Multiple Cardiac Sensors for the Management of Heart Failure
Phase: NA
Conditions: Heart Failure, Congestive
Sponsor: Boston Scientific Corporation

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Multiple cArdiac seNsors for mAnaGEment of Heart Failure 
 
(MANAGE-HF) 
 
 
Post-Approval Study of HeartLogic™ Heart Failure 
Diagnostics 
 
CLINICAL INVESTIGATION PLAN 
 
C2041 
 
 
 
 
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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Contact Information 
Role 
Contact  
Clinical Contacts 
Stephen Ruble, PhD 
Fellow, Senior Clinical Trial Manager 
P: +1.651.582.4397 
C: +1.651.324.7352    
E-mail: Stephen.ruble@bsci.com 
 
Boston Scientific Corporation 
4100 Hamline Ave North 
MS 9-3-167 
St. Paul, MN 55112-5798, USA 
 
Kate Frost, PhD 
Clinical Trial Manager 
P: +1.651.338.2217 
Email:  kate.frost@bsci.com 
 
Boston Scientific Corporation 
125 Cambridge Park Drive 
Cambridge, MA 02140 
Coordinating 
Principal 
Investigator 
Adrian Hernandez, MD 
Professor of Medicine 
Duke University 
Department of Medicine 
Durham, NC 27710 
Phone: +1.919.668.7515 
Email: adrian.hernandez@duke.edu 
 
 
 
 
 
 
 
 
 
 

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Current Version: February 1, 2018 
 
Revision History 
Revision 
Number 
Release 
Date 
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number 
and 
version 
Section 
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Reason for 
Change 
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February 
6, 2017 
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NA 
NA 
Initial Release 
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Throughout 
Fixed typos, 
added 
clarifications, 
Corrections 
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Synopsis 
Multiple 
Updated 
content to 
reflect changes 
in the protocol 
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Synopsis 
Added text: “A 
detailed 
description of 
HeartLogic is 
available in the 
HeartLogic 
Technical Guide 
which is available 
through the 
Boston Scientific 
website.”  
Clarification  
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Section 6 
Deleted 
“unscheduled 
from “Additional 
unscheduled visits 
will occur in 
response to 
HeartLogic 
alerts” 
Additional 
visits may 
include 
unscheduled 
and well as 
scheduled 
visits 
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200th Phase I 
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12 month visit” to 
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Phase I subjects 
complete 12 
Clarify all 
actively 
enrolled phase 
I subjects will 
be exited. 

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Revision History 
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month visit” 
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Scientific will 
communicate to 
the sites the 
strategy for 
exiting subjects at 
the end of the 
study.” 
Strategy for 
exiting patients 
at the end of 
the study 
clarified 
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Table 6.1, 
Table 9-1, 
Section 
9.3.2,  
Modified 
“Baseline visit 
(minimum 45 
days of heart 
failure sensor data 
collection)” to 
read as “Baseline 
visit  
(minimum 45 
days of heart 
failure sensor data 
collection; 
maximum 4 mo 
from Enrolment)” 
Added upper 
bound of 4 
months 
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in-clinic visit may 
substitute for the 
phone call, but the 
CRF must still be 
completed per 
protocol.” 
Clarification 
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Table 9-1, 
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“Informed 
consent process 
(subject must 
meet inclusion 
and exclusion 
Corrected to 
clarify that 
eligibility 
criteria 
requires that 
the Patient 

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criteria)” to read 
as “Informed 
consent process 
(subject must 
meet eligibility 
criteria)” 
meets the 
inclusion and 
do not meet the 
exclusion 
criteria 
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“LATITUDE and 
HeartLogic 
enabled 
confirmation” to 
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heart failure 
sensors enabled 
confirmation, 
including weight 
and blood 
pressure home 
unit 
Clarified 
LATITUDE 
sensors 
information 
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“Demographics, 
Cardiac Disease 
History, 
Comorbidities” to 
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“Demographics, 
and Medical 
History” 
Medical 
history will 
include cardiac 
disease and 
comorbidities 
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replaced with 
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Medical 
History is 
combined with 
“Demographics
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requirement of 
‘Physical 
exam” 

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Table 9-1, 
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failure patient 
assessment” from  
“NYHA Class” 
Data collection 
requirements 
are different 
for various 
visits 
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“HeartLogic 
Index 
Programming” 
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collection of 
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chemistry and 
EKG as a part of 
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medical 
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blood labs and 
EKG done as 
part of standard 
of care 
evaluation 
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Saturation 
Additional data 
item 
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“Qualified heart 
failure treatment  
upon alert” 
Clarification 
that qualified 
treatment may 
include other 
conditions that 
might trigger 
HeartLogic 
alert 
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Consistency 
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modification in 
Table 9.1 
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Added “The alerts 
will be turned on 
by Boston 
Scientific and that 
data will begin to 
transmit through 
the patient 
bedside 
communicator 
once you have 
completed the 
CRF for the 
baseline visit.  If 
you have 
questions, please 
contact your 
Boston Scientific 
representative.” 
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HeartLogic 
alert can only 
be turned on by 
Boston 
Scientific. 
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HeartLogic Alert 
Action Visit 
The process for 
HeartLogic 
Alert visit 
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detail 
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HeartLogic Alert 
Management 
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Consistency 
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compliance 
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phone calls 
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Data Collection at 
HeartLogic Alert 
Action Visit 
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Section 9.5 
The disc or flash 
drive should be 
kept in the 
subject’s 
MANAGE-HF 
study binder at 
the investigative 
site, and copy 
should be mailed 
to the sponsor.   
Instruction for 
back up data 
collection if 
LATITUDE 
transmissions 
are not 
available 
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Documentation 
Requirements 
 
Updated to 
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17.2 
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Physician’s 
Technical 
Manuals  for the 
study devices 
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regarding 
Anticipated 
Adverse 
Device Effects 
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“After the 
baseline visit the 
nominal setting 
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Boston 
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Clarification of 
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programmabilit
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HeartLogic 
feature. 
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calibrate   
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1 Protocol Synopsis 
 
Multiple cArdiac seNsors for mAnaGEment of Heart Failure (MANAGE-HF) 
Study Objective(s) 
MANAGE–HF has two objectives and will fulfill the 
requirements of the post-approval study:   
1. To evaluate and optimize HeartLogic™ Heart Failure 
Diagnostics (called HeartLogic from here on) clinical 
integration and the alert management process (Phase I) 
2. To evaluate HeartLogic in regards to patient outcomes 
of death and heart failure hospitalizations (Phase II)  
Planned Indication(s) for 
Use  
The study will use commercially approved CRT-D and ICD 
devices that have the HeartLogic feature.  Only patients that 
meet the eligibility criteria will be eligible to enroll in the 
study.   
Test Device 
Phases I and II: ICD and CRT-D devices with HeartLogic 
alerts turned ON 
Control Device 
Phase I: Not applicable; Single arm  
Phase II: ICD and CRT-D devices with HeartLogic alerts 
turned OFF 
Device Sizes 
All devices range in size from 28.5-32.5 cc (volume) 
depending on the specific model  
Study Design 
The MANAGE-HF study is a multi-center, global, 
prospective, open label, multi-phase trial.  Phase I will be non-
randomized.  Phase II will be randomized. 
Planned Number of Subjects Between 1700 and 2700 subjects will be enrolled in the study. 
 Phase I: Up to 200 subjects 
 Phase II: 1500 to 2500 subjects 
Planned Number of 
Investigational Sites / 
Countries 
Phase I: Up to 50 sites globally (at least 50% of the subjects 
coming from the US). 
Phase II: Up to 120 sites globally (at least 50% of the subjects 
coming from the US) 
Primary Endpoint(s) 
The primary endpoint will evaluate all-cause mortality and 
heart failure hospitalizations, comparing Phase II patients 
randomized to HeartLogic Alerts ON vs. HeartLogic Alerts 
OFF.  Phase I patients will not count toward the primary 
endpoint. 

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Multiple cArdiac seNsors for mAnaGEment of Heart Failure (MANAGE-HF) 
Additional Endpoints 
The following secondary endpoints will be evaluated, 
comparing the HeartLogic Alerts ON vs. Alerts OFF: 
 Freedom from all-cause mortality 
 Freedom from heart failure hospitalizations (time-to-
first event) 
 Risk of multiple heart failure hospitalizations 
 Change in NYHA classification 
 Change in Quality of Life 
 Change in NT-proBNP 
 Change in Medication Status 
Phase I patients will not count toward the secondary 
endpoints. 
Method of Assigning 
Subjects to Treatment 
Phase I:   
 Single arm 
 All subjects will be assigned to HeartLogic Alerts ON 
starting at the baseline visit. 
 
Phase II:  
 1:1 randomization will occur in the electronic data 
capture (EDC) system.  
 Subjects will be randomized at the baseline visit to 
HeartLogic Alerts ON (treatment group) or HeartLogic 
Alerts OFF (control group). 
 Randomization will be stratified by investigational 
center and device type (ICD or CRT-D) 
Follow-up Schedule 
The required protocol study visits are as follows: 
 Enrollment Visit 
 Baseline Visit 
 Scheduled follow-up visits 
o Annual Phone Calls (6, 18, 30, 42 months, … 
from baseline visit) 
o Annual In-Clinic (12, 24, 36, 48 months, … 
from baseline visit) 
 Additional Follow-up Visits 
o HeartLogic Alert Action Visit 
o Additional Subject Interactions (i.e., Not in 
Response to HeartLogic Alerts) 
 End of Study  
 

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Multiple cArdiac seNsors for mAnaGEment of Heart Failure (MANAGE-HF) 
Phase I subjects will be followed until the last Phase I subject 
has completed the 12 month visit, or upon recommendation 
from Steering Committee.  Phase II subjects will be followed 
until the necessary number of primary endpoint events has 
been accrued.    
Study Duration 
The trial duration is estimated to be up to 7 years from 1st 
enrollment in Phase I to study closure in Phase II. 
Inclusion Criteria 
1. Subject is age 18 or above, or of legal age to give 
informed consent  
2. Implanted with an CRT-D or ICD device that has 
HeartLogic 
3. Current symptomatic heart failure or NYHA Class II 
or III at the time of enrollment  
4. Remotely monitored by LATITUDE NXT 5.0 (or 
future versions) 
5. Willing and capable of participating in all study visits 
and complying with medication/treatment 
requirements associated with this clinical study at an 
approved clinical study center. 
6. Meet at least one of the three following conditions:   
 At least one documented hospitalization with a 
primary diagnosis of worsening for heart 
failure during the 12 months prior to 
enrollment; or 
 Unscheduled outpatient visit with IV diuretic 
therapy for acute worsening of HF during 90 
days prior to enrollment; or 
 NT-proBNP greater than 600 pg/mL or BNP 
greater than 150 pg/mL at any time during 90 
days prior to enrollment 
Key Exclusion Criteria 
1. The subject is unable to sign or refuses to sign the 
patient informed consent 
2. Symptomatic heart failure at rest or NYHA Class IV at 
the time of enrollment 
3. The subject is implanted with unipolar RA or RV leads  
4. Subject has received or is scheduled to receive a heart 
transplant or ventricular assist device within the next 6 
months 

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Multiple cArdiac seNsors for mAnaGEment of Heart Failure (MANAGE-HF) 
5. Subject is pregnant or planning to become pregnant 
during the study  
6. Subject is enrolled in any other concurrent study 
(without prior written approval from BSC, excluding 
registries)  
7. GFR <25 mL/min who are non-responsive to diuretic 
therapy or are on chronic renal dialysis 
8. Regularly scheduled IV heart failure therapy (e.g. 
inotropes or diuretics) 
9. A life expectancy of less than 12 months per clinician 
discretion 
10. APPLICABLE TO PHASE II ONLY:  Subject 
enrolled in Phase I of MANAGE-HF 
11. APPLICABLE TO PHASE II ONLY:  Subject has 
been managed with HeartLogic Alerts ON at anytime 
within the past 6 months.    
 
Statistical Methods  
Primary 
Statistical 
Hypothesis 
Phase I:  There are no formal hypotheses or endpoints in Phase I  
Phase II: The following set of hypotheses will be evaluated: 
H0:  The risk of mortality and heart failure hospitalization for the 
HeartLogic group will be greater than or equal to the risk for the 
control group 
HA:  The risk of mortality and heart failure hospitalization for the 
HeartLogic group will be less than the risk for the control group  
Statistical Test 
Method 
Statistical methodologies used to evaluate the primary endpoint are 
described in a separate Statistical Analysis Plan that is not a part of this 
study protocol.   
 
Sample Size 
Parameters 
Phase I:  Up to 200 enrolled subjects are required in Phase I to build 
critical knowledge regarding the clinical integration of HeartLogic and 
the alert management process. 
     
Phase II:  An event-driven design will be used.  Between 1500 and 2500 
subjects will be enrolled in Phase II to accrue the necessary number of 
primary endpoint events.  Parameters used to calculate the sample size 

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Multiple cArdiac seNsors for mAnaGEment of Heart Failure (MANAGE-HF) 
range are described in a separate Statistical Analysis Plan.  Final sample 
size will be determined during the study using a sample size re-estimation 
interim analysis. 
 
 
 

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Table of Contents 
1 
PROTOCOL SYNOPSIS ........................................................................................................ 12 
2 
INTRODUCTION ................................................................................................................. 22 
3 
DEVICE AND HEARTLOGIC FEATURE DESCRIPTION ....................................................... 23 
4 
STUDY OBJECTIVES .......................................................................................................... 25 
5 
STUDY ENDPOINTS ............................................................................................................ 25 
6 
STUDY DESIGN .................................................................................................................. 26 
6.1 
Scale and Duration ................................................................................................. 27 
6.2 
Treatment Assignment........................................................................................... 29 
6.2.1 
Treatment and Control ............................................................................... 29 
6.3 
Justification for the Study Design ......................................................................... 29 
6.4 
Transition from Phase I to Phase II ..................................................................... 30 
7 
SUBJECT SELECTION ......................................................................................................... 30 
7.1 
Study Population and Eligibility ........................................................................... 30 
7.2 
Inclusion Criteria ................................................................................................... 30 
7.3 
Exclusion Criteria .................................................................................................. 31 
8 
SUBJECT ACCOUNTABILITY .............................................................................................. 32 
8.1 
Point of Enrollment ................................................................................................ 32 
8.2 
Point of Study Exit ................................................................................................. 32 
8.2.1 
Study Completion ...................................................................................... 32 
8.2.2 
Withdrawal ................................................................................................ 33 
8.3 
Enrollment Controls .............................................................................................. 33 
9 
STUDY METHODS .............................................................................................................. 34 
9.1 
Data Collection ....................................................................................................... 34 
9.2 
Enrollment Screening ............................................................................................ 37 
9.3 
Study Visits ............................................................................................................. 37 
9.3.1 
Enrollment Visit ......................................................................................... 39 
9.3.1.1 
Informed Consent Process ........................................................ 39 

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9.3.1.2 
Enrollment Visit Data Collection.............................................. 39 
9.3.2 
Baseline Visit ............................................................................................. 39 
9.3.2.1 
Phase I Baseline Visit ............................................................... 39 
9.3.2.2 
Phase II Baseline Visit .............................................................. 40 
9.3.3 
Scheduled Follow-up Visits ....................................................................... 42 
9.3.3.1 
Annual Phone Calls (6, 18, 30, 42 months,…) ......................... 42 
9.3.3.2 
Annual In-Clinic Visits (12, 24, 36, 48 months, …)................. 42 
9.3.4 
Additional Follow-up Visits ...................................................................... 43 
9.3.4.1 
HeartLogic Alert Action Visit .................................................. 43 
9.3.4.2 
Additional Subject Interactions (i.e., Not in Response to 
HeartLogic Alerts) .................................................................... 44 
9.3.5 
End of Study .............................................................................................. 44 
9.4 
HeartLogic Alert Action Visit ............................................................................... 44 
9.4.1 
Qualified Treatments ................................................................................. 47 
9.4.2 
Heart Logic Alert Management Guide ...................................................... 48 
9.5 
Device Interrogation .............................................................................................. 48 
9.6 
Alert Monitoring Center........................................................................................ 48 
9.7 
Posture Sensor Calibration ................................................................................... 48 
9.8 
Randomization Crossovers (Phase II only) ......................................................... 49 
9.9 
Study Completion ................................................................................................... 49 
9.10 Source Documents .................................................................................................. 49 
10 STUDY ENDPOINTS AND STATISTICAL CONSIDERATIONS ................................................ 50 
10.1 Primary Endpoint .................................................................................................. 51 
10.1.1 
Hypothesis for Primary Endpoint .............................................................. 51 
10.1.2 
Sample Size for Primary Endpoint ............................................................ 51 
10.1.3 
Statistical Methods for Primary Endpoint ................................................. 51 
10.2 Secondary Endpoints ............................................................................................. 51 
10.2.1 
Secondary Endpoint 1: Freedom from all-cause mortality ........................ 51 
10.2.2 
Secondary Endpoint 2: Freedom from heart failure hospitalizations (time-
to-first event) ............................................................................................. 51 
10.2.3 
Secondary Endpoint 3: Risk of multiple heart failure hospitalizations ..... 52 
10.2.4 
Secondary Endpoint 4: Change in NYHA Classification .......................... 52 
10.2.5 
Secondary Endpoint 5: Change in Quality of Life .................................... 52 
10.2.6 
Secondary Endpoint 6: Change in NT-proBNP ......................................... 52 
10.2.7 
Secondary Endpoint 7: Change in Medication Status ............................... 52 

