of another device, drug, 
treatment or other risk factors); 
- the event does not depend on a false result given by the study device used for 
diagnosis, when applicable; harms to the subject are not clearly due to use 
error; 
- 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 
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17.4 Investigator Reporting Requirements 
The communication requirements for reporting to BSC are as shown in  
Adverse events must always be reported through the EDC system for PREEMPT-HF. 
However, in the case of any issues where alternative method of reporting is necessary (i.e. 
the EDC system is not available); please report the adverse event to Boston Scientific by 
sending the Event Notification Form via email to the following email address: 
PREEMPT.Safety@bsci.com 
 
event. 
Unlikely Related 
Ref: MEDDEV 2.7/3 
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 
Ref: MEDDEV 2.7/3 
The relationship with the use of the study 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 
Ref: MEDDEV 2.7/3 
The relationship with the use of the study device seems relevant and/or the 
event cannot reasonably be explained by another cause, but additional 
information may be obtained. 
Causal Relationship 
Ref: MEDDEV 2.7/3 
The serious event is associated with the study 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 the study device use/application or 
procedures; 
- the event involves a body-site or organ that 
-the study device or procedures are applied to; 
-the study 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 study device used for 
diagnosis, when applicable; 
- 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. 
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Table 17-3: Communication Requirements for Adverse Events 
Event Classification 
Communication Method 
Communication Timeline post-
market studies* 
(MEDDEV 2.12/2:  
GUIDELINES ON A MEDICAL 
DEVICE VIGILANCE SYSTEM) 
Unanticipated Adverse 
Device Effect / 
Unanticipated Serious 
Adverse Device Effect  
Complete AE eCRF page with all 
available new and updated 
information.  
• Within 1 business day of first 
becoming aware of the event. 
• Terminating at the end of the 
study.  
Provide all relevant source 
documentation (unidentified) for 
reported event.  
• Upon request of sponsor. 
Serious Adverse Event  
Complete AE eCRF page with all 
available new and updated 
information.  
• Within 10 business days after 
becoming aware of the event or 
as per local/regional regulations. 
• For Austria: within 2 business 
days of first becoming aware of 
the event  
• Reporting required through end 
of study. 
Provide all relevant source 
documentation (unidentified) for 
reported event.  
• When documentation is available 
Serious Adverse Device 
Effects 
Complete AE eCRF page with all 
available new and updated 
information. 
• Within 2 business days of first 
becoming aware of the event or 
as per local/regional regulations. 
• Reporting required through the 
end of the study 
Provide all relevant source 
documentation (unidentified) for 
reported event.  
• When documentation is available 
Device Deficiencies 
(including but not limited 
to failures, malfunctions, 
and product 
nonconformities) 
Note: Any 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 
Complete DD eCRF with all 
available new and updated 
information.  
• Within 2 business days of first 
becoming aware of the event. 
Reporting required through the 
end of the study 
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Event Classification 
Communication Method 
Communication Timeline post-
market studies* 
(MEDDEV 2.12/2:  
GUIDELINES ON A MEDICAL 
DEVICE VIGILANCE SYSTEM) 
event. 
 
Adverse Event including 
Adverse Device Effects 
Complete AE eCRF page, which 
contains such information as date of 
AE, treatment of AE resolution, 
assessment of seriousness and 
relationship to the device.  
• In a timely manner (e.g., 
recommend within 30 business 
days) after becoming aware of 
the information 
• Reporting required through end 
of study 
Provide all relevant source 
documentation (unidentified) for 
reported event.  
17.5 Safety definitions  
Boston Scientific uses the safety definition below to help with appropriate internal coding 
and classification of protocol defined reportable adverse events.   
Table 17-4 Safety Definitions 
 
Unanticipated Serious Adverse 
Device Effect (USADE) 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3  
 
