Heart Failure Indication and Sudden Cardiac Death Prevention Trial Japan
Conditions: Heart Failure, Arrhythmias, Cardiac, Sudden Cardiac Death
Sponsor: Boston Scientific Corporation

 
 
Form/Template 92120219 Rev/Ver A 
 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
  
Page 1 of 100 
 
 
Heart Failure Indication and Sudden Cardiac Death Prevention Trial Japan 
HINODE 
 
 
CLINICAL INVESTIGATION PLAN 
 
 
BSC Project Number C2076 
 
Sponsored By 
Boston Scientific, Rhythm Management (RM) 
4100 Hamline Avenue North 
St. Paul, MN 55112 
United States 
 
and 
 
Guidant Europe NV 
A Boston Scientific Company 
Clinical Department Rhythm Management 
Green Square 
Lambroekstraat 5D 
1831 Diegem 
Belgium 
 
 
 
 
 
This Clinical Investigation Plan (CIP) contains confidential information for use by the 
Investigators and their designated representatives participating in this clinical investigation. 
The CIP should be held confidential and maintained in a secure location. 
Do not copy or distribute without written permission from Boston Scientific Corporation. 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 1 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 2 of 100 
  
Contact Information 
Role 
Contact  
Clinical Contact 
Dr. Torsten Kayser 
Senior Fellow Clinical Department Rhythm Management 
Guidant Europe NV, a Boston Scientific Company 
Green Square 
Lambroekstraat 5D 
1831 Diegem 
Belgium 
Reception +32 2 41 (67216) 
Torsten.Kayser@bsci.com 
 
Technical Service Contact Information 
eurotechservice@bsci.com or japantechservice@bsci.com 
+32 2 41 67222 
+61 2 8063 8299 
 
CIP Authors and Affiliation 
Dr. Torsten Kayser, Senior Fellow, Boston Scientific 
Olivier Hauswirth, Senior Statistician, ICON Plc 
Takeshi Akagi, Project Manager, ICON Plc 
Dr. Susanne Herzig, Senior Medical Writer, ICON Plc 
Coordinating Principal 
Investigator 
Professor Kazutaka AONUMA 
University of Tsukuba, Cardiology, Internal Medicine, Faculty of 
Medicine, School of Medical Science 
Ibaraki, Japan 
 
Steering Committee 
Members 
Professor Akihiko NOGAMI 
University of Tsukuba 
Japan 
 
Associate Professor Takeshi MITSUHASHI 
Saitama Medical Center, Jichi Medical University 
Japan 
 
Professor Kenzo HIRAO 
Tokyo Medical and Dental University 
Japan 
 
Professor Wataru SHIMIZU 
Nippon Medical School 
Japan 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 2 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 3 of 100 
  
Role 
Contact  
 
Professor Takanori IKEDA 
Toho University Faculty of Medicine 
Japan 
 
Professor Toyoaki MUROHARA 
Nagoya University 
Japan 
 
Professor Yasushi SAKATA 
Osaka University 
Japan 
 
Lecturer Nobuhiro NISHII 
Okayama University 
Japan 
 
Directing Consultant and Chief Director Kenji ANDO 
Kokura Memorial Hospital 
Japan 
 
Vendors/Labs 
A list of vendors/laboratories involved in the trial is maintained by 
the sponsor. A complete listing of applicable vendors will be 
provided to investigational sites. 
 
 
 
 
 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 3 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 4 of 100 
  
 
Original Release: 24 Feb 2017  
Current Version: March 29, 2018 
 
Revision History 
Revision 
Number 
Release 
Date 
Template 
number 
and version 
Section 
Change 
Reason for 
Change 
Version 
AA  
Doc 
92082863  
24 February 
2017  
90702637, 
version AH 
2016 
 
Initial Release 
 
Version B  
Doc 
92082863 
27 February 
2017 
 
9.2.5. 
Adding: ” or DCM (dilated 
cardiomyopathy)”. As 
clarification to the non-device 
inclusion criteria  
 
Inconsistency 
in wording 
with ICD 
inclusion 
criteria  
Version C  
Doc 
92082863 
13 March 
2017 
 
2. 
 
 
4. 
 
7.3 
 
9.2. 
 