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10.3 General Statistical Methods .................................................................................. 52 
10.3.1 
Study Success Criteria ............................................................................... 52 
10.3.2 
Analysis Sets .............................................................................................. 52 
10.3.3 
Control of Systematic Error Bias ............................................................... 53 
10.3.4 
Control of Type-I Error ............................................................................. 53 
10.3.5 
Number of Subjects per Investigative Site ................................................ 53 
10.3.6 
Interim Analyses ........................................................................................ 53 
10.3.6.1 Sequential Stopping Rules ........................................................ 53 
10.3.6.2 Sample Size Re-estimation ....................................................... 53 
10.3.7 
Subgroup Analyses .................................................................................... 54 
10.3.8 
Multivariate analyses ................................................................................. 54 
10.3.9 
Justification of Pooling .............................................................................. 54 
10.3.10 Health Economic Analyses ........................................................................ 54 
10.3.11 Changes to Planned Analyses .................................................................... 54 
11 DATA MANAGEMENT ........................................................................................................ 54 
11.1 Data Collection, Processing, and Review ............................................................. 54 
11.2 Data Retention ........................................................................................................ 55 
12 AMENDMENTS ................................................................................................................... 55 
13 DEVIATIONS ...................................................................................................................... 55 
14 DEVICE/EQUIPMENT ACCOUNTABILITY .......................................................................... 56 
15 COMPLIANCE ..................................................................................................................... 56 
15.1 Statement of Compliance ....................................................................................... 56 
15.2 Investigator Responsibilities ................................................................................. 56 
15.2.1 
Delegation of Responsibility ..................................................................... 58 
15.3 Institutional Review Board/ Ethics Committee ................................................... 58 
15.4 Sponsor Responsibilities ........................................................................................ 58 
15.4.1 
Role of Boston Scientific Representatives ................................................ 59 
15.5 Insurance ................................................................................................................. 59 
16 MONITORING ..................................................................................................................... 60 
17 POTENTIAL RISKS AND BENEFITS .................................................................................... 60 
17.1 Anticipated Adverse Events .................................................................................. 60 

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17.2 Anticipated Adverse Device Effects ...................................................................... 60 
17.3 Risks Associated with the Study Device(s) ........................................................... 60 
17.4 Risks associated with Participation in the Clinical Study .................................. 61 
17.5 Possible Interactions with Concomitant Medical Treatments ........................... 61 
17.6 Risk Minimization Actions .................................................................................... 61 
17.7 Anticipated Benefits ............................................................................................... 61 
17.8 Risk to Benefit Rationale ....................................................................................... 61 
18 SAFETY REPORTING .......................................................................................................... 62 
18.1 Reportable Events by Investigational site to Boston Scientific .......................... 62 
18.2 Definitions and Classification ............................................................................... 62 
18.3 Relationship to Study Device(s) or Procedures ................................................... 65 
18.4 Investigator Reporting Requirements .................................................................. 67 
18.5 Boston Scientific Device Deficiencies .................................................................... 68 
18.6 Reporting to Regulatory Authorities / IRBs / ECs / Investigators .................... 69 
18.7 Subject Death Reporting ....................................................................................... 69 
19 INFORMED CONSENT......................................................................................................... 70 
20 COMMITTEES .................................................................................................................... 71 
20.1 Safety Monitoring Process ..................................................................................... 71 
20.2 Data Monitoring Committee ................................................................................. 71 
20.3 Clinical Events Committee .................................................................................... 72 
21 SUSPENSION OR TERMINATION ........................................................................................ 72 
21.1 Premature Termination of the Study ................................................................... 72 
21.1.1 
Criteria for Premature Termination of the Study ....................................... 72 
21.2 Termination of Study Participation by the Investigator or Withdrawal of 
IRB/ EC Approval .................................................................................................. 72 
21.3 Requirements for Documentation and Subject Follow-up ................................. 73 
21.4 Criteria for Suspending/Terminating a Study Site ............................................. 73 
22 PUBLICATION POLICY ....................................................................................................... 73 
23 REIMBURSEMENT AND COMPENSATION FOR SUBJECTS .................................................. 74 

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23.1 Subject Reimbursement......................................................................................... 74 
23.2 Compensation for Subject’s Health Injury ......................................................... 74 
24 BIBLIOGRAPHY .................................................................................................................. 74 
25 ABBREVIATIONS AND DEFINITIONS .................................................................................. 75 
25.1 Abbreviations are shown in Table 25-1. ............................................................... 75 
25.2 Definitions ............................................................................................................... 78 
 
Table of Figures 
Figure 3-1: LATITUDE NXT 5.0 System .............................................................................. 25 
Figure 6-1:  MANAGE-HF Study Design .............................................................................. 28 
Figure 9-1:  MANAGE-HF Detailed Study Flow Chart ......................................................... 38 
Figure 9-2:  HeartLogic Alert Management Process .............................................................. 46 
Table of Tables 
Table 3-1: HeartLogic State .................................................................................................... 24 
Table 6-1:  Scheduled Visits ................................................................................................... 27 
Table 7-1:   Inclusion Criteria ................................................................................................. 31 
Table 7-2: Exclusion Criteria .................................................................................................. 32 
Table 9-1:  Data Collection and Visit Schedule ...................................................................... 35 
Table 9-2: Annual Phone Call Schedule ................................................................................. 42 
Table 9-3: Annual In-Clinic Visit Schedule ........................................................................... 42 
Table 9-4: Data Collection at HeartLogic Alert Action Visit ................................................. 47 
Table 9-5: Source Documentation Requirements ................................................................... 50 
Table 18-1: Safety Definitions ................................................................................................ 62 
Table 18-2: Assessing Relationship of Study Device or Procedure to Adverse Event .......... 66 
Table 18-3: Investigator Reporting Requirements .................................................................. 67 
Table 25-1: Abbreviations ...................................................................................................... 75 
Table 25-2: Definitions ........................................................................................................... 78 
 

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2 Introduction 
Heart failure (HF) hospitalizations are associated with high mortality, readmission, and 
economic burden, with a direct cost of over $20 billion attributed [1].  Monitoring of weight 
and symptoms is encouraged [2] but hasn’t been shown to reduce hospitalizations [3].  Thus, 
new diagnostic tools are needed to decrease cost and improve patient outcomes.    
 
Improvement of patient outcomes with the help of a HF diagnostic rests on two crucial 
components: 1) the HF diagnostic must be able to detect HF worsening on top of standard 
clinical care; 2) the HF diagnostic must be properly integrated into clinical workflow.   
 
Cardiac implantable electronic devices (Implantable Cardioverter Defibrillators (ICD), 
cardiac resynchronization therapy (CRT)) with sensors have been used to develop HF 
diagnostics which indicate early changes leading up to hospitalizations [4, 5].  Yet studies 
using these diagnostics have failed to reach endpoints on sensitivity and false positive rate, 
and have not  shown reductions in HF events [6-8].   Most of these studies used single 
sensors which make prediction of outcomes challenging in a complex condition such as heart 
failure [9-11].  A more robust approach has been to combine information from a diverse set 
of sensors to develop an algorithm and alert for detecting worsening heart failure [12].    
 
However, alert algorithm performance alone is not sufficient.  The alerts must be translated 
to drive clinical action in order to improve patient outcomes.  Initial tele-monitoring trials 
based on single sensors demonstrated that compliance with algorithm-generated alerts was 
often inadequate [3, 4] failing to give the diagnostic an opportunity to add benefit, or even 
leading to worsened patient outcomes [6].  Given the significant variation in HF care 
pathways [13] and remote monitoring utilization[14], subsequent investigations that have 
more closely integrated diagnostics with clinical practice have shown measurable and 
sustained impact on patient outcomes [7, 15, 16]. Additionally, data recently presented from 
a retrospective sub-analysis of the CHAMPION trial showed that the HF hospitalization rate 
in patients in whom interventions were based only on clinical findings (e.g. signs and 
symptoms) was not different from control, whereas patients in whom interventions were 
influenced by pulmonary pressure readings, guided by the study specific clinical intervention 
guidelines, had a 67% reduction in HF hospitalization rate [17].   Recently presented data 
from the REM-HF study [18], which included manual review of multiple individual device 
parameters also failed to show improvement in patient outcomes.   
 
Boston Scientific has developed a high-performing algorithm which detects early onset of HF 
events. The development was performed via MultiSENSE study [12]. The MultiSENSE 
(Multisensor Chronic Evaluations in Ambulatory Heart Failure Patients) was a single arm, 
multi-center, observational, non-randomized study designed to collect chronic ambulatory 
data from multiple sensors available to implanted cardiac devices in order to develop an 
algorithm for the early detection of worsening Heart Failure. The study was conducted in 93 
centers worldwide and designed to enroll up to a total of 990 patients with implanted 
COGNIS® CRT-D devices. Upon enrollment, the patient’s CRT-D device was converted 

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into Sensor Research Device (SRD-1) by downloading investigational software to enable the 
collection of sensor data without affecting the device hardware or the delivered therapy. 
Patients were followed for up to a year. The sensor data were continuously collected by the 
device. The sensor data included metrics derived from accelerometer-based first and third 
heart sounds, thoracic impedance, respiration rate, relative tidal volume, heart rate, and 
patient activity. In addition to device-based sensor data, clinical data was captured. The 
clinical data included clinical assessments and measurements required by the MultiSENSE 
study that were entered by site personnel.  Event adjudication was performed by  an 
independent clinical events committee. 
 
A subset of 400 patients was sequestered (Test Set) and the set of the remaining 500 patients 
was used to develop the HeartLogic algorithm - a multi-sensor algorithm for detection of 
usable HF events. Usable HF events were defined as HF hospitalization or outpatient 
intravenous decongestive therapy with sufficient sensor data available. The algorithm was 
then validated on the Test Set with predefined endpoints for sensitivity and unexplained alert 
rate.  The results showed that the HeartLogic algorithm passed pre-specified  endpoints and 
effectively detected usable HF events with a median early notification of 34 days, a 
sensitivity of 70%, and an unexplained alert rate of 1.46 per patient per year.  
 
HeartLogic algorithm and its supporting sensors, referred to as HeartLogic Heart Failure 
Diagnostic Service, will be available in the RESONATE family of pulse generators, 
including CRT-Ds and ICDs. MANAGE-HF will be the first prospective post-market study 
to evaluate HeartLogic integration, utilization, and impact on heart failure hospitalization and 
patient mortality.  Phase I will be used to develop an alert management and treatment 
process.  The importance of developing the alert management and treatment process is 
evident from previous clinical trials.  Proper clinical utilization of a HF diagnostic, in 
addition to its performance, is crucial for improving patient outcomes [3, 6-8, 13-16, 19]. 
Phase II will then test HeartLogic in reducing mortality and heart failure hospitalizations by 
comparing patients that have HeartLogic Heart Failure Diagnostic Service ON vs. 
HeartLogic Heart Failure Diagnostic Service OFF.    
 
Phase II of the MANAGE-HF trial will begin after the primary objective of Phase I – to 
evaluate and optimize HeartLogic clinical integration and the alert management process – has 
been fulfilled. Boston Scientific will communicate to sites the authorization to initiate 
enrollment into Phase II.  Subjects enrolled in Phase I will be ineligible to enroll in Phase II. 
3 Device and HeartLogic Feature Description 
 
Both Phase I and Phase II of the MANAGE-HF study will use device models that are 
commercially approved and have HeartLogic.  The feature being studied in MANAGE-HF is 
called HeartLogic Heart Failure Diagnostic Service (or simply HeartLogic).  A detailed 

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description of HeartLogic is available in the HeartLogic Technical Guide which is available 
through the Boston Scientific website.   
 
The HeartLogic feature is comprised of a composite trend called the HeartLogic Index and a 
configurable yellow alert.  These data and alerts are delivered to the clinical team and to 
Boston Scientific via the LATITUDE™ remote monitoring system. HeartLogic has been 
validated as a diagnostic tool to detect gradual worsening of heart failure over days or weeks 
using multiple physiologic measurements [12].   
 
The HeartLogic Index aggregates measurements from multiple device-based sensors (Heart 
Sounds, Thoracic Impedance, Respiration, and Night Heart Rate) and reflects changes over 
time in the subject’s sensor trend data from their respective baseline values. HeartLogic 
provides additive information for clinicians to use in context with standard-of-care patient 
treatment.  However, it should not replace standard-of-care treatment. 
 
There are three HeartLogic states defined in this protocol – Alerts On, Alerts Off and Sensors 
Disabled.  Descriptions of each state are found in the table below.   
 
Table 3-1: HeartLogic State 
 
State 
HeartLogic Sensors 
Enabled and Collecting 
Data 
Access to HeartLogic 
Index 
Access to HeartLogic 
Alerts 
HeartLogic Alerts ON 
Yes 
Yes 
Yes 
HeartLogic Alerts OFF 
Yes 
No 
No 
HeartLogic Disabled 
No 
No 
No 
 
 
 
The CRT-D or ICD device, along with its associated leads, constitutes the implantable 
portion of the system.  The external portion of the system includes the commercially 
available LATITUDE NXT 5.0 System (or future versions) and the Model 3120 Programmer 
Recorder Monitor (or future versions).  The external portion of the system allows 
interrogation and programming of the PG, as well as access to the PG’s diagnostic features.  
  
Communication between the internal and external portions of the system is conducted 
through a handheld wand and/or wireless telemetry. Data are then transmitted to the clinician 
care team.  The complete LATITUDE NXT 5.0 system is shown in Figure 3-1. Data will 
automatically be uploaded and transmitted to the clinician for review on the scheduled 
interval.  When the HeartLogic alert threshold is met or exceeded, a yellow alert is generated 
which triggers the health care professional to review the data and take appropriate action.      
 
Boston Scientific has performed safety risk management activities, design verification and 
design validation testing to demonstrate that devices with the HeartLogic feature function 

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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 acceptable for normal product use in accordance with product labeling.   
 
 
Figure 3-1: LATITUDE NXT 5.0 System 
 
 
4 Study Objectives 
There are two objectives of the MANAGE-HF multi-phase study : 
 
 Phase I:  To evaluate and optimize HeartLogic clinical integration and alert 
management process.   
 Phase II: To evaluate HeartLogic in regards to patient outcomes of death and heart 
failure hospitalizations.  Additionally, Phase II will fulfill regulatory requirements of 
post-approval study for HeartLogic. 
 
Phase II of the MANAGE-HF trial will begin following completion of Phase I.  Subjects 
enrolled in Phase I will be ineligible to enroll in Phase II. 
 
5 Study Endpoints 
The primary endpoint will assess the composite of all-cause mortality and heart failure 
hospitalizations collected in Phase II of the trial, comparing HeartLogic Alerts ON vs. Alerts 
OFF. 
The following secondary endpoints will be evaluated using data collected during Phase II, 
comparing the HeartLogic Alerts ON vs. Alerts OFF: 
 Freedom from all-cause mortality 

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 Freedom from heart failure hospitalizations (time to first event) 
 Change in NYHA classification 
 Change in Quality of Life 
 Change in NT-proBNP 
 Change in Medication Status 
 
All randomized subjects in Phase II will be eligible for inclusion in the analyses of all study 
endpoints.  No data from Phase I will be included in the analysis for the primary or secondary 
endpoints.   
6 Study Design 
MANAGE-HF is a multi-center, global, prospective, open label, multi-phase trial.  Phase I 
will be non-randomized and a single arm.  Phase II will be randomized in a 1:1 allocation to 
HeartLogic Alerts ON vs. Alerts OFF.  Phase II will begin after the primary objective of 
Phase I – to evaluate and optimize HeartLogic clinical integration and the alert management 
process – has been fulfilled. Boston Scientific will communicate to sites the authorization to 
initiate enrollment into Phase II.   
 