 
Serious adverse device effect which by its nature, incidence, severity, 
or outcome has not been identified in the current version of the risk 
analysis report. 
NOTE 1: Anticipated serious adverse device effect (ASADE) is an 
effect which by its nature, incidence, severity or outcome has been 
identified in the risk analysis report. 
Device Deficiency 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3  
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. 
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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 
Submission of 
Research and Marketing 
Applications for Permanent 
Pacemaker Leads and for 
Pacemaker Lead Adaptor 
510(k) Submissions 
Not related to the investigational device(s), system component(s), or 
labeling, but would not have occurred in the absence of the 
investigational device(s) and/or system component(s).  This includes 
clinical events related to commercially released devices that are used 
in conjunction with investigational device(s) or protocol procedures. 
Type IV 
Ref: FDA Guidance for the 
Submission of 
Research and Marketing 
Applications for Permanent 
Pacemaker Leads and for 
Pacemaker Lead Adaptor 
510(k) Submissions 
Related to a change in patient’s condition. 
Type V 
Comments Only.  On occasion, comments were inadvertently entered 
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Ref: FDA Guidance for the 
Submission of 
Research and Marketing 
Applications for Permanent 
Pacemaker Leads and for 
Pacemaker Lead Adaptor 
510(k) Submissions 
in the adverse event text field of the case report form (CRF). 
Comments identified by the CRF reviewer were assigned a Type V 
code and not included in this report. 
Abbreviations: EC=Ethics Committee; IRB=Institutional Review Board 
 