Eligible subjects in Phase I and Phase II will already be implanted with a device that contains 
HeartLogic, and must meet the inclusion and exclusion criteria as described in Sections 7.2 
and 7.3.  Subjects in Phase I are ineligible to be enrolled in Phase II.  
 
The follow-up schedules are identical for all subjects in Phases I and II.  Only the point of 
study exit differs between the phases.  Follow-up for subjects in each phase are shown in the 
table below.  Additional visits will occur in response to HeartLogic alerts.   
 

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Table 6-1:  Scheduled Visits 
Visit 
Window 
Phase I 
Phase II 
Enrollment 
After device implant 
X 
X 
Baseline 
At least 45 days of heart failure 
sensor data collection. 
At most 4 months from 
enrollment. 
X 
X 
Phone call 
180 ± 30 days from baseline 
545 ± 30 days from baseline 
910 ±  30 days from baseline 
1275 ± 30 days from baseline 
1640 ±  30 days from baseline  
X1 
X2 
Annual visit 
365 ± 30 days from baseline 
730 ± 30 days from baseline 
1095 ± 30 days from baseline  
1460 ± 30 days from baseline 
1825 ± 30 days from baseline 
X1 
X2 
Subject 
Study Exit 
 
After  Phase I 
subjects complete 
12 month visit3 
After necessary 
number of primary 
endpoint events has 
been accrued 
1. Follow-ups continue for Phase I subjects through the end of Phase I 
2. Follow-ups continue for Phase II subjects through the end of Phase II 
3. Phase I may complete early upon recommendation from Steering Committee 
 
After a minimum of 45 days of heart failure sensor data collection, all subjects (Phases I and 
II) will be evaluated at a baseline visit  and will  be followed  annually for in-clinic visits.  In 
addition, a 6 month phone call for all subjects will be placed in between annual visits.  
Subjects in Phases I and II will continue to be seen until the study phase is completed. Phase 
I ends when the final subject completes the 12 month follow-up visit, or upon 
recommendation from the Steering Committee.   Phase II ends when the necessary number of 
primary endpoint events has been accrued. A detailed flow-chart of the study visits can be 
found in Section 9.   
6.1 
Scale and Duration 
The study will enroll up to a total of 2700 subjects across two study phases.  Up to 200 
subjects will be enrolled in Phase I in order to build critical knowledge about the clinical 
integration of HeartLogic and the alert management process.  A minimum of 50% of the 
subjects in Phase I will come from US sites.  Phase I will be concluded upon completion of 
the last Phase I subject’s 12 month follow-up, or upon recommendation from the Steering 
Committee that the study should progress to Phase II.  Subjects in Phase I will be ineligible 
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Up to 2500 subjects will be enrolled in Phase II to sufficiently power the primary endpoint in 
Phase II.  A minimum of 50% of the subjects in Phase II will come from US sites.  Follow-up 
for Phase II will continue until a pre-specified stopping boundary has been achieved or  the 
necessary number of primary endpoint events has been accrued.  Details of the pre-specified 
Primary Endpoint are defined in Section 10.1 and in a separate Statistical Analysis Plan.  
Phase I events will not count toward the primary endpoint of the study.    
 
Figure 6-1 illustrates the study flow of both phases of the MANAGE-HF trial. Enrollment 
durations of Phases I and II are expected to last 15 and 24 months, respectively.  A gap in 
time between completion of Phase I enrollments and initiation of Phase II enrollments is 
anticipated as Phase I patients may be followed until the final patient finishes the 12 month 
visit. 
 
 
Figure 6-1:  MANAGE-HF Study Design 
 
 
 
 

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6.2 
Treatment Assignment 
The MANAGE-HF post-approval study is a multi-phase study.  Phase I is single arm and 
open label; all enrolled Phase I subjects will be actively managed with HeartLogic alerts.  
Subjects in Phase I will be ineligible to be enrolled in Phase II. 
 
Phase II is randomized, controlled, two arm and open label.    Phase II subjects will be 
randomized to HeartLogic Index and Alerts ON or HeartLogic Index and Alerts OFF using a 
1:1 allocation. Randomization will be stratified by investigational center and device type 
(ICD or CRT-D).  
 
The devices are commercially approved for use in patients indicated for an ICD or CRT-D.  
However, there are specific study criteria that are identical for both phases of MANAGE-HF 
that must be met to be eligible for enrollment (Section 7).   
6.2.1 Treatment and Control 
Phase I: 
 
 All subjects in Phase I will be implanted with ICD or CRT-D devices that have the 
HeartLogic feature.   
 HeartLogic Index and Alerts will be ON for all subjects enrolled in Phase I starting at 
the baseline visit.   
 There will be no control subjects in Phase I.   
 Subjects enrolled in Phase I will be ineligible for Phase II. 
 Phase I data does not count toward Phase II endpoints.   
 
Phase II: 
 
 All subjects in Phase II will be implanted with ICD or CRT-D devices that have the 
HeartLogic feature. 
 Subjects enrolled in Phase II will be randomized to HeartLogic Alerts ON (treatment) 
or HeartLogic Alerts OFF (control). 
 Phase II subjects randomized to the treatment arm will be actively managed with the 
HeartLogic Alerts ON and the subjects randomized to the control arm will be 
managed with HeartLogic Alerts OFF.    
 Randomized subjects in Phase II are eligible to contribute data to all endpoint 
analyses. 
6.3 
Justification for the Study Design 
The multi-phase nature of MANAGE-HF is required to evaluate the multiple objectives of 
the trial.  The use of a single arm in Phase I was chosen as the most appropriate and efficient 

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design to evaluate and optimize HeartLogic clinical integration and alert management 
process.  Learnings from Phase I will be incorporated into Phase II and reflected in a separate 
statistical analysis plan that will be approved by Boston Scientific and the FDA. The use of a 
randomized controlled design in Phase II was chosen to minimize bias in the findings, and is 
to the gold-standard to demonstrate a true treatment effect.   
6.4 
Transition from Phase I to Phase II 
It is anticipated that 200 subjects followed for a minimum of 12 months is required to fulfill 
the objectives of Phase I.  After the final Phase I subject has completed their 12 month visit, 
or upon recommendation from the Steering Committee, Boston Scientific will notify sites to 
begin exiting Phase I subjects from the study.   
 
Boston Scientific will notify sites of Phase II initiation, at which time all approved-to-enroll 
sites may begin enrolling Phase II subjects.  Phase I subjects are ineligible to participate in 
Phase II.  The request for randomization  of subjects will occur at the baseline visit for Phase 
II subjects. 
7 Subject Selection 
7.1 
Study Population and Eligibility  
Eligibility for study enrollment is determined by specific inclusion and exclusion criteria as 
described in Sections 7.2 and 7.3.   
7.2 
Inclusion Criteria 
Inclusion criteria are identical for Phases I and II.  Subjects who meet all of the following 
criteria (see Table 7-1) may be given consideration for inclusion in this clinical investigation, 
provided no exclusion criterion (see Section 7.3) is met.  
 
  
 

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Table 7-1:   Inclusion Criteria 
CI1 
Subject is age 18 or above, or of legal age to give informed consent  
CI2 
Implanted with an CRT-D or ICD device that has HeartLogic 
CI3 
Current symptomatic heart failure or NYHA Class II or III at the time of 
enrollment  
CI4 
Remotely monitored by LATITUDE NXT 5.0 (or future versions) 
CI5 
Willing and capable of participating in all study visits and complying with 
medication/treatment requirements associated with this clinical study at an 
approved clinical study center. 
CI6 
Meet at least one of the three following conditions:   
 At least one documented hospitalization with a primary diagnosis of 
worsening for heart failure during the 12 months prior to enrollment; or 
 Unscheduled outpatient visit with IV diuretic therapy for acute worsening 
of HF during 90 days prior to enrollment; or 
 NT-proBNP greater than 600 pg/mL or BNP greater than 150 pg/mL at any 
time during 90 days prior to enrollment 
 
7.3 
Exclusion Criteria 
All exclusion criteria apply to subjects in Phases I and II, except for criteria 10 and 11, which 
are applicable to Phase II subjects only.  Subjects who meet any one of the following criteria 
(see Table 7-2) will be excluded from this clinical study. 
 

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Table 7-2: Exclusion Criteria 
CE1 
The subject is unable to sign or refuses to sign the patient informed consent 
CE2 
Symptomatic heart failure at rest or NYHA Class IV at the time of enrollment 
CE3 
The subject is implanted with unipolar RA or RV leads  
CE4 
Subject has received or is scheduled to receive a heart transplant or ventricular assist 
device within the next 6 months 
CE5 
Subject is pregnant or planning to become pregnant during the study  
CE6 
Subject is enrolled in any other concurrent study (without prior written approval 
from BSC, excluding registries)  
CE7 
GFR <25 mL/min who are non-responsive to diuretic therapy or are on chronic renal 
dialysis 
CE8 
Regularly scheduled IV heart failure therapy (e.g. inotropes or diuretics) 
 
CE9 
A life expectancy of less than 12 months per clinician discretion 
CE10 APPLICABLE TO PHASE II ONLY:  Subject enrolled in Phase I of MANAGE-HF 
CE11 APPLICABLE TO PHASE II ONLY:  Subject has been managed with HeartLogic 
Alerts ON at anytime within the past 6 months.    
Abbreviations:  RA=right atrial; RV=right ventricle   
8 Subject Accountability 
8.1 
Point of Enrollment 
All details in this section apply to subjects in Phases I and II.   
 
Subjects are considered enrolled at the point when they sign and date the informed consent 
form.  Confirmation that inclusion and exclusion criteria are met must take place prior to 
consent.  The consent may be obtained at any point in time following the implantation of the 
device, but not before.     
8.2 
Point of Study Exit 
8.2.1 Study Completion 
All details described in this section apply to subjects in Phases I and II. 
 
Phase I: 
After the final Phase I subject has completed their 12 month visit, or upon recommendation 
from the Steering Committee, Boston Scientific will notify sites to begin exiting Phase I 
subjects from the study.  Boston Scientific will communicate to the sites the strategy for 
exiting subjects at the end of the study. 
 

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Phase II: 
After the necessary number of primary endpoint events has been accrued, Boston Scientific 
will notify sites to begin exiting Phase II subjects from the study.   
8.2.2 Withdrawal 
All details described in this section apply to subjects in Phases I and II. 
 
All subjects enrolled in the clinical study (including those withdrawn from the clinical study 
or lost to follow-up) shall be accounted for and documented. If a subject withdraws from the 
clinical investigation, the reason(s) shall be reported. If such withdrawal is due to problems 
related to investigational device safety or performance, the investigator shall ask for the 
subject’s permission to follow his/her status/condition outside of the clinical study.  
  
A subject who becomes inactive in the study as defined by clinician recommendation, subject 
choice, has their device explanted, or is lost to follow-up will be classified as “Withdrawal”.  
All applicable case report forms up to the point of withdrawal and a “Subject Status” form 
must be completed. Investigators who have “lost-to-follow-up” subjects should have at least 
three documented attempts to contact them prior to completion of the “Patient Status” form. 
  
After a subject has been withdrawn from the study or after a subject has withdrawn his/her 
consent, for whatever reason, additional data may no longer be collected after the point of 
withdrawal, and HeartLogic alerts may be turned OFF. 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.  Boston Scientific will not actively collect any information on subjects who 
have been withdrawn from the study after the withdrawal date.  However, all post-
withdrawal adverse events of which Boston Scientific is notified will be recorded in the 
patient file. 
8.3 
Enrollment Controls 
Up to 2700 patients will be enrolled in MANAGE-HF – up to 200 in Phase I and up to 2500 
in Phase II.  A single site may not enroll more than 20 subjects in Phase I or 100 subjects in 
Phase II without written authorization from Boston Scientific.  There are no specific 
limitations on gender or race.   
 
To ensure Phase I does not exceed 200 subjects, when the study is nearing 200 enrolled 
subjects sites will be notified that future enrollments must be approved by Boston Scientific.  
Similarly, when Phase II is nearing the desired enrollment number (between 1500 and 2500, 
as determined during the study via an interim sample size assessment), sites will be notified 
that future enrollments must be approved by Boston Scientific.   

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9 Study Methods 
9.1 
Data Collection 
Details in this section apply to all subjects in Phases I and II.   
 
The data collection schedule is shown in Table 9-1..  Details for each study visit are found in 
section 9.3.  However, all required data elements should be entered into the electronic case 
report forms that are in the MANAGE-HF database in a timely manner.  For HeartLogic 
alerts, it is imperative to adhere to the timelines for patient contact, treatment and data entry 
as shown in  Figure 9-2 to avoid protocol deviations.   

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Table 9-1:  Data Collection and Visit Schedule 
Procedure/Assessment 
Enrollment 
 
Baseline visit 
(minimum 45 days of 
heart failure sensor data 
collection; maximum 4 
mo from Enrolment) 
Follow-up Visits 
End of Study  
Annual Phone Call 
(6, 18, 30, 42 mo… 
from baseline) 
Annual In-Clinic Visit 
(12, 24, 36, 48 mo… 
from baseline)1 
HeartLogic Alert Action 
(phone calls and/or  in-
clinic visits) 
Additional Subject 
Interactions 
(phone calls and/or in-clinic 
visits) 
Protocol Section 
9.2, 
9.3.1.1, 
9.3.1.2 
 
9.3.2 
0 
9.3.3.2 
9.3.4.1, 
9.4 
9.3.4.2 
9.3.5 
 
Inclusion/Exclusion  
 
R 
 
 
 
 
 
 
 
Informed consent process (subject must 
meet eligibility criteria) 
 
R 
 
 
 
 
 
 
 
Device information (model and serial 
numbers, implant date) 
 
R 
 
 
 
 
 
 
 
LATITUDE and heart failure sensors 
enabled confirmation, including weight 
and blood pressure home unit 
 
R 
 
 
 
 
 
 
 
Demographics and Medical History 
 
 
R 
 
 
 
 
 
 
Phase I, Phase II HeartLogic Alerts ON 
group:  
 
HeartLogic alerts turned on and 
threshold set at 16 
Phase II HeartLogic Alerts OFF group: 
 
HeartLogic alerts turned off 
 
 
 
R 
 
 
 
 
 
Physical Exam 
 
R 
 
R 
R (in-clinic only) 
 
 
 
Heart failure patient assessment  
 
 
R 
R 
R 
R 
O 
 
 
NYHA3 Class 
 
 
R 
 
R 
R (in-clinic only) 
O 
 
 
Posture Sensor Calibration 
 
 
R 
 
R 
 
 
 
 
HeartLogic Index Programming  
 
 
R 
R 
R 
R 
R 
 

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Procedure/Assessment 
Enrollment 
 
Baseline visit 
(minimum 45 days of 
heart failure sensor data 
collection; maximum 4 
mo from Enrolment) 
Follow-up Visits 
 
 
 
End of Study 
Annual Phone Call 
(6, 18, 30, 42 mo… 
from baseline) 
Annual In-Clinic Visit 
(12, 24, 36, 48 mo… 
from baseline)1 
HeartLogic Alert Action 
(phone calls and/or  in-
clinic visits) 
Additional Subject 
Interactions 
(phone calls and/or in-clinic 
visits) 
 
NT-proBNP 
 
 
R 
O 
R 
O 
O 
 
 
Blood chemistry and EKG as a part of 
standard of care medical evaluation 
 
 
O 
O 
O 
O 
O 
 
 
Subject reported outcomes ( KCCQ3 and 
EQ-5D-5L) 
 
 
R 
 
R 
O 
 
 
 
Weight, Blood Pressure and Heart Rate 
 
 
R 
 
R 
O 
 
 
 
Oxygen Saturation 
 
 
O 
 
O 
O 
 
 
 
Medications 
 
 
R 
R 
R 
R 
R 
 
 
Adverse Events/Device Deficiencies4 
 
 
R 
R 
R 
R 
R 
 
 
Device data (disk download) 
 
 
 
 
R2 
R2 
R2 
 
 
Qualified treatment  upon alert 
 
 
 
 
 
R 
 
 
R = required; O = optional but recommended.1Phase I subjects will only be followed for annual visits until the final Phase I subject has completed their 12 month visit (or upon recommendation by the Steering Committee), at which point the 
subject will exit the study and have no additional follow-up visits. 
2 Required per Boston Scientific request, if LATITUDE data are unavailable (Section 9.5)   
3Abbreviations:   NYHA=New York Heart Association; KCCQ=Kansas City Cardiomyopathy Questionnaire  
4Adverse event data also includes hospital admission regardless of cause.  

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9.2 
Enrollment Screening 
Details in this section apply to all subjects in Phases I and II.  Subjects will be recruited from the investigator’s 
general heart failure population. The investigator has the responsibility of screening potential subjects and 
selecting only those who meet the eligibility criteria.  Screening logs should be maintained for all screened 
subjects and kept at investigative sites.  Screen failures should be entered in the RAVE database and the date of 
screening, and the reason for screen failure will be captured.     
9.3 
Study Visits 
Details in this section apply to all subjects in Phases I and II.   
 
The required protocol study visits are as follows: 
 
 Enrollment Visit 
 Baseline Visit 
 Scheduled follow-up visits 
o Annual Phone Calls (6, 18, 30, 42 months, … from baseline visit) 
o Annual In-Clinic (12, 24, 36, 48 months, … from baseline visit) 
 Additional Follow-up Visits 
o HeartLogic Alert Action Visit 
o Additional Subject Interactions (i.e., Not in Response to HeartLogic Alerts) 
 End of Study  
 
Phase I subjects will be followed until the last Phase I subject has completed the 12 month visit, or upon 
recommendation from Steering Committee.  Phase II subjects will be followed until the necessary number of 
primary endpoint events has been accrued.    
 
 

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Figure 9-1:  MANAGE-HF Detailed Study Flow Chart 
 
Screening
Optional screening form 
prior to patient consent
Enrollment
Confirm inclusion/exclusion requirements
Informed consent
Heart failure sensors enabled
Latitude enabled; device information
Baseline Visit
( min of 45d of sensor data collected since implant*)

Demographics and Medical History

Heart failure assessment, including NYHA Class, KCCQ, EQ-
5D-5L

NT-proBNP, 

Medications

Posture sensor calibration

Weight scale and BP cuff requested (via database)

Adverse Events/Device Deficiencies
Annual Phone Calls and Annual In-Clinic Visits

Heart failure assessment

HeartLogic Programming

NT-proBNP

HF and cardiovascular medication changes

NYHA, KCCQ, EQ-5D-5L (in-clinic only)

Posture sensor calibration (in-clinic only)

Optional data disk download (in-clinic only)

Blood chemistry and EKG (optional)

Adverse Events/Device Deficiencies
End of Study
NO
Do not 
consider for 
enrollment
Patient refuses 
consent?
Sufficient Primary 
Endpoint Events 
Accrued
HeartLogic alert visits and phone calls

Heart failure assessment, including NYHA

HF and cardiovascular medication changes 

Document treatment plan per protocol guidance, including 
medication changes

Device data assessment

Optional weight and blood pressure, KCCQ, EQ-5D-5L

Optional NT-proBNP (only for in-clinic visit)

Adverse Events/Device Deficiencies
*If less than 45 days, reschedule baseline visit
All Phase I patients exit 
the study after the final 
patient completes 12 
months or upon 
recommendation from 
the Steering Committee
Phase II
Patients randomized 1:1 to 
HeartLogic Alerts ON or OFF
Phase I
HeartLogic ON in all patients
Inclusion and exclusion 
criteria met?
 
 

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9.3.1 Enrollment Visit 
Details in this section apply to all subjects in Phases I and II.     
9.3.1.1 Informed Consent Process 
All subjects must undergo the informed consent process, and sign and date the informed consent before any 
study procedures are performed.  Subjects will be considered enrolled at the time of  informed consent.  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.  
 
9.3.1.2 Enrollment Visit Data Collection 
The following information must be gathered for the implanted CRT-D or ICD system and entered into the 
RAVE database in a timely manner: 
 Inclusion/Exclusion  Screening Form 
 Manufacturer, model and serial number of pulse generator and active leads 
 Implant date for all active devices 
 Anatomical locations of pulse generator and leads 
 Confirmation that subject has been or will be remotely monitored with LATITUDE NXT 5.0 (or 
equivalent) 
o If the subject has at least 45 days of heart failure sensor data collection the subject may also 
complete the baseline visit (see section 9.3.2). 
o If subject does not have at least 45 days of heart failure sensor data, schedule baseline visit 
accordingly. 
 
If the Enrollment Visit does not occur on the same day as the Baseline visit, the clinician (and if needed with 
assistance from Boston Scientific) will ensure that HeartLogic Alerts are OFF and Heart Failure Sensor Data 
Collection have not been disabled (i.e., still in nominal setting).      
9.3.2 Baseline Visit 
The baseline visit will occur for all enrolled subjects (Phases I and II) who have a minimum of 45 days of heart 
failure sensor data in the pulse generator.  If there are fewer than 45 days, the baseline visit must be 
rescheduled.  The baseline visit will occur after the subject has consented, but can occur on the same day as 
enrollment.  The baseline visit must occur at most 4 months from enrollment.  
 
Procedures followed and data collected differ by phase and are presented separately by phase in Sections 9.3.2.1 
(Phase I) and 9.3.2.2 (Phase II).   
9.3.2.1 Phase I Baseline Visit 
The following actions must be taken at the baseline visit for Phase I subjects: 
 Required Blood Draw: 
o NT-proBNP per investigative site procedures. Other BNP values are not permitted in the study. 
 Required Programming at Baseline visit: 

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o Through the LATITUDE system, HeartLogic Alert Threshold must be programmed to 16 
(nominal HeartLogic Alert Threshold setting) and “daily interrogations until alert condition is 
resolved” programmed on .  After the baseline visit, the nominal HeartLogic Alert Threshold 
setting of 16 may be changed with appropriate documentation, in the RAVE database, of the 
rationale for changing this value.   
 Required for all patients in Phase I and Phase II HeartLogic ON group  
o All other therapies/device settings are at the discretion of the clinician. 
 Required attempt to calibrate the posture sensor 
 
The following information must be entered into the electronic database: 
 Patient demographics and medical history 
 Physical Exam 
 Heart failure assessment 
 NYHA Classification  
 Posture sensor calibration (Section 9.7)  
 HeartLogic Alert Threshold activated 
 NT-proBNP  
 Blood chemistry and EKG as a part of standard of care medical evaluation (optional) 
 Kansas City Cardiomyopathy Questionnaire (KCCQ) 
 EQ-5D-5L 
 Weight, Blood Pressure and Heart Rate 
 Oxygen saturation (optional) 
 Changes to heart failure and cardiovascular related medications and treatments 
 Applicable adverse event/device deficiency reporting (Section 18) 
 
At the end of the visit, the clinician, with assistance from Boston Scientific, will ensure that the HeartLogic 
feature is activated and that the HeartLogic Alert Threshold is programmed to 16 (nominal setting).  After the 
baseline visit, the alerts will be turned on once you have completed the CRF or called Boston Scientific, and the 
data will begin to transmit through the patient bedside communicator  If you have questions, please contact your 
Boston Scientific representative.  This ensures that if the alert threshold is met or exceeded, an alert will be sent 
to the clinician and to the Alert Monitoring Center (AMC Section 9.6).  Physicians may adjust the threshold, but 
the change must be documented in the RAVE database.  Refer to the HeartLogic Technical guide for 
information on how adjusting the alert threshold affects the sensitivity and the alert rate.    
 
9.3.2.2 Phase II Baseline Visit 
If subjects has had HeartLogic Alerts ON at any point between enrollment and the baseline visit, the subject 
must be exited from the study.  Use of HeartLogic Alerts prior to the randomized portion of the study may bias 
the endpoint results. 
 
The following actions must be taken at the baseline visit for Phase II subjects: 
 Randomization of subjects to HeartLogic Alerts ON and HeartLogic Alerts OFF 
 Required Blood Draw: 

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o NT-proBNP per investigative site procedures. Other BNP values are not permitted in the study. 
 Required Programming at Baseline visit: 
o HeartLogic Alert Threshold must be programmed to 16 (nominal setting).  After the baseline 
visit the nominal setting may be changed with  appropriate documentation, in the RAVE 
database, with the rationale for changing this value. 
 Phase II HeartLogic ON group  
o All other therapies/device settings are at the discretion of the clinician. 
 Required attempt to calibrate the posture sensor 
 
The following information must be entered into the electronic database: 
 Patient demographics and medical history 
 Physical Exam 
 Heart failure assessment 
 NYHA Classification  
 Posture sensor calibration (Section 9.7)  
 HeartLogic Alert Threshold activated 
 HeartLogic Index Programming 
 NT-proBNP  
 Blood chemistry and EKG as a part of standard of care medical evaluation (optional) 
 Kansas City Cardiomyopathy Questionnaire (KCCQ) 
 EQ-5D-5L 
 Weight, Blood Pressure and Heart Rate 
 Oxygen saturation (optional) 
 Changes to heart failure and cardiovascular related medications and treatments 
 Applicable adverse event/device deficiency reporting (Section 18) 
 
For subjects randomized to HeartLogic Alerts ON: 
At the end of the visit, the clinician, and if needed with assistance from Boston Scientific, will ensure that the 
HeartLogic feature is activated and that the HeartLogic Alert Threshold is programmed to 16 (nominal setting). 
The alerts will be turned on by Boston Scientific and that data will begin to transmit through the patient bedside 
communicator once you have completed the CRF for the baseline visit.  If you have questions, please contact 
your Boston Scientific representative.  This ensures that if the alert threshold is met or exceeded, an alert will be 
sent to the clinician and to the AMC.  Following a HeartLogic Alert, physicians may adjust the threshold, but 
the change must be documented in the RAVE database.  Refer to the HeartLogic Technical guide for 
information on how adjusting the alert threshold affects the sensitivity and specificity.    
 
For subjects randomized to HeartLogic Alerts OFF: 
At the end of the visit, the clinician, and if needed with assistance from Boston Scientific, will ensure that 
HeartLogic Alerts are OFF and that Heart Failure Sensor Data Collection have not been disabled (i.e., still in 
nominal setting).      

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9.3.3 Scheduled Follow-up Visits 
Details in this section apply to all subjects in Phases I and II.    
9.3.3.1 Annual Phone Calls (6, 18, 30, 42 months,…) 
Starting at 6 months after the baseline visit, the clinician must call the subject to assess changes in medications 
and to collect adverse event information.  The visit windows are listed below.   
 
Table 9-2: Annual Phone Call Schedule 
Visit 
Visit Window 
6 month 
180 ± 30 days from baseline 
18 month 
545 ± 30 days from baseline 
30 month 
910 ± 30 days from baseline 
42 month 
1275 ± 30 days from baseline 
54 month 
1640 ± 30 days from baseline 
66 month 
2005 ± 30 days from baseline 
78 month 
2370 ± 30 days from baseline 
 
The annual phone calls will continue until the completion of the study phase.  Completion of Phase I will occur 
after the final Phase I subject has completed their 12 month visit, or upon recommendation from the Steering 
Committee. Completion of Phase II will occur after the necessary number of primary endpoint events has been 
accrued. 
 
Since the previous visit, the clinician will call the subjects to determine if there are any reportable adverse 
events (Section 18) and failure treatments (Section 9.4.1).   
 
The following information must be entered into the electronic database: 
 Heart failure assessment 
 HeartLogic Index Programming (if changed from nominal setting of 16) 
 NT-proBNP (optional) 
 Blood chemistry and EKG as a part of standard of care medical evaluation (optional) 
 Changes to heart failure and cardiovascular related medications and treatments 
 Applicable adverse event/device deficiency reporting (Section 18) 
9.3.3.2 Annual In-Clinic Visits (12, 24, 36, 48 months, …) 
Starting at 12 months after the baseline visit, the subjects must  be seen in-clinic annually. The visit windows 
are listed below. 
 
Table 9-3: Annual In-Clinic Visit Schedule 
Visit 
Visit Window 
12 month 
365 ± 30 days from baseline 
24 month 
730 ± 30 days from baseline 

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36 month 
1095 ± 30 days from baseline 
48 month 
1825 ± 30 days from baseline 
60 month 
2190 ± 30 days from baseline 
72 month 
2555 ± 30 days from baseline 
 
 
The following actions must be taken at the annual in-clinic visit for all subjects: 
 Required Blood Draw: 
o NT-proBNP per investigative site procedures. Other BNP values are not permitted in the study. 
 Required attempt to calibrate the posture sensor. 
 
The following information must be entered into the electronic database: 
 Physical Exam 
 Heart failure assessment 
 NYHA Classification  
 Posture sensor calibration (Section 9.7)  
 HeartLogic Alert Threshold activated 
 HeartLogic Index Programming (if changed from nominal setting of 16) 
 NT-proBNP  
 Blood chemistry and EKG as a part of standard of care medical evaluation (optional) 
 Kansas City Cardiomyopathy Questionnaire (KCCQ) 
 EQ-5D-5L 
 Weight, Blood Pressure and Heart Rate 
 Oxygen saturation (optional) 
 Changes to heart failure and cardiovascular related medications and treatments 
 Applicable adverse event/device deficiency reporting (Section 18) 
 Device data (disk download) Required per Boston Scientific request, if LATITUDE data are unavailable 
(Section 9.5)   
9.3.4 Additional Follow-up Visits 
9.3.4.1 HeartLogic Alert Action Visit 
Details apply to subjects in Phases I and II with HeartLogic Alerts ON.  The follow-ups that must be 
documented in response to a HeartLogic alert or re-alert are described in Section 9.4. 
 
The following information must be entered into the electronic database: 
 Physical Exam (required for in-office only) 
 Heart failure assessment 
 NYHA Classification (in-clinic only) 
 HeartLogic Index Programming (if changed from nominal setting of 16) 
 HeartLogic alert assessment 
 NT-proBNP (optional) 
 Blood chemistry and EKG as a part of standard of care medical evaluation (optional) 

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 Kansas City Cardiomyopathy Questionnaire (KCCQ) (optional) 
 EQ-5D-5L (optional) 
 Weight, Blood Pressure and Heart Rate (optional) 
 Oxygen saturation (optional) 
 Changes to heart failure and cardiovascular related medications and treatments 
 Applicable adverse event/device deficiency reporting (Section 18) 
 Device data (disk download) Required per Boston Scientific request, if LATITUDE data are unavailable 
(Section 9.5) 
 Qualified treatment upon alert   
 
9.3.4.2 Additional Subject Interactions (i.e., Not in Response to HeartLogic Alerts) 
Details apply to all subjects in Phases I and II. Research personnel must document an additional subject 
interaction if a subject is contacted by phone or has an in-clinic visit (other than a protocol-mandated follow-up 
or follow-up response to HeartLogic Alert) and there is a change in medications, device programming, device 
deficiencies or any reportable adverse event information, including heart failure related events. Blood chemistry 
analysis and EKG are optional data items which can be reported as a part of the standard of care visit.     
 
If settings for HeartLogic Alert Threshold are changed complete HeartLogic Programming CRF (for subjects 
with HeartLogic Alerts ON) 
 
The following information must be entered into the electronic database: 
 Heart failure assessment (optional) 
 NYHA Classification (optional) 
 HeartLogic Index Programming (if changed from nominal setting of 16) 
 NT-proBNP (optional) 
 Blood chemistry and EKG as a part of standard of care medical evaluation (optional) 
 Changes to heart failure and cardiovascular related medications and treatments 
 Applicable adverse event/device deficiency reporting (Section 18) 
 Device data (disk download) Required per Boston Scientific request, if LATITUDE data are unavailable 
(Section 9.5) 
 
9.3.5 End of Study 
Details apply to all subjects in Phases I and II.   
 
End of study for a subject occurs when the subject dies, withdraws, completes study/phase participation or is 
withdrawn by the investigator.  The clinician must document reason for study exit and date of study exit. 
HeartLogic Alerts may be configured at the discretion of the clinician at the end of the study.   
9.4 
HeartLogic Alert Action Visit 
Details in this section apply to subjects in Phases I and II with HeartLogic Alerts ON.   