17.6 Boston Scientific Device Deficiencies 
For purposes of the PREEMPT-HF Study, the Boston Scientific Pulse Generator (PG) will be 
referred to as the device under study. Only device deficiencies related to the PG should be 
reported; no other PG manufacturers should be reported. When relevant and if possible, the 
device(s) should be returned to BSC for analysis. Instructions for returning the device(s) will 
be provided as needed. Device deficiencies should also be documented in the subject’s 
source records. 
Device deficiencies are not necessarily adverse events. However, a serious adverse event that 
results from a device deficiency would be recorded as on the appropriate eCRF. 
17.7 Reporting to Regulatory Authorities / IRBs / ECs / REBs/ Investigators 
BSC is responsible for reporting adverse event information to all participating Principal 
Investigators, IRBs/ECs/REBs and regulatory authorities, as applicable.  
The Principal Investigator is responsible for informing the IRB/EC/REB, and regulatory 
authorities of UADEs and SAEs as required by local/regional regulations. 
BSC shall notify all participating Chinese study centers if SAEs/SADEs occur which imply a 
possible increase in the anticipated risk of the procedure or use of the device or if the 
occurrence of certain SAEs/SADEs demands changes to the protocol or the conduct of the 
study to further minimize the unanticipated risks. 
17.8 Subject Death Reporting  
A subject death during the study must be reported to Boston Scientific as soon as possible 
and, in any event, within three (3) calendar days of center aware date. The center’s IRB/EC 
must be notified of any deaths in accordance with that center’s IRB/EC policies and 
procedures. Whenever possible, the device should be interrogated and BSC system 
components (e.g., the device) should be removed intact and returned promptly to BSC RM 
for analysis.  
A detailed narrative (death letter) that provides detailed information describing the 
circumstances surrounding the death is required. A death narrative in the local language is 
acceptable, if accompanied by a translation in English. The details listed below should be 
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addressed in the death narrative, for BSC to understand the circumstance surrounding the 
death:  
• Date and time of death; 
• Place death occurred; 
• Immediate cause of death; 
• Rhythm at the time of death, if known (include any available documentation); 
• Whether or not the death was witnessed; 
• Whether the subject had worsening HF; 
• Any other circumstances surrounding the death; 
• Approximate time interval from the initiating event to death (temporal course) – items 
to consider include, but are not limited to: information regarding last time subject was 
seen by investigator, last office visit, etc. 
• Investigator or co-Investigator signature and date. 
Whenever possible, the CRT-D or ICD device is recommended be interrogated. Other Source 
documents maybe requested at BSC. BSC Medical Safety representatives must review 
information regarding subject deaths. 
18 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 use of any study devices, study-required procedures and/or testing, or data 
collection.  
The obtaining and documentation of Informed Consent must be in accordance with the 
principles of the Declaration of Helsinki, ISO 14155, any applicable national regulations, and 
local Ethics Committee and/or Regulatory authority body, as applicable. The ICF must be 
accepted by BSC or its delegate (e.g. CRO), and approved by the site’s IRB/EC/REB, 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 
investigational site’s IRB/EC/REB. Any modification requires acceptance from BSC prior to 
use of the form. The ICF must be in a language understandable to the subject and if needed, 
BSC will assist the site in obtaining a written consent translation. Translated consent forms 
must also have IRB/EC/REB approval prior to their use. Privacy language shall be included 
in the body of the form or as a separate form as applicable.  
The process of obtaining Informed Consent shall at a minimum include the following steps, 
as well as any other steps required by applicable laws, rules, regulations and guidelines: 
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• be conducted by the Principal Investigator or designee authorized to conduct the process,  
• include a description of all aspects of the clinical study that are relevant to the subject’s 
decision to participate throughout the clinical study, 
• avoid any coercion of or undue influence of subjects to participate, 
• not waive or appear to waive subject’s legal rights, 
• use native language that is non-technical and understandable to the subject, 
• provide ample time for the subject to consider participation and ask questions if 
necessary, 
• ensure important new information is provided to new and existing subjects throughout the 
clinical study.  
The ICF shall always be signed and personally dated by the subject. The original signed ICF 
will be retained by the site and a copy of the signed and dated document and any other 
written information must be given to the person signing the form.  
Failure to obtain subject consent will be reported by BSC to the applicable regulatory body 
according to their requirements (e.g., FDA requirement is within 5 working days of learning 
of such an event). Any violations of the informed consent process must be reported as 
deviations to the sponsor and local regulatory authorities (e.g. IRB/EC/REB), as appropriate. 
If new information becomes available that can significantly affect a subject's future health 
and medical care, that information shall be provided to the affected subject(s) in written form 
via a revised ICF or, in some situations, enrolled subjects may be requested to sign and date 
an addendum to the ICF. In addition to new significant information during the course of a 
study, other situations may necessitate revision of the ICF, such as if there are amendments 
to the applicable laws, protocol, a change in Principal Investigator, administrative changes, or 
following annual review by the IRB/EC/REB. The new version of the ICF must be approved 
by the IRB/EC/REB. Acceptance by Boston Scientific is required if changes to the revised 
ICF are requested by the site’s IRB/EC/REB. The IRB/EC/REB will determine the subject 
population to be re-consented. 
19 Committees 
19.1 Safety Monitoring Process 
The BSC Medical Safety group reviews unmonitored data as soon as the event is reported, 
and on a continuous basis. During scheduled monitoring activities, clinical research monitors 
will support this continuous review through their review of source document and other data 
information. The BSC Medical Safety group includes physicians with expertise in 
electrophysiology, and with the necessary therapeutic and subject matter expertise to evaluate 
and classify the events into the categories outlined above. 
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19.2 BSC Internal Medical Record Review 
Source documentation will be collected for reviewable clinical events per the source data 
requirements outlined in Table 9-2. Copies of the subject source documents provided by sites 
will be assembled into clinical event dossier for internal review by Boston Scientific (BSC). 
The purpose of the BSC internal review is to extract contextual data about the RCE for the 
association with HF sensors.   
20 Suspension or Termination 
20.1 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 business reasons and reasons related 
to protection of subjects. Investigators, associated IRBs/ECs/REBs, and regulatory 
authorities, as applicable, will be notified in writing in the event of study termination. 
20.2 Criteria for Premature Termination of the Study 
Possible reasons for premature study termination include, but are not limited to, the 
following. 
• The occurrence of unanticipated adverse device effects that present a significant or 
unreasonable risk to subjects enrolled in the study. 
• An enrollment rate far below expectation that prejudices the conclusion of the study.  
20.3 Termination of Study Participation by the Investigator or Withdrawal of IRB/ 
EC/REB Approval 
Any investigator, or IRB/ EC/ REB in the PREEMPT-HF 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/REBs, and regulatory 
authorities, as applicable, will be notified in writing in the event of these occurrences. 
20.4 Requirements for Documentation and Subject Follow-up 
In the event of premature study termination, a written statement as to why the premature 
termination has occurred will be provided to all participating sites by Boston Scientific. The 
IRB/EC/REB and regulatory authorities, as applicable, will be notified. Detailed information 
on how enrolled subjects will be managed thereafter will be provided.  
In the event an IRB, REB or EC terminates participation in the study, participating 
investigators, associated IRBs/ECs/REBs, 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. 
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In the event a Principal Investigator terminates participation in the study, study responsibility 
will be transferred to another investigator, if possible. In the event there are no opportunities 
to transfer Principal Investigator responsibility; detailed information on how enrolled 
subjects will be managed thereafter will be provided by Boston Scientific. 
The Principal Investigator or his/her designee must return all study-related documents and 
devices, if supplied by Boston Scientific, unless this action would jeopardize the rights, 
safety, or welfare of the subjects. 
20.5 Criteria for Suspending/Terminating a Study Site 
Boston Scientific Corporation reserves the right to stop the inclusion of subjects at a study 
site at any time after the study initiation visit if subject enrollment at a site is slower than 
projected rate, or if the site has multiple or severe protocol violations/noncompliance without 
justification and/or fails to follow remedial actions. 
The IRB/EC/REB and regulatory authorities, as applicable, will be notified. Study 
participants will be contacted, as applicable, and be informed of changes to study visit 
schedule. 
21 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 criteria set forth in the Uniform 
Requirements of the International Committee of Medical Journal Editors (ICMJE; 
http://www.icmje.org). 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 contribution 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.  
In Japan, Investigators shall register a summary of this research-study in one public database 
operated by the National University Hospital Council of Japan, the Japan Pharmaceutical 
Information Center, or the Japan Medical Association. Below are the lists of public databases 
available: 
• UMIN-CTR: http://www.umin.ac.jp/ctr/index-j.htm 
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• Iyaku Search: http://database.japic.or.jp/is/top/index.jsp 
• JMA CCT: https://dbcentre3.jmacct.med.or.jp/jmactr/ 
Investigators shall update the registered contents appropriately according to revisions of the 
research-study protocol, the progress of the research-study, and shall register the results of 
the research-study when the research is completed. 
22 Reimbursement and Compensation for Subjects 
22.1 Subject Reimbursement 
Expenses incurred by subjects as a result of participation may be reimbursed for study 
required visits if they fall within the follow-up period, and are outside of the standard of care 
visits. Reimbursement will be done in accordance with pertinent country laws and 
regulations and per the study site’s regulations.  
22.2 Compensation for Subject’s Health Injury 
Boston Scientific Corporation will purchase an insurance policy to cover the cost of potential 
health injury for study subjects, if required by applicable law.  
23 Bibliography 
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Floyd J, Fornage M, Gillespie C, Isasi CR, Jimenez MC, Jordan LC, Judd SE, 
Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Mackey RH, 
Matsushita K, Mozaffarian D, Mussolino ME, Nasir K, Neumar RW, Palaniappan L, 
Pandey DK, Thiagarajan RR, Reeves MJ, Ritchey M, Rodriguez CJ, Roth GA, 
Rosamond WD, Sasson C, Towfighi A, Tsao CW, Turner MB, Virani SS, Voeks JH, 
Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P. Heart disease and 
stroke statistics-2017 update: A report from the american heart association. 
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Whellan DJ, Lindenfeld J. Easy to predict, difficult to prevent. JACC. Heart failure. 
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FJ, Criner GJ. Heart failure and respiratory hospitalizations are reduced in patients 
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elevation angle in heart failure patients indicates orthopnea and paroxysmal nocturnal 
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Curtis JP, Akar JG. Addition of blood pressure and weight transmissions to standard 
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Akar JG, Bao H, Jones P, Wang Y, Chaudhry SI, Varosy P, Masoudi FA, Stein K, 
Saxon LA, Curtis JP. Use of remote monitoring of newly implanted cardioverter-
defibrillators: Insights from the patient related determinants of icd remote monitoring 
(predict rm) study. Circulation. 2013;128:2372-2383 
34. 
Innovator research (https://www.Resdac.Org/cms-data/request/innovator-
research).2017 
24 Abbreviations and Definitions  
24.1 Abbreviations 
Abbreviations are shown in Table 24-1. 
 