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The LATITUDE communicator will collect and compute HeartLogic data as part of the daily alert checks.  
Patients should be in daily contact with the LATITUDE communicator to maximize access to HeartLogic data.  
Extended absence from the communicator (e.g., > 7 days) is discouraged. 
 
 
Figure 9-2 details the response to all HeartLogic Alerts (new and re-alerts), and applies to patients in Phase I 
and Phase II with HeartLogic Alerts ON. Clinicians must treat all patients with alerts unless there is a patient 
safety concern associated with treatment. Sites may be provided additional guidance regarding treatment in 
response to HeartLogic alert, based on recommendations from the Steering Committee (see Section 9.4.2 for 
details regarding the HeartLogic Alert Management Guide). A HeartLogic alert is not itself an adverse event, 
however it is the responsibility of the investigator to assess the patient and report adverse events to BSC as 
described in section 18.   
 
 
When a patient is in alert, the clinician will receive a notification in LATITUDE, and may also opt to receive a 
text messages and/or email.  If patient is in contact with the LATITUDE communicator and the patient is in 
alert, the site will be notified of the alert via LATITUDE.   
 
For each HeartLogic alert (initial alert or re-alert) the process below must be followed (see figure 9.2). Within 3 
calendar days from the alert being transmitted from the communicator to LATITUDE, the clinician should 
review the Heart Failure Management Report in the LATITUDE system and the patient’s medical treatments. If 
a qualified treatment was initiated within the 7 days prior to the HeartLogic alert transmission or the HeartLogic 
Index has decreased below the recovery threshold, the site may opt to not contact the patient for evaluation of 
the alert.  Otherwise, the center  must attempt to contact the patient (by phone or via in-clinic visit) for 
evaluation no later than 3 calendar days from alert transmission date.  When the patient is contacted, the patient 
must be assessed using the HeartLogic Alert CRF.  The clinician should then initiate a qualified treatment 
(section 9.4.1) for the patient and document the change. If no treatment is initiated as a result of a phone 
contact, then the center must attempt to schedule the patient for a clinic visit for further evaluation within 6 days 
from the date of alert transmission. At the clinic evaluation, a qualified treatment should be initiated and 
documented (section 9.4.1).  If no treatment is initiated the rationale must be documented in the CRF.  
 
If settings for HeartLogic Alert Threshold are changed complete HeartLogic Programming CRF (for subjects 
with HeartLogic Alerts ON) 
 

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Figure 9-2:  HeartLogic Alert Management Process 
 
Attempt to contact patient 
within 3 calendar days of 
alert transmission
Document
Alert transmission 
via e-mail, SMS or 
LATITUDE
Qualified treatment in the last 7 
calendar days since alert 
transmission?
HeartLogic 
Alert 
Review Heart Failure 
Management Report and patient 
medical treatment
Qualified treatment 
started?
No
Yes
Attempt to schedule clinic 
visit within 6 calendar 
days of alert transmission 
No
Yes
  
 

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The following table outlines the actions and data collection associated with a HeartLogic Alert Action Visit. 
 
Table 9-4: Data Collection at HeartLogic Alert Action Visit 
 
Phone call with no treatment,  
then in-clinic visit 
Phone call with treatment 
Alert Date 
X 
 
X 
 
Heart Logic alert assessment 
X 
 
X 
 
Phone call documented 
X 
 
X 
 
Action taken documented 
X 
 
X 
 
Heart Failure Assessment 
X 
 
X 
 
Adverse Event Assessment 
X 
 
X 
 
NYHA Assessment 
X 
 
X 
 
NT-ProBNP 
X 
(Optional) 
- 
 
Blood lab values chemistry and 
EKG as a part of standard of care 
medical evaluation 
X 
(Optional) 
- 
 
Weight/Blood Pressure/Heart rate 
X 
(Optional) 
X 
(Optional) 
Oxygen Saturation 
 
 
 
 
KCCQ and EQ-5D-5L 
X 
(Optional) 
- 
 
Data disk if latitude not available 
X 
(Optional) 
- 
 
HF medications/cardiac meds 
changes 
X 
 
X 
 
HeartLogic Programming (if 
changed from nominal setting of 
16) 
X 
 
X 
 
 
All alerts will follow the process shown in Figure 9-2, including re-alerts. The process is designed to facilitate 
remote management of the patient, and to encourage a treatment response when there is an active HeartLogic 
Alert.   
 
HeartLogic has been validated as a diagnostic tool to detect gradual worsening of heart failure over days or 
weeks using multiple physiologic measurements.  It is possible for an alert to resolve without a commensurate 
improvement in patient condition. HeartLogic alert resolution should not be used as an indicator of patient 
health status.  Therefore, patients should continue to be evaluated and treated with standard of care after alert 
resolution per clinician discretion.  
9.4.1 Qualified Treatments  
Details in this section apply to all subjects in Phases I and II.   
 
Qualified treatments in response to a HeartLogic Alert or in response to worsening of heart failure are: 
 If patient is not adhering to medications; enforce adherence.   
 Change in current medications related to worsening symptoms of heart failure: 
o Increase dose of at least one currently prescribed medication (e.g. doubling of diuretic dose; may 
be temporary) 
o Addition of a new class of medication (e.g. adding an MRA when none was being taken) 
o Adding an additional medication of the same class  
o Change of medication within the same class (e.g. switching ẞ-blockers) 

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 Other treatments for conditions believed to have triggered a HeartLogic alert, with appropriate rationale 
and documentation.  
 
Note:  while reminders of diet, hydration and exercise are encouraged as a part of chronic heart failure care, 
when taken alone, do not qualify as a treatment response to a HeartLogic Alert or worsening heart failure.  
9.4.2 Heart Logic Alert Management Guide 
The HeartLogic Alert Management Guide is a separate document that will be generated  for the sharing of best 
practices identified by the Steering Committee and informed by the study investigators. This document may 
provide referrals to heart failure management guidelines, frequently asked questions, rates of adverse events 
associated with HeartLogic false positives and logistical solutions to common implementation problems. The 
document will not prescribe specific treatments and will not be informed by the Phase II results. 
 
9.5 
Device Interrogation 
Details apply to all subjects in Phases I and II.   
 
There are no required routine device interrogations for this study because data will be available through home 
communicator uploads to LATITUDE.  However, if device interrogation using a home communicator is not 
possible (e.g during extended hospitalization) , sites will be notified when the data must be manually obtained 
through one of two methods of device interrogation: using a Consult or using a programmer. If a programmer 
interrogation is used, the “device data dump” (not “save all to disk”) option should be chosen. If data are stored 
on a disc or flash drive, the disc or flash drive should be kept in the subject’s MANAGE-HF study binder at the 
investigative site, and copy should be mailed to the sponsor.   
9.6 
Alert Monitoring Center  
Details apply to all subjects in Phases I and II.  
 
The AMC is operated by Boston Scientific staff that is trained to provide technical support of all commercial 
pacemaker and defibrillator devices.  They also provide support for the LATITUDE patient management 
system.  The AMC does not provide any site monitoring; site monitoring is detailed in Section 16. 
 
During Phases I and II of the MANAGE-HF study, the AMC will provide support to clinical sites. 
The AMC will not practice medicine or provide any independent medical recommendations for patients.  While 
the AMC will be blinded to study endpoint data, they will have access to metrics related to integration of 
HeartLogic into the clinic, and may provide advice in the form of best practices.   
 
Study investigators will also be provided with a HeartLogic Alert Management guide (Section 9.4.2).   
9.7 
Posture Sensor Calibration 
Details apply to all subjects in Phases I and II.   
 

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Posture sensor calibrations are attempted by the clinician and patient using the programmer application at 
baseline and again at every annual follow-up visit.  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.  Once the patient is in position, the clinician will run the software 
on the programmer for the data collection.  It takes approximately 10 seconds of data collection for each 
position.  The entire procedure should take about 1-2 minutes.   
 
There may be instances where the posture sensor is unable to be calibrated. This occurs because the sensor is 
still initializing, or collecting data, and has not yet reached a state in which it can be calibrated. If the calibration 
is attempted and unsuccessful, the participant does not need to be brought back for an additional visit with the 
only purpose of attempting the calibration again. However, the calibration may be attempted at the next 
scheduled visit. 
 
Important:  The device will NOT collect any Sleep Incline data until a body calibration has been 
performed.  Thus, an attempt to calibrate the posture sensor is a required step at the baseline and every annual 
in-clinic follow-up visit. If the calibration is unsuccessful, the attempt and reason for lack of success should be 
documented.    
9.8 
Randomization Crossovers (Phase II only) 
In Phase II, crossing over from one randomized group to the other group (from HeartLogic Alerts OFF to ON or 
vice versa) is not allowed.  
9.9 
Study Completion 
Phase I will be complete after the final Phase I subject has been followed for 12 months, or upon 
recommendation from the Steering Committee.  Phase II will be complete after the required number of primary 
endpoint events has been accrued, or until a futility point has been reached. The study will be complete after 
Phase II has concluded.  
 
Upon completion of each phase, sites will be notified that the phase has ended and instructed to exit subjects  
from actively followed in the applicable phase.  No additional follow-up visits will occur in the phase, and no 
additional adverse event reporting will occur once the phase has finished.  Subjects will continue to be followed 
as determined by their health care professional, but not as a part of the clinical trial.   
 
If the study fails to meet the pre-specified primary endpoint, HeartLogic may be turned off if there are patient 
safety concerns.  Importantly, turning off HeartLogic does not affect any other performance aspect of the 
device.   
9.10 Source Documents 
Details apply to both phases (Phases I and II) of the MANAGE-HF study.   
 
Source documents are “printed, optical or electronic document containing source data”, the source data being 
“all information in original records… necessary for the reconstruction and evaluation of the clinical 
investigation”. 

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Source documentation is required during this study. The participating investigator must maintain original source 
documents that are accurate, complete, and current related to the subject’s participation in this study. Source 
documentation must include but is not limited to:  
 
 Medical record verification that subject meets Inclusion and Exclusion Criteria 
 Completed patient informed consent  
 Patient medical file with all required study data elements 
 Prescribed cardiovascular and heart failure medications  
 Documentation of adverse events, including hospitalizations 
 Printed copies of HeartLogic sensors/alerts and LATITUDE data 
 
Table 9-5: Source Documentation Requirements 
Requirement 
Disposition 
Screening form 
Retain at center 
Informed consent form 
Retain at center 
Demographic data 
Retain at center 
HeartLogic Sensors and Alert 
Programming 
Retain at center 
Medications 
Retain at center 
Heart failure assessment 
Retain at center 
NT-proBNP 
Retain at center 
NYHA classification 
Retain at center 
KCCQ and EQ-5D-5L 
Retain at center 
Treatment documentation 
Retain at center 
Device data assessment 
Retain at center 
Adverse events 
Retain at center 
Weight and blood pressure 
Retain at center 
Protocol deviations 
Retain at center 
Hospitalizaion 
Retain at center and send a copy to BSC 
Death Information 
Retain at center and send a copy to BSC 
Subject Randomization 
Electronic Data Capture system 
Abbreviations: NYHA: New York Heart Association; KCCQ: Kansas 
City Cardiomyopathy Questionnaire; AMC:  Alert monitoring center 
 
10 Study Endpoints and Statistical Considerations 
All analyses described in this section apply to subjects randomized in Phase II.  No data from subjects enrolled 
in Phase I will contribute data to any endpoint analyses. 

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10.1 Primary Endpoint 
The primary endpoint of the MANAGE-HF trial will assess the freedom from all-cause mortality and heart 
failure hospitalizations, as adjudicated the Clinical Events Committee (CEC, described in Section 20.3).  The 
primary endpoint will compare randomized HeartLogic and Control groups and be assessed using data collected 
following randomization in Phase II of MANAGE-HF. 
10.1.1 Hypothesis for Primary Endpoint 
The following set of hypotheses will be evaluated for the primary endpoint: 
H0:  The risk of mortality and heart failure hospitalization for the HeartLogic group will be greater than 
or equal to the risk for the control group 
HA:  The risk of mortality and heart failure hospitalization for the HeartLogic group will be less than the 
risk for the control group  
10.1.2 Sample Size for Primary Endpoint 
The sample size required for Phase II of MANAGE-HF is event-driven.  Between 1500 and 2500 subjects will 
be enrolled in the trial to accrue the necessary number of endpoint events to sufficiently power the primary 
endpoint.  Final sample size will be determined during the study using a sample size re-estimation interim 
analysis.  The assumptions used to calculate the sample size are described in a separate MANAGE-HF 
Statistical Analysis Plan.  
10.1.3 Statistical Methods for Primary Endpoint 
The methods used to evaluate the Primary Endpoint are described in a separate MANAGE-HF Statistical 
Analysis Plan.  
10.2 Secondary Endpoints 
Descriptions of the Secondary Endpoints and associated data evaluated are described in the following sections.  
The statistical methods used to evaluate the Secondary Endpoints are described in a separate MANAGE-HF 
Statistical Analysis Plan.  
10.2.1 Secondary Endpoint 1: Freedom from all-cause mortality 
Survival (freedom from all-cause mortality) between the randomized groups will be assessed, including all 
deaths occurring during Phase II of the trial. 
10.2.2 Secondary Endpoint 2: Freedom from heart failure hospitalizations (time-to-first event) 
Freedom from a heart failure hospitalization will be evaluated and compared between the randomized groups.  
Each subject’s first heart failure hospitalization will contribute to the endpoint.  Data observed during Phase II 
of the trial will be included in the analysis. 

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10.2.3 Secondary Endpoint 3: Risk of multiple heart failure hospitalizations 
Multiple heart failure hospitalizations will be evaluated and compared between the randomized groups.  All 
heart failure hospitalizations for each subject will contribute to the endpoint.  Data observed during Phase II of 
the trial will be included in the analysis. 
10.2.4 Secondary Endpoint 4: Change in NYHA Classification 
Change in NYHA from baseline through 12 months will be evaluated and compared between the randomized 
groups.  Data observed during Phase II of the trial will be included in the analysis. 
10.2.5 Secondary Endpoint 5: Change in Quality of Life 
Change in Quality of Life from baseline through 12 months will be evaluated and compared between the 
randomized groups.  Data observed during Phase II of the trial will be included in the analysis. 
10.2.6 Secondary Endpoint 6: Change in NT-proBNP 
Change in NT-proBNP from baseline through 12 months will be evaluated and compared between the 
randomized groups.  Data observed during Phase II of the trial will be included in the analysis. 
10.2.7 Secondary Endpoint 7: Change in Medication Status 
Change in medication status from baseline through 12 months will be evaluated and compared between the 
randomized groups.  Data observed during Phase II of the trial will be included in the analysis. 
 
10.3 General Statistical Methods 
All sample size calculations were performed and all statistical analyses will be done with SAS version 9.3 or 
higher. 
10.3.1 Study Success Criteria 
The study will be considered successful if the null hypothesis for the primary endpoint is rejected. 
10.3.2 Analysis Sets 
All primary and secondary endpoint analyses will be performed following intention-to-treat (ITT) methodology, 
in which each subject is analyzed per their intended (i.e., randomized) treatment assignment.  An as-treated 
analysis will be performed as well, in which subjects would be analyzed per the treatment received and may be 
time-varying to accommodate cross-overs.  A per-protocol analysis will also be performed.   

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10.3.3 Control of Systematic Error Bias 
Selection of subjects for enrollment in both phases will be made from the Investigator’s usual subject load. All 
subjects meeting the eligibility criteria and having signed the ICF will be eligible for enrollment in the study. 
 
To reduce the possible introduction of selection bias, subjects in Phase II will be randomized to their treatment 
assignment.  To reduce the possible introduction of observer bias, deaths and heart failure hospitalizations will 
be adjudicated by an independent Clinical Events Committee (CEC).  
10.3.4 Control of Type-I Error 
Overall Type I error for the primary endpoint will not exceed one-sided 2.5%.  Type I error will be split and 
managed for the interim superiority analyses by employing an O’Brien-Fleming-type error spending function.   
Secondary endpoints and other sensitivity analyses will be performed at the nominal one-sided 2.5% and will 
not be adjusted for the interim primary endpoint analyses.   
10.3.5 Number of Subjects per Investigative Site 
To avoid any center effect and bias, one center will not be authorized to enroll more than 20 subjects in Phase I 
and 100 subjects in Phase II for this study, without approval from Boston Scientific. 
10.3.6 Interim Analyses  
Analyses of adverse events and device deficiencies will occur at frequent intervals during the course of the 
study.  Results of these analyses will be reviewed by an independent Data Monitoring Committee (DMC) and 
the Boston Scientific Medical Safety Group to evaluate the safety of the subjects under study.  Information 
about the group sequential stopping rules and interim sample size re-estimation are found in the following 
sections. 
10.3.6.1 Sequential Stopping Rules 
Interim analyses will be performed during Phase II to assess the superiority of HeartLogic.  Five analyses (four 
interim analyses and one final) are planned.  Futility analyses will also be performed at each interim analysis. 
The Type I error/alpha spending will be managed using an O’Brien-Fleming-type error spending function.  The 
alpha will maintained at an overall one-sided level of 2.5%.   
10.3.6.2 Sample Size Re-estimation 
At the start of Phase II, a sample size range of 1500 to 2500 patients will be considered.  The final sample size 
will be determined through use of interim sample size re-estimation analyses.  The sample size re-estimation 
analyses will evaluate two items: (1) the primary endpoint event rate in the control group only, and (2) the 
enrollment rate in the trial.  Based on the results of these analyses, a final sample size will be determined that 
will allow for sufficient primary endpoint powering while minimizing trial burden.    
The analysis will be performed in a blinded fashion; neither the primary endpoint event rate in the HeartLogic 
group nor the hazard ratio comparing groups will be calculated. Due to the blinded nature of the analysis, no 

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inflation of type I error is introduced.  Therefore, the sample size re-estimation can be performed without 
adjustment to the type I error for the primary endpoint.  The analysis will be performed prior to the first 
sequential interim analysis, as specified in Section 10.3.6.1.   
10.3.7 Subgroup Analyses 
Analyses will be performed to assess whether significant interactions exist between randomization group and 
various baseline characteristics.  The specific baseline characteristics and their corresponding subgroups that 
will be analyzed are described in a separate Statistical Analysis Plan. 
Regardless of the results of the interaction test for each characteristic, analyses of each subgroup will be 
performed.  Analyses will be conducted for the primary endpoint and all secondary endpoints. 
10.3.8 Multivariate analyses  
The purpose of the multivariate analyses is to determine covariates associated with the primary and secondary 
endpoints.  Covariates considered for inclusion in the final multivariate models include, but are not limited to, 
the characteristics studied as part of the subgroup analyses.  Details can be found in a separate Statistical 
Analysis Plan. 
10.3.9  Justification of Pooling 
Pooling of devices, geographies and sexes for the Primary Endpoint will be evaluated.  Details of the pooling 
analyses are described in a separate MANAGE-HF Statistical Analysis Plan. 
10.3.10Health Economic Analyses  
Analyses used to understand the health economics associated with HeartLogic usage may be performed during 
either phase of the study. 
10.3.11 Changes to Planned Analyses 
Any changes to the planned statistical analyses made prior to conducting endpoint analyses will be documented 
in an amended Statistical Analysis Plan approved prior to conducting endpoint analyses. Changes from the 
planned statistical methods after conducting the analyses will be documented in the clinical study report along 
with a reason for the modification. 
11 Data Management 
Details in this section apply to both phases (Phases I and II) of the MANAGE-HF study.   
11.1 Data Collection, Processing, and Review 
Subject data will be recorded in a limited access secure electronic data capture (EDC) system.  
 

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The clinical database will reside on a production server hosted by EDC System. All changes made to the 
clinical data will be captured in an electronic audit trail and available for review by the sponsor or its 
representative. The associated RAVE software and database have been designed to meet regulatory compliance 
for deployment as part of a validated system compliant with laws and regulations applicable to the conduct of 
clinical studies pertaining to the use of electronic records and signatures. Database backups are performed 
regularly. 
 
The Investigator provides his/her electronic signature on the appropriate electronic case report forms (eCRFs) in 
compliance with local regulations. A written signature on printouts of the eCRFs must also be provided if 
required by local regulation. Changes to data previously submitted to the sponsor require a new electronic 
signature by the Investigator acknowledging and approving the changes. 
 
Visual and/or electronic data review will be performed to identify possible data discrepancies. Manual and/or 
automatic queries will be created in the EDC system and will be issued to the site for appropriate response. Site 
staff will be responsible for resolving all queries in the database. 
11.2 Data Retention 
The Investigator or his/her designee or Investigational site will maintain, at the investigative site, all essential 
study documents and source documentation that support the data collected on the study subjects in compliance 
with ICH/GCP guidelines.  Documents must be retained for at least 2 years after the last approval of a 
marketing application or until at least 2 years have elapsed since the formal discontinuation of the clinical 
investigation of the product. These documents will be retained for a longer period of time by agreement with 
BSC or in compliance with other country/regional/local regulations. 
 
The Investigator or his/her designee will take measures to ensure that these essential documents are not 
accidentally damaged or destroyed. If for any reason the 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.  
12 Amendments  
If a protocol revision is necessary, during Phases I or II, which affects the rights, safety or welfare of the subject 
or scientific integrity of the data, an amendment is required. Appropriate approvals (e.g., IRB/EC/FDA/CA) of 
the revised protocol must be obtained prior to implementation. 
13 Deviations 
Details in this section apply to both phases (Phases I and II) of the MANAGE-HF study.   
 
An Investigator must not make any changes or deviate from this protocol, except to protect the life and physical 
well-being of a subject in an emergency. An investigator shall notify the sponsor and the reviewing IRB/EC of 
any deviation from the investigational plan to protect the life or physical well-being of a subject in an 
emergency, and those deviations which affect the scientific integrity of the clinical investigation. Such notice 

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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 visit and the reason for the deviation, must be documented 
and reported to the sponsor using the electronic data base. Sites may also be required to report deviations to the 
IRB/EC, per local guidelines and government regulations.  
 
Deviations will be reviewed and evaluated on an ongoing basis and, as necessary, appropriate corrective and 
preventive actions including FDA notification, site re-training, or site discontinuation/termination) will be put 
into place by the sponsor. 
14 Device/Equipment Accountability 
Devices used in both phases (Phase I and II) of the MANAGE-HF study are commercially available.  
15 Compliance 
Details in this section apply to both phases (Phases I and II) of the MANAGE-HF study.   
15.1 Statement of Compliance 
This study will be conducted in accordance 21 CFR part 56 and part 50, ISO 14155, ethical principles that have 
their origins in the Declaration of Helsinki, and pertinent local laws and regulations. The study shall not begin 
until the required approval/favorable opinion from the IRB/EC and/or the regulatory authority has been 
obtained, if appropriate. Any additional requirements imposed by the IRB/EC or the regulatory authority shall 
be followed, if appropriate. 
15.2 Investigator Responsibilities 
The Principal Investigator of an investigational site is responsible for ensuring that the study is conducted in 
accordance with the Clinical Study Agreement, the clinical investigation plan/, ISO 14155, ethical principles 
that have their origins in the Declaration of Helsinki, any conditions of approval imposed by the reviewing 
IRB/EC, and prevailing local and/or country laws and/or regulations, whichever affords the greater protection to 
the subject. 
The Principal Investigator’s responsibilities include, but are not limited to, the following.  
 Prior to beginning the study, sign the Clinical Study Agreement and comply with the Investigator 
responsibilities as described in such Agreement.   
 Prior to beginning the study, sign the Investigator Brochure Signature Page (if applicable) and Protocol 
Signature page documenting his/her agreement to conduct the study in accordance with the protocol. 
 Provide his/her qualifications and experience to assume responsibility for the proper conduct of the 
study and that of key members of the site team through up-to-date curriculum vitae or other relevant 
documentation and disclose potential conflicts of interest, including financial, that may interfere with the 
conduct of the clinical study or interpretation of results. 

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 Make no changes in or deviate from this protocol, except to protect the life and physical well-being of a 
subject in an emergency; document and explain any deviation from the approved protocol that occurred 
during the course of the clinical investigation. 
 Create and maintain source documents throughout the clinical study and ensure their availability with 
direct access during monitoring visits or audits; ensure that all clinical-investigation-related records are 
retained per requirements. 
 Ensure the accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the 
CRFs and in all required reports. 
 Record, report, and assess (seriousness and relationship to the device/procedure) every adverse event as 
applicable per the protocol and observed device deficiency. 
 Report to sponsor, per the protocol requirements, all SAEs and device deficiencies that could have led to 
a SADE and potential/USADE or UADE. 
 Report to the IRB/EC and regulatory authorities any SAEs and device deficiencies that could have led to 
a SADE and potential/USADE or UADE, if required by the national regulations or this protocol or by 
the IRB/EC, and supply BSC with any additional requested information related to the safety reporting of 
a particular event. 
 Maintain the device accountability records and control of the device, ensuring that the investigational 
device is used only by authorized/designated users and in accordance with this protocol and 
instructions/directions for use. 
 Allow the sponsor to perform monitoring and auditing activities, and be accessible to the clinical 
research monitor or auditor and respond to questions during monitoring visits or audit(s). 
 Allow and support regulatory authorities and the IRB/EC when performing auditing activities. 
 Ensure that informed consent is obtained in accordance with applicable laws, this protocol and local 
IRB/EC requirements. 
 Provide adequate medical care to a subject during and after a subject’s participation in a clinical study in 
the case of adverse events, as described in the Informed Consent Form (ICF). 
 Inform the subject of the nature and possible cause of any adverse events experienced. 
 As applicable, provide the subject with necessary instructions on proper use, handling, storage, and 
return of the investigational device when it is used/operated by the subject. 
 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 
clinician about the subject’s participation in the clinical investigation. 
 Make all reasonable efforts to ascertain the reason(s) for a subject’s premature withdrawal from clinical 
investigation while fully respecting the subject’s rights. 

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 Ensure that an adequate investigation site team and facilities exist and are maintained and documented 
during the clinical investigation. 
 Ensure that maintenance and calibration of the equipment relevant for the assessment of the clinical 
investigation is appropriately performed and documented, where applicable. 
15.2.1 Delegation of Responsibility 
When specific tasks are delegated by an investigator, including but not limited to conducting the informed 
consent process, the Principal Investigator is responsible for providing appropriate training and adequate 
supervision of those to whom tasks are delegated. The investigator is accountable for regulatory violations 
resulting from failure to adequately supervise the conduct of the clinical study.  
15.3 Institutional Review Board/ Ethics Committee 
Prior to gaining Approval-to-Enroll status, the investigational site will provide to the sponsor documentation 
verifying that their IRB/EC is registered or that registration has been submitted to the appropriate agency, as 
applicable according to national/regulatory requirements.   
 
A copy of the written IRB/EC and/or competent authority approval of the protocol (or permission to conduct the 
study) and Informed Consent Form, must be received by the sponsor before recruitment of subjects into the 
study and shipment of investigational product/equipment. Prior approval must also be obtained for other 
materials related to subject recruitment or which will be provided to the subject. 
 
Annual IRB/EC approval and renewals will be obtained throughout the duration of the study as required by 
local/country or IRB/EC requirements. Copies of the Investigator’s reports and the IRB/EC continuance of 
approval must be provided to the sponsor.  
15.4 Sponsor Responsibilities 
All information and data sent to BSC concerning subjects or their participation in this study will be considered 
confidential by BSC. Only authorized BSC personnel or a BSC representative including, but not limited to 
Contract Research Organization (CRO) will have access to these confidential records. Authorized regulatory 
personnel have the right to inspect and copy all records pertinent to this study. Study data collected during this 
study may be used by BSC for the purposes of this study, publication, and to support future research and/or 
other business purposes. All data used in the analysis and reporting of this study will be without identifiable 
reference to specific subject name. 
 
Boston Scientific will keep subjects’ identifiable health information confidential in accordance with all 
applicable laws and regulations.  Boston Scientific may use subjects’ health information to conduct this 
research, as well as for additional purposes, such as overseeing and improving the performance of its device, 
new medical research and proposals for developing new medical products or procedures, and other business 
purposes. Information received during the study will not be used to market to subjects; subject names will not 
be placed on any mailing lists or sold to anyone for marketing purposes.  

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15.4.1 Role of Boston Scientific Representatives 
Boston Scientific personnel can provide technical support to the investigator and other health care personnel 
(collectively called clinicians) as needed during implant, testing required by the protocol, and follow-ups. 
Support may include clinician training, addressing clinician questions, or providing clarifications to clinicians 
concerning the operation of BSC equipment/devices (including programmers, analyzers, and other support 
equipment). 
 
At the request of the investigator and while under investigator supervision, BSC personnel may operate 
equipment during implant or follow-up, assist with the conduct of testing specified in the protocol, and interact 
with the subject to accomplish requested activities.  
 
Typical tasks may include the following: 
 Interrogating the device or programming device parameters to investigator-requested settings as well as 
operating investigational equipment 
 Performing lead diagnostic testing using a Pacing System Analyzer or programmer to obtain pacing and 
sensing thresholds and impedance measurements 
 Clarifying device behavior, operation or diagnostic output as requested by the investigator or other 
health care personnel 
 Assisting with the collection of study data from Pacing System Analyzers, programmers, and other 
equipment 
 Print out programming reports directly from the clinician programmer and provide original to clinical 
site as source documentation 
 Provide technical expertise/support to subjects during office visits and/or during teleconference 
calls/electronic communications with the principal investigator or their delegated site staff and the 
subject.  
 
In addition, BSC personnel may perform certain activities to ensure study quality. These activities may include 
the following: 
 Observing testing or medical procedures to provide information relevant to protocol compliance 
 Reviewing collected data and study documentation for completeness and accuracy 
 
Boston Scientific personnel will not do the following:  
 Practice medicine 
 Provide medical diagnosis or treatment to subjects 
 Discuss a subject’s condition or treatment with a subject without the approval and presence of the 
investigator 
 Independently collect critical study data (defined as primary or secondary endpoint data) 
 Enter data in electronic data capture systems or on paper case report forms 
 
15.5 Insurance  
Where required by local/country regulation, proof and type of insurance coverage for subjects in the study will 
be obtained by BSC. 

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16 Monitoring 
Details in this section apply to both phases (Phases I and II) of the MANAGE-HF study.   
 
Monitoring will be performed by Boston Scientific or its designees during the study, on site or remotely, 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. 
 
Monitoring described in this section is different from the responsibilities of the AMC, described in 9.6. 
17 Potential Risks and Benefits 
Details in this section apply to both phases (Phases I and II) of the MANAGE-HF study.   
17.1 Anticipated Adverse Events  
The following anticipated adverse events (AE) have been identified for this study: 
 Anticipated adverse events with this study are expected to be side effects from the changes in patient 
care as a result of HeartLogic Alerts.  These adverse events would include an increase in side effects as a 
result of changes to medications, addition of new medications, or other treatments added to avoid further 
worsening of heart failure.   
17.2 Anticipated Adverse Device Effects  
There are no anticipated Adverse Device Effects beyond those that would be expected from a commercially 
approved device.  Please refer to the Resonate family of CRT-D and ICD Physician’s Technical Manuals for 
potential adverse events.  The HeartLogic Index and Alert do not provide therapy, and do not interfere with the 
normal function of the CRT-D or ICD.   
17.3 Risks Associated with the Study Device(s)  
There are no risks associated with the study devices beyond those that would be expected from commercially 
approved devices.  The HeartLogic Index and Alert are not calculated within the device.  Calculations are 
performed in the patient communicator and transmitted to LATITUDE.   Therefore, there are no anticipated 

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Adverse Device Effects with the implanted CRT-D or ICD.  The approved labelling for the devices does not list 
any specific risks associated with the use of HeartLogic.   
17.4 Risks associated with Participation in the Clinical Study 
The risk of participating in this study is not significantly different from routine clinical care of a subject that is 
implanted with a BSC commercially approved and market available CRT-D and/or ICD device with the 
HeartLogic feature.  Identifiable risks for subjects enroll in the trial include:  
 Bruising or bleeding blood draw 
 HeartLogic alerts that result in changes to medications or treatments that lead to adverse events 
 Subject anxiety about worsening of their heart failure   
17.5 Possible Interactions with Concomitant Medical Treatments 
There are no anticipated interactions with concomitant medical treatments.   
17.6 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. 
17.7 Anticipated Benefits 
There may be no benefit to the subject.  However, the subject may benefit from more intensive heart failure 
management and follow up due to the clinical protocol schedule. Subjects may also be followed more carefully 
and their medical status, as well as their device and lead status, is checked by various study personnel and 
systems: investigators, data coordinators, monitors and automatic warning systems in the clinical study database 
set to monitor the data as it is submitted to Boston Scientific.   
In addition, the HeartLogic alert is intended to notify the health care professional when the subject is at an 
increased risk for a heart failure related adverse event. This may lead to earlier medical intervention and could 
result in avoiding a heart failure event.    
 