Table 24-1: Abbreviations 
Abbreviation/Acronym 
Term 
AE 
Adverse Event 
ASADE 
Anticipated serious adverse device effect 
ATR 
Atrial Tracking Recovery 
BNP 
B-Type Natriuretic Peptide 
BSC 
Boston Scientific Corporation 
CA 
Competent Authority 
CHF 
Congestive Heart Failure 
CMS 
Center for Medicare and Medicaid Services 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CRT-D 
Cardiac Resynchronization Therapy-Defibrillator 
DD 
Device Deficiency 
EC 
Ethics Committee 
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Table 24-1: Abbreviations 
Abbreviation/Acronym 
Term 
ECG 
ECG electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ER 
Emergency Room 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HF 
Heart Failure 
HFrEF 
HF with reduced ejection fraction 
HFpEF 
HF with preserved ejection fraction 
HFmEF 
HF with mid-range ejection fraction 
ICD 
Implantable Cardioverter Defibrillator 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
ID 
Identification 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
IV 
Intravenous 
LAR 
Legal Authorized Representative 
LVEF 
Left Ventricular Ejection Fraction 
MEDDEV 
European Medical Device Vigilance System 
MultiSENSE 
Evaluation of Multisensor Data in Heart Failure Patients With 
Implanted Devices 
NT-ProBNP 
NT-proB-type Natriuretic Peptide 
NYHA 
New York Heart Association 
PA 
Pulmonary Artery 
PG 
Pulse Generator 
PMT 
Pacemaker Mediated Tachycardia 
PREEMPT-HF 
Precision Event Monitoring of Patients with Heart Failure using 
HeartLogic 
PRM 
Programmer 
RCE 
Reviewable Clinical Event 
REB 
Research Ethics Board 
ROC 
Receiver Operator Curve 
SAE 
Serious Adverse Event 
SADE 
Serious Adverse Device Effect 
SAS 
Statistical Analysis Software 
UADE 
Unanticipated Adverse Device Effects 
USADE 
Unanticipated Serious Adverse Device Effects 
US 
United States 
VAD 
Ventricular Assist Device 
VF 
Ventricular Fibrillation 
VT 
Ventricular Tachycardia 
 