17.8 Risk to Benefit Rationale 
The CRT-D and ICD device systems and accessories the subjects received prior to enrollment in the study will 
be commercially available and are considered to be standard of care for subjects indicated for their respective 
therapy. The risks involved with subject participation in this study are essentially the same as those for subjects 
not participating in the study. This study is designed to demonstrate clinical integration of HeartLogic is safe, 
and to establish an appropriate treatment response when an alert is issued.  The benefit of reduced heart failure 
events outweighs any foreseen risks.   

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18 Safety Reporting 
Details in this section apply to both phases (Phases I and II) of the MANAGE-HF study.   
18.1 Reportable Events by Investigational site to Boston Scientific 
It is the responsibility of the investigator to assess and report to BSC the following adverse events: 
 
 All Serious Adverse Events 
 All cardiac related Adverse Events, including new onset of cardiac events, or worsening in severity or 
frequency of pre-existing cardiac condition(s) 
 All Device Deficiencies  
 Unanticipated Adverse Device Effects/Unanticipated Serious Adverse Device Effects  
 Protocol required procedures that result in an adverse event 
 Adverse Device Effects including Serious Adverse Device Effects 
  
HeartLogic Alerts are not considered  adverse events, but may indicate the presence of an adverse event.  If the 
criteria of a reportable adverse event have been fulfilled, an adverse event must be reported. 
 
When possible, the medical diagnosis should be reported as the Event Term instead of individual symptoms.  
Multiple symptoms related to a single medical diagnosis should be reported within one (1) adverse event (i.e. 
shortness of breath and edema are related to a diagnosis of ‘worsening heart failure’). 
 
If it is unclear whether or not an event fits one of the above categories, or if the event cannot be isolated from 
the device or procedure, it should be submitted as an adverse event and/or device deficiency. 
 
Any AE experienced by the study subject after informed consent (as defined in study subject classification 
section) must be recorded in the eCRF.  All AEs must be reported until the study phase is completed for each 
subject. 
 
Underlying diseases are not reported as AEs unless there is an increase in severity of frequency during the 
course of the investigation.  Death should not be recorded as an AE, but should only be reflected as an outcome 
of one (1) specific SAE (see Table 18-1 for AE definitions). 
 
Refer to Section 17.3 for the known risks associated with the study device(s). 
 
18.2 Definitions and Classification 
Adverse event definitions are provided in Table 18-1.  Events which are required to be reported are listed above.  
Administrative edits were made on the definition of serious adverse event from ISO 14155and MEDDEV 2.7/3 
for clarification purposes. 
 
Table 18-1: Safety Definitions 
Term 
Definition 

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Table 18-1: Safety Definitions 
Term 
Definition 
Adverse Event (AE) 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3  
 
 
Any untoward medical occurrence, unintended disease or injury, or any untoward clinical 
signs (including an abnormal laboratory finding) in subjects, users or other persons, whether 
or not related to the investigational medical device.  
Adverse Device Effect (ADE) 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3  
Adverse event related to the use of an investigational medical device 
NOTE 1: This includes any adverse event resulting from insufficiencies or inadequacies 
in the instructions for use, the deployment, the implantation, the installation, the 
operation, or any malfunction of the investigational medical device. 
NOTE 2: This definition includes any event resulting from use error or intentional 
abnormal use of the investigational medical device. 
Serious Adverse Event (SAE) 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3  
Note: This definition meets the reporting objectives and requirements of ISO 14155 and  
MEDDEV 2.7/3. 
Adverse event that: 
a) Led to death, 
b) Led to  serious deterioration in the health of the subject as defined by either: 
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body function, or 
3) in-patient hospitalization or prolongation of existing hospitalization, or 
4) medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function 
c) Led to fetal distress, fetal death, or a congenital abnormality or birth defect. 
NOTE 1: Planned hospitalization for a pre-existing condition, or a procedure required by 
the clinical investigational plan, without a serious deterioration in health, is not considered a 
serious adverse event.  
Serious Adverse Device Effect 
(SADE) 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3  
Adverse device effect that has resulted in any of the consequences characteristic of a serious 
adverse event. 
 
Unanticipated Adverse Device Effect 
(UADE) 
 
Ref: 21 CFR Part 812 
 
 
Any serious adverse effect on health or safety or any life-threatening problem or death 
caused by, or associated with, a device, if that effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence in the investigational plan or 
application (including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects.   
Unanticipated Serious Adverse Device 
Effect (USADE) 
 
Ref: ISO 14155 
 
Serious adverse device effect which by its nature, incidence, severity, or outcome has not 
been identified in the current version of the risk analysis report. 
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. 

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Table 18-1: Safety Definitions 
Term 
Definition 
Ref: MEDDEV 2.7/3  
 
 
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. 
 
 
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 
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. 

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Table 18-1: Safety Definitions 
Term 
Definition 
Pacemaker Lead Adaptor 
510(k) Submissions 
Type IV 
 Ref: FDA Guidance for the 
Submission of 
Research and Marketing 
Applications for Permanent 
Pacemaker Leads and for 
Pacemaker Lead Adaptor 
510(k) Submissions 
Related to a change in patient’s condition. 
Type V 
 Ref: FDA Guidance for the 
Submission of 
Research and Marketing 
Applications for Permanent 
Pacemaker Leads and for 
Pacemaker Lead Adaptor 
510(k) Submissions 
Comments Only.  On occasion, comments were inadvertently entered in the adverse event 
text field of the case report form (CRF). Comments identified by the CRF reviewer were 
assigned a Type V code and not included in this report. 
Abbreviations: EC=Ethics Committee; IRB=Institutional Review Board 
 
18.3 Relationship to Study Device(s) or Procedures 
The Investigator must assess the relationship of the AE to the study device or procedure. See criteria in Table 
18-2:  

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Table 18-2: Assessing Relationship of Study Device or Procedure to Adverse 
Event 
Classification 
Description 
Not Related 
Relationship to the device or procedures can be excluded when: 
- the event is not a known side effect of the product category the device belongs to or of similar 
devices and procedures; 
- the event has no temporal relationship with the use of the investigational device or the 
procedures; 
- the serious event does not follow a known response pattern to the medical device (if the 
response pattern is previously known) and is biologically implausible; 
- the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible – and reintroduction of its use (or increase of the 
level of activation/exposure), do not impact on the serious event; 
- the event involves a body-site or an organ not expected to be affected by the device or 
procedure; the serious event can be attributed to another cause (e.g. an underlying or concurrent 
illness/ clinical condition, an effect of another device, drug, treatment or other risk factors); 
- the event does not depend on a false result given by the investigational device used for 
diagnosis, when applicable; harms to the subject are not clearly due to use error; 
- In order to establish the non-relatedness, not all the criteria listed above might be met at the 
same time, depending on the type of device/procedures and the serious event. 
Unlikely Related 
The relationship with the use of the device seems not relevant and/or the event can be reasonably 
explained by another cause, but additional information may be obtained. 
Possibly Related 
The relationship with the use of the investigational device is weak but cannot be ruled out 
completely. Alternative causes are also possible (e.g. an underlying or concurrent illness/ clinical 
condition or/and an effect of another device, drug or treatment). Cases were relatedness cannot be 
assessed or no information has been obtained should also be classified as possible. 
Probably Related 
The relationship with the use of the investigational device seems relevant and/or the event cannot 
reasonably explained by another cause, but additional information may be obtained. 
Causal Relationship 
The serious event is associated with the investigational device or with procedures beyond 
reasonable doubt when: 
- the event is a known side effect of the product category the device belongs to or of similar 
devices and procedures; 
- the event has a temporal relationship with investigational device use/application or procedures; 
- the event involves a body-site or organ that 
o the investigational device or procedures are applied to; 
o the investigational device or procedures have an effect on; 
- the serious event follows a known response pattern to the medical device (if the response pattern 
is previously known); 
- the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of activation/exposure), 
impact on the serious event (when clinically feasible); 
- other possible causes (e.g. an underlying or concurrent illness/ clinical condition or/and an effect 
of another device, drug or treatment) have been adequately ruled out; 
- harm to the subject is due to error in use; 
- the event depends on a false result given by the investigational device used for diagnosis, when 
applicable; 

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Table 18-2: Assessing Relationship of Study Device or Procedure to Adverse 
Event 
Classification 
Description 
- In order to establish the relatedness, not all the criteria listed above might be met at the same 
time, depending on the type of device/procedures and the serious event. 
 
18.4 Investigator Reporting Requirements 
The communication requirements for reporting to BSC are as shown in Table 18-3. 
 
Table 18-3: Investigator Reporting Requirements 
Event 
Classification 
Communication 
Method  
Communication Timeline post-market 
studies**  
(MEDDEV 2.12/2 :  
GUIDELINES ON A MEDICAL DEVICE 
VIGILANCE SYSTEM) 
Unanticipated 
Adverse Device 
Effect / 
Unanticipated 
Serious Adverse 
Device Effect  
 
Complete AE eCRF 
page with all available 
new and updated 
information.  
 
d) Within 1 business day of first becoming aware 
of the event. 
e) Terminating at the end of the study 
Serious Adverse 
Event  
Complete AE eCRF 
page with all available 
new and updated 
information.  
f) Within 10 business days after becoming aware 
of the event or as per local/regional regulations.  
g) For Austria: within,2 business days of first 
becoming aware of the event.  
h) Reporting required through the end of the study 
NOTE: Deaths are reported within 3 calendar days 
per Section 18.7 
Provide all relevant 
source documentation 
(unidentified) for 
reported event  
i) As soon as possible 
Serious Adverse 
Device Effects 
Complete AE eCRF 
page with all available 
new and updated 
information. 
j) Within 2 business days of first becoming aware 
of the event or as per local/regional regulations. 
k) Reporting required through the end of the study 
Provide all relevant 
source documentation 
(unidentified) for 
reported event 
l) When documentation is available 
Device Deficiencies 
(including but not 
Complete the device 
deficiency eCRF with 
m) 
Within 2 business days 
of first becoming aware of the event. Reporting 

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Table 18-3: Investigator Reporting Requirements 
Event 
Classification 
Communication 
Method  
Communication Timeline post-market 
studies**  
(MEDDEV 2.12/2 :  
GUIDELINES ON A MEDICAL DEVICE 
VIGILANCE SYSTEM) 
limited to failures, 
malfunctions, and 
product 
nonconformities) 
Note:  Any 
Investigational 
Device Deficiency 
that might have led 
to a serious adverse 
event if a) suitable 
action had not been 
taken or b) 
intervention had not 
been made or c) if 
circumstances had 
been less fortunate 
is considered a 
reportable event. 
 
all available new and 
updated information.  
required through the end of the study 
Adverse Event 
including Adverse 
Device Effects 
Complete AE eCRF 
page, which contains 
such information as date 
of AE, treatment of AE 
resolution, assessment 
of seriousness and 
relationship to the 
device.  
n) In a timely manner  (e.g. recommend within 30 
business days) after becoming aware of the 
information 
o) Reporting required through the end of the study 
Abbreviations: AE=adverse event; CRF=case report form; IDE=Investigational Device Exemption; 
UADE=unanticipated adverse device effect 
* Please note that pre-market studies are clinical studies with investigational devices or with medical 
devices that bear the regulatory approval and are not being used for the same approved indications. 
**Please note that post-market studies are clinical studies where the medical devices used in the study 
bear the regulatory approval and are used for the same approved indications. 
 
 
 
 
18.5 Boston Scientific Device Deficiencies 
All device deficiencies (including but not limited to failures, malfunctions, use errors, product nonconformities, 
and inadequacy in the information supplied by the manufacturer) will be documented and reported to BSC. If 
possible, the device(s) should be returned to BSC for analysis. Instructions for returning the investigational 
device(s) will be provided in the investigator site manual. If it is not possible to return the device, the 

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investigator should document in the eCRF why the device was not returned and the final disposition of the 
device. Device failures and malfunctions should also be documented in the subject’s medical record. 
 
Device deficiencies (including but not limited to failures, malfunctions, and product nonconformities) are not 
adverse events. However, an adverse event that results from a device failure or malfunction would be recorded 
as an adverse event on the appropriate eCRF. 
 
Any Device Deficiency that might have led to a serious adverse event if a) suitable action had not been taken or 
b) intervention had not been made or c) if circumstances had been less fortunate is considered a reportable 
event. 
18.6 Reporting to Regulatory Authorities / IRBs / ECs / Investigators 
BSC is responsible for reporting adverse event information to all participating Principal Investigators and 
regulatory authorities, as applicable.  
The Principal Investigator is responsible for informing the IRB/EC, and regulatory authorities of UADE and 
SAE as required by local/regional regulations. 
 
18.7 Subject Death Reporting 
A subject death during the study should be reported to Boston Scientific as soon as possible preferably within 
three (3) calendar days of notification to the investigational center. The site’s IRB/EC must be notified of any 
deaths in accordance with policies and procedures.  A detailed statement (death letter) that provides detailed 
information describing the circumstances surround the death must be provided. A death letter in the local 
language is acceptable.  The details listed below should be addressed in the death narrative in order for BSC to 
understand the circumstances surrounding the death:  
 Date and time of death 
 Place death occurred 
 Immediate cause of death 
 Rhythm at the time of death 
 Relationship to pulse generator, lead, clinical investigation procedure or patient condition 
 Whether or not the death was witnessed 
 The device status and/or activity at the time of death, if applicable 
 Whether or not the patient had worsening heart failure 
 Any other circumstances surrounding the death 
 The approximate time interval from the initiating event to death (temporal course) 
 Investigator or sub-investigator signature and date 
 
Also submit the following documentation if the patient died in the hospital: 
 A copy of the medical records for that admission (e.g. test results, operative report, progress notes) 
 Death certificate (if available) 
 Autopsy report (if available) 
 Whenever possible, the IPG should be interrogated.    
 

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If the patient died outside the hospital: 
 A copy of the most recent clinic visit (if not already submitted) 
 Death certificate (if available) 
 Whenever possible, the IPG should be interrogated.   
 
Upon death, the device may be interrogated using a Consult or using a programmer. If a programmer 
interrogation is used, the “device data dump” (not “save all to disk”) option should be chosen. If data are stored 
on a disc or flash drive, the disc or flash drive should be kept in the subject’s MANAGE-HF study binder at the 
investigative site, and copy should be mailed to the sponsor   
 
19 Informed Consent 
Details in this section apply to both phases (Phases I and II) of the MANAGE-HF study.   
 
Subject participation in this clinical study is voluntary.  Informed Consent is required from each subject.  There 
is a separate consent form for Phase I and Phase II.  Subjects can only consent and participate in one phase.  The 
Investigator is responsible for ensuring that Informed Consent is obtained prior to the use of any investigational 
devices, study-required procedures and/or testing, or data collection.  
 
The obtaining and documentation of Informed Consent must be in accordance with the principles of the 
Declaration of Helsinki, ISO 14155, any applicable national regulations, and local Ethics Committee and/or 
Regulatory authority body, as applicable. The ICF must be accepted by BSC or its delegate (e.g. CRO), and 
approved by the site’s IRB/EC, or central IRB, if applicable. 
 
Boston Scientific will provide a study-specific template of the ICF to investigators participating in this study. 
The ICF template may be modified to meet the requirements of the investigative site’s IRB/EC.  Any 
modification requires acceptance from BSC prior to use of the form.  The ICF must be in a language 
understandable to the subject and if needed, BSC will assist the site in obtaining a written consent translation. 
Translated consent forms must also have IRB/EC approval prior to their use.  Privacy language shall be 
included in the body of the form or as a separate form as applicable.   
 
The process of obtaining Informed Consent shall at a minimum include the following steps, as well as any other 
steps required by applicable laws, rules, regulations and guidelines: 
 be conducted by the Principal Investigator or designee authorized to conduct the process,  
 include a description of all aspects of the clinical study that are relevant to the subject’s decision to 
participate throughout the clinical study, 
 avoid any coercion of or undue influence of subjects to participate, 
 not waive or appear to waive subject’s legal rights, 
 use native language that is non-technical and understandable to the subject or his/her legal 
representative, 
 provide ample time for the subject to consider participation and ask questions if necessary, 
 ensure important new information is provided to new and existing subjects throughout the clinical study.  
 