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24.2 Definitions 
Terms are defined in Table 24-2 
Table 24-2: Definitions 
Term 
Definition 
HeartLogic 
HeartLogic is a diagnostic tool that includes a composite index 
monitored over time designed to deliver proactive alerts of worsening 
heart failure to clinicians. 
LATITUDE 
Consists of a patient communicator for transmitting device data, 
weight scale and blood pressure monitor, and a website for clinicians 
to review data 
MEDDEV 
European directive on medical devices 
RAVE 
The electronic data base used for the clinical trial 
Source data 
All information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the 
trial. Source data are contained in the source documents (original 
records or certified copies). 
Source documents 
Original documents, data, and records 
 
 
 
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25 Appendix 
25.1  Data Collection Requirements for Demographics, Cardiac Disease History, 
Physical Assessment and Blood Labs 
Demographics 
Age 
Gender 
Race and Ethnicity 
Height 
Smoking history 
Socioeconomic status 
Cardiac Disease 
History 
Worsening HF hospitalization history 
LVEF 
NYHA or ACC/AHA HF stage 
Ischemic 
Dilated cardiomyopathy 
Idiopathic cardiomyopathy 
Valvular disease 
Valvular surgery 
Thoracic surgery 
Myocardial infarction 
CABG 
Atrial fibrillation 
Comorbidities 
Hypertension 
Hyperlipidemia 
Diabetes 
Anemia 
Chronic obstructive pulmonary disease 
Hepatic disease 
Cerebrovascular disease 
Peripheral vascular disease 
Pulmonary hypertension and type 
Renal dysfunction 
Depression 
Sleep apnea and AHI classification 
 
 
 
 
 
 
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Physical assessment 
Weight 
BP (systolic and diastolic) 
Dyspnea on exertion 
Dyspnea at rest 
Orthopnea 
Paroxysmal nocturnal dyspnea 
Pulmonary rales 
Jugular venous pressure 
Hepatojugular reflux 
3rd heart sound 
4th heart sound 
Mitral regurgitation 
Tricuspid regurgitation 
Peripheral edema 
Blood labs 
Natriuretic peptides (NT-proBNP or BNP) 
Creatinine 
25.2 PI Classification of Primary Organ Cause  
Cardiac 
Heart Failure 
MI 
Acute Coronary Syndrome 
Arrhythmia 
Complication of cardiac medication 
Cardiac Procedure 
Other (specify) 
Non-Cardiac 
Pulmonary  
Renal 
Diabetes 
Infection 
Non-cardiac chest pain 
Gastrointestinal  
Genitourinary 
Vascular 
Neurologic 
Orthopedic 
Oncologic 
Complication of non-cardiac medication 
Other (specify) 
 
 
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