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The ICF shall always be signed and personally dated by the subject under the applicable laws, rules, regulations 
and guidelines and by the investigator and/or an authorized designee responsible for conducting the informed 
consent process.  The original signed ICF will be retained by the site and a copy of the signed and dated 
document and any other written information must be given to the person signing the form.  
 
Failure to obtain subject consent will be reported by BSC to the applicable regulatory body according to their 
requirements (e.g., FDA requirement is within 5 working days of learning of such an event). Any violations of 
the informed consent process must be reported as deviations to the sponsor and local regulatory authorities (e.g. 
IRB/EC), as appropriate. 
If new information becomes available that can significantly affect a subject's future health and medical care, 
that information shall be provided to the affected subject(s) in written form via a revised ICF or, in some 
situations, enrolled subjects may be requested to sign and date an addendum to the ICF. In addition to new 
significant information during the course of a study, other situations may necessitate revision of the ICF, such 
as if there are amendments to the applicable laws, protocol, a change in Principal Investigator, administrative 
changes, or following annual review by the IRB/EC. The new version of the ICF must be approved by the 
IRB/EC. Acceptance by Boston Scientific is required if changes to the revised ICF are requested by the site’s 
IRB/EC. The IRB/EC will determine the subject population to be re-consented. 
 
An EDC Screening/enrollment may be maintained to document select information about candidates who fail to 
meet the general or “other specific” entry criteria.   
20 Committees 
Details in this section apply to both phases (Phases I and II) of the MANAGE-HF study.   
20.1 Safety Monitoring Process 
To promote early detection of safety issues, the Boston Scientific Medical Safety group and MANAGE-HF 
Steering Committee will evaluate the ongoing safety of the trial.   Success of this approach requires dynamic 
collection of unmonitored data as soon as the event is reported. During regularly scheduled monitoring 
activities, clinical research monitors will support the dynamic reporting process through their review of source 
documents and other data information. The BSC Medical Safety and Steering Committee groups include 
physicians and nurses with expertise in electrophysiology, heart failure, and general cardiology and with the 
necessary therapeutic and subject matter expertise to evaluate safety.  
 
20.2 Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will be formed to monitor patient safety and the trial 
conduct.  A detailed DMC Charter will be written to govern the activities of this committee.  The DMC will be 
independent from the sponsor, the investigators, and the Steering Committee. The board will be composed of 
three to five members, including at least one with expertise in the following areas: biostatistics, heart failure, 
and cardiac electrophysiology/device management. At least one member will also have extensive clinical trial 
experience. The DMC will have access to unblinded patient-level and aggregated study results throughout the 

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course of the study. The DMC may recommend early termination of the trial if there are safety concerns or if a 
pre-defined stopping criterion has been fulfilled.   
 
The DMC will convene within 6 months after the first patient is enrolled.  The DMC will meet periodically, or 
as needed, to review the results of the trial and to evaluate any safety issues that may arise during the course of 
the study.   
20.3 Clinical Events Committee 
The Clinical Event Committee (CEC) is constituted of a group of independent clinical experts external to the 
study and to the Sponsor. The CEC will provide an independent review of all Serious Adverse Events (SAE) 
which resulted in a hospitalization or an outcome of death.  The CEC will adjudicate events that count towards 
the primary endpoint, as indicated in Section 10.1. 
 
Other events, at the discretion of BSC may also be submitted to the CEC for review.   
21 Suspension or Termination 
21.1 Premature Termination of the Study 
Boston Scientific Corporation reserves the right to terminate the study at any stage but intends to exercise this 
right only for valid scientific or administrative reasons and reasons related to protection of subjects.  
Investigators, associated IRBs/ECs, and regulatory authorities, as applicable, will be notified in writing in the 
event of study termination. 
21.1.1 Criteria for Premature Termination of the Study 
Possible reasons for premature study termination include, but are not limited to, the following. 
 A pre-defined primary endpoint stopping rule has been fulfilled (defined in a separate MANAGE-HF 
Statistical Analysis Plan). 
 The DMC has recommended early termination of the study (Section 20.2). 
 The occurrence of unanticipated adverse device effects that present a significant or unreasonable risk to 
subjects enrolled in the study. 
 An enrollment rate far below expectation that prejudices the conclusion of the study.  
 A decision on the part of Boston Scientific to suspend or discontinue development of the device. 
21.2 Termination of Study Participation by the Investigator or Withdrawal of IRB/ EC Approval 
Any investigator, or IRB/ EC in the MANAGE-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, and regulatory authorities, as applicable, will be notified in writing in the event of these 
occurrences. 

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21.3 Requirements for Documentation and Subject Follow-up 
In the event of premature study termination a written statement as to why the premature termination has 
occurred will be provided to all participating sites by Boston Scientific. The IRB/EC and regulatory authorities, 
as applicable, will be notified. Detailed information on how enrolled subjects will be managed thereafter will be 
provided.  
 
In the event an IRB or EC terminates participation in the study, participating investigators, associated 
IRBs/ECs, and regulatory authorities, as applicable, will be notified in writing. Detailed information on how 
enrolled subjects will be managed thereafter will be provided by Boston Scientific. 
 
In the event a Principal Investigator terminates participation in the study, study responsibility will be transferred 
to another investigator, if possible. In the event there are no opportunities to transfer Principal Investigator 
responsibility; detailed information on how enrolled subjects will be managed thereafter will be provided by 
Boston Scientific. 
 
The Principal Investigator or his/her designee must return all study-related documents and investigational 
product to Boston Scientific, unless this action would jeopardize the rights, safety, or welfare of the subjects. 
21.4 Criteria for Suspending/Terminating a Study Site 
Boston Scientific Corporation reserves the right to stop the inclusion of subjects at a study site at any time after 
the study initiation visit if no subjects have been enrolled for a period beyond 6 months after site initiation, or if 
the site has multiple or severe protocol violations/noncompliance without justification and/or fails to follow 
remedial actions. The IRB/EC and regulatory authorities, as applicable, will be notified. All subjects enrolled in 
the study at the site will continue to be followed by their clinician for routine medical care.   
22 Publication Policy 
Details in this section apply to both phases (Phases I and II) of the MANAGE-HF study.   
 
BSC requires disclosure of its involvement as a sponsor or financial supporter in any publication or presentation 
relating to a BSC study or its results. BSC will submit study results for publication (regardless of study 
outcome) following the conclusion or termination of the study. Boston Scientific Corporation adheres to the 
contributorship criteria set forth in the Uniform Requirements of the International Committee of Medical 
Journal Editors (ICMJE; http://www.icmje.org). In order to ensure the public disclosure of study results in a 
timely manner, while maintaining an unbiased presentation of study outcomes, BSC personnel may assist 
authors and investigators in publication preparation provided the following guidelines are followed. 
 
All authorship and contributorship requirements as described above must be followed. 
BSC involvement in the publication preparation and the BSC Publication Policy should be discussed with the 
Coordinating Principal Investigator(s) and/or Executive/Steering Committee at the onset of the project. 
 
The First and Senior authors are the primary drivers of decisions regarding publication content, review, 
approval, and submission.  

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23 Reimbursement and Compensation for Subjects 
Details in this section apply to both phases (Phases I and II) of the MANAGE-HF study.   
23.1 Subject Reimbursement 
Travel and other expenses incurred by subjects as a result of participation in the study will be reimbursed in 
accordance with pertinent country laws and regulations and per the study site’s regulations.   
23.2 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, and if required by applicable law.  
24 Bibliography 
 
1. 
Mozaffarian, D., et al., Heart Disease and Stroke Statistics-2016 Update: A Report From the American 
Heart Association. Circulation, 2016. 133(4): p. e38-360. 
2. 
Yancy, C.W., et al., 2013 ACCF/AHA guideline for the management of heart failure: a report of the 
American College of Cardiology Foundation/American Heart Association Task Force on practice 
guidelines. Circulation, 2013. 128(16): p. e240-327. 
3. 
Chaudhry, S.I., et al., Telemonitoring in patients with heart failure. N Engl J Med, 2010. 363(24): p. 
2301-9. 
4. 
Yu, C.M., et al., Intrathoracic impedance monitoring in patients with heart failure: correlation with 
fluid status and feasibility of early warning preceding hospitalization. Circulation, 2005. 112(6): p. 841-
8. 
5. 
Samara, M.A. and W.H. Tang, Device monitoring strategies in acute heart failure syndromes. Heart Fail 
Rev, 2011. 16(5): p. 491-502. 
6. 
van Veldhuisen, D.J., et al., Intrathoracic impedance monitoring, audible patient alerts, and outcome in 
patients with heart failure. Circulation, 2011. 124(16): p. 1719-26. 
7. 
Hindricks, G., et al., Implant-based multiparameter telemonitoring of patients with heart failure (IN-
TIME): a randomised controlled trial. Lancet, 2014. 384(9943): p. 583-90. 
8. 
Bohm, M., et al., Fluid status telemedicine alerts for heart failure: a randomized controlled trial. Eur 
Heart J, 2016. 
9. 
Conraads, V.M., et al., Sensitivity and positive predictive value of implantable intrathoracic impedance 
monitoring as a predictor of heart failure hospitalizations: the SENSE-HF trial. Eur Heart J, 2011. 
32(18): p. 2266-73. 
10. 
Heist, E.K., et al., Analysis of different device-based intrathoracic impedance vectors for detection of 
heart failure events (from the Detect Fluid Early from Intrathoracic Impedance Monitoring study). Am J 
Cardiol, 2014. 114(8): p. 1249-56. 
11. 
Auricchio, A., et al., Long-term effectiveness of the combined minute ventilation and patient activity 
sensors as predictor of heart failure events in patients treated with cardiac resynchronization therapy: 

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Results of the Clinical Evaluation of the Physiological Diagnosis Function in the PARADYM CRT 
device Trial (CLEPSYDRA) study. Eur J Heart Fail, 2014. 16(6): p. 663-70. 
12. 
Boehmer, J.P., Hariharan, R., Devecchi, F.G., Smith, A.L., Molon, G., Capucci, A., An, Q., Averina, V., 
Stolen, C.M., Thakur, P.H., Thompson, J.A. Wariar, R., Zhang, Y., Singh, J.P. , A Multi-sensor 
Algorithm Predicts Heart Failure Events in Patients with Implanted Devices: Results from the 
MultiSENSE Study. , in JACC-HF. 2016. 
13. 
Bradley, E.H., et al., Contemporary evidence about hospital strategies for reducing 30-day 
readmissions: a national study. J Am Coll Cardiol, 2012. 60(7): p. 607-14. 
14. 
Akar, J.G., et al., 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(22): p. 2372-83. 
15. 
Abraham, W.T., et al., Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a 
randomised controlled trial. Lancet, 2011. 377(9766): p. 658-66. 
16. 
Loh, J.P., I.M. Barbash, and R. Waksman, Overview of the 2011 Food and Drug Administration 
Circulatory System Devices Panel of the Medical Devices Advisory Committee Meeting on the 
CardioMEMS Champion Heart Failure Monitoring System. J Am Coll Cardiol, 2013. 61(15): p. 1571-6. 
17. 
Abraham, W.T., et al., Sustained efficacy of pulmonary artery pressure to guide adjustment of chronic 
heart failure therapy: complete follow-up results from the CHAMPION randomised trial. Lancet, 2016. 
387(10017): p. 453-61. 
18. 
Morgan, J.M., et al., Rationale and study design of the REM-HF study: remote management of heart 
failure using implanted devices and formalized follow-up procedures. Eur J Heart Fail, 2014. 16(9): p. 
1039-45. 
19. 
Koehler, F., et al., Telemedical Interventional Monitoring in Heart Failure (TIM-HF), a randomized, 
controlled intervention trial investigating the impact of telemedicine on mortality in ambulatory patients 
with heart failure: study design. Eur J Heart Fail, 2010. 12(12): p. 1354-62. 
20. 
Wittes, J. and E. Brittain, The role of internal pilot studies in increasing the efficiency of clinical trials. 
Stat Med, 1990. 9(1-2): p. 65-71; discussion 71-2. 
 
25 Abbreviations and Definitions  
25.1 Abbreviations are shown in Table 25-1.   
 
Table 25-1: Abbreviations 
AE 
Adverse Event 
ACE 
angiotensin converting enzyme  
ADE 
Adverse Device Effect 
AHI 
Apnea–Hypopnea Index  
AMC 
Alert Monitoring Center 
ARB  
Angiotensin Receptor Blocker 
ASADE  
Anticipated serious adverse device effect 
ATP 
anti-tachycardia pacing 
BNP 
Brain Natriuretic Peptide 

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Table 25-1: Abbreviations 
BP 
Blood pressure 
BSC  
Boston Scientific 
CA 
competent authority 
CAPTIVATE  
Evaluation of Automatic Threshold Algorithms 
CC 
cubic centimeter 
CEC 
clinical events committee 
CFR 
complication-free rate 
CHAMPION 
CardioMEMS Heart Sensor Allows Monitoring of 
Pressure to Improve Outcomes in Class III Heart 
Failure 
CNT 
Control 
COMPASS-HF 
Chronicle Offers Management to Patients With 
Advanced Signs and Symptoms of Heart Failure 
COPD 
Chronic Obstructive Pulmonary Disease (COPD) 
CPAP 
continuous positive airway pressure, 
CRO 
Contract Research Organization 
CRT-D 
Cardiac Resynchronization Therapy Defibrillator 
DOT-HF 
Diagnostic Outcome Trial in Heart Failure 
DMC 
Data Monitoring Committee 
DVT 
deep vein thrombosis 
EC 
Ethics Committee 
Echo 
Echocardiography 
ECG 
electrocardiogram 
eCRF 
electronic case report forms 
EDC 
electronic data capture 
EF 
Ejection Fraction 
ER  
Emergency Room 
EU 
European Union 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
FU 
Follow up 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
HA  
alternative hypothesis 
H0 
null hypothesis 
HF  
Heart Failure 
HL 
HeartLogic 
ICD 
implantable cardioverter defibrillators 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IDE 
Investigational Device Exemption 
IPG 
Implanted pulse generator 

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Table 25-1: Abbreviations 
IN-TIME 
Influence of Home Monitoring on the Clinical Status of 
Heart Failure Patients With an Impaired Left 
Ventricular Function 
IMPEDANCE-
HF 
The Non-invasive Lung IMPEDANCE-guided 
Preemptive Treatment in Patients with Chronic Heart 
Failure (IMPEDANCE-HF) Trial 
ISO 
International Organization for Standardization 
IRB 
Institutional Review Board 
IV 
intravenous 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LBBB 
Left bundle branch block  
LSS of 4-SITE 
Longitudinal Surveillance Study of the 4-SITE 
Lead/Header System 
LV 
Left Ventricle 
M/Mo 
Month 
MANAGE-HF 
Multiple cArdiac seNsors for mAnaGEment of Heart 
Failure 
MADIT-CRT 
Multicenter Automatic Defibrillator Implantation Trial 
With Cardiac Resynchronization Therapy 
Mcg 
microgram 
Mg  
milligram 
MI 
Myocardial Infarction 
MN 
Minnesota 
ms 
milliseconds 
MUGA 
Multiple gated acquisition scan 
MultiSENSE 
Evaluation of Multisensor Data in Heart Failure 
Patients With Implanted Devices 
NAVIGATE X4 
Evaluation of ACUITY™ X4 Quadripolar Coronary 
Venous Leads and RELIANCE™ 4-FRONT 
Defibrillation Leads 
NT-proBNP 
N-terminal pro b-type natriuretic peptide 
NYHA 
New York Heart association 
NSAID 
nonsteroidal anti-inflammatory drugs 
O  
optional but recommended 
OOS  
Out of service 
OPT 
optimal pharmacologic therapy  
PG 
Pulse generator 
Pt 
Patient 
R 
Required 
RA 
Right atrium 
REM-HF 
Remote Management of Heart Failure Using 
Implantable Electronic Devices 
RV 
Right Ventricle 

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Table 25-1: Abbreviations 
SADE 
Serious Adverse Device Effects 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis Software 
Tx 
Therapy 
TZD 
thiazolidinediones 
UADE 
Unanticipated Adverse Device Effects 
 US  
United States 
USADE 
Unanticipated Serious Adverse Device Effects 
Vs  
versus 
Yr 
Year 
 
25.2 Definitions 
Definitions are shown in Table 25-2.  
 
Table 25-2: Definitions 
Term 
Definition 
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