9.3. 
11.1 
12.3 
Adjustment of synopsis 
Wording issues across the 
document 
Introduction; rational for 
pacemaker arm 
7.3. Add Endpoint on cause 
of death 
9.2 Adding and adjusting 
inclusion  
9.3 and exclusion criteria 
11.1 Adjustments 
12.3 Adjustments 
Inconsistency 
in wording and 
the need for 
more specific 
details for a 
well-defined 
subject cohort 
by inclusion 
and exclusion 
criteria 
Version D  
Doc 
92082863 
29 March 
2018 
92120219, 
version A 
 
 
 
 
Contact 
Information 
 
2. 
 
 
5., 11.4 
 
 
 
8.1, 8.2, 
10.4, 12 
 
Figure 8.1-1 
 
 
9.2 
 
 
 
CIP Authors and Affiliation 
updated to reflect current 
contact details 
Adjustment of synopsis 
wording issues across the 
document 
Clarification added regarding 
data collection in case subjects 
cannot be connected to 
Latitude 
Adjustments to content for 
minimum number of subjects 
required to meet endpoints 
Close-out window for last 
subject added for clarification 
purposes 
Adjusting inclusion criteria; 
typo’s, data collection, 
timelines aligned with SOC, 
clarifications 
Correction of 
typo’s and 
inconsistencies 
and addition of 
clarifications 
across the 
document 
Need for 
adjusting 
inclusion and 
exclusion 
criteria 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 4 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 5 of 100 
  
 
Revision History 
Revision 
Number 
Release 
Date 
Template 
number 
and version 
Section 
Change 
Reason for 
Change 
9.3 
 
 
 
10.1 
 
 
 
Table 11.1-1 
11.4 
 
 
 
8., 11.1, 
11.4, 11.5, 
11.8, 11.9, 
17.4, 20.4, 
27.1 
21. 
 
 
2., 8.1, 8.2, 
12.2.2, 27.1 
 
 
 
Removing and adjusting 
exclusion criteria; removal of 
exclusion criteria for non-
device cohort, clarifications 
Clarification added for 
eligibility criteria handling 
between protocol version C and 
D 
Adjustment of wording across 
the document 
Adjustments to content for 
data collection and timelines to 
align with SOC 
Adjustments to wording 
 
 
 
 
Adjustments to content 
regarding legally authorized 
representative 
Adjustment to content 
regarding Korea participation 
as Korea will not join the study 
 
 
      
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 5 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 6 of 100 
  
2. Synopsis 
Heart Failure Indication and Sudden Cardiac Death Prevention Trial Japan 
HINODE 
 
Study 
Objectives 
The purpose of this cohort therapy study is to collect clinical event and 
outcome data in a study population with a majority of Japanese subjects 
on sudden cardiac death (SCD), heart failure (HF) events, and 
appropriately treated ventricular adverse events in predefined subject 
cohorts. These event rates will be compared with available data mainly 
from Europe and the United States. It is the intention to add evidence in 
treatment with implanted Implantable cardioverter-defibrillator (ICD) and 
treatment with cardiac resynchronization therapy-defibrillator (CRT-D) 
devices. 
Selected Subject Cohorts: 
1. 
Selected subject cohort with criteria for SCD (without spontaneous 
prior ventricular sustained arrhythmia) and de novo ICD device 
treatment. 
2. 
Selected subject cohort with criteria for SCD and widely accepted 
standard cardiac resynchronization therapy (CRT) indication who 
received a de novo CRT-D device treatment. 
3. 
Selected subject cohort who are clinically expected to require >40% 
right ventricular pacing with a left ventricular ejection fraction 
(LVEF) ≤50%, any determined New York Heart Association 
(NYHA) Class, and receiving pacemaker (PM) or CRT-pacemaker 
(CRT-P) therapy despite previous device history (de novo, box 
changes, system revisions or upgrades). 
4. 
Selected subject cohort with criteria for SCD fulfilling European 
Society of Cardiology (ESC) ICD or CRT-D therapy guidelines 
(2016) with an LVEF ≤35%, having 2 to 5 predefined SCD risk 
factors but do not have or had have a cardiac implanted defibrillator, 
CRT-D, PM, or CRT-P. 
Test Device 
Implanted subjects will receive one of 4 types of Boston Scientific (BSC) 
devices prior to enrolment in the study: 
1. 
ICD (only magnetic resonance imaging [MRI] conditionally safe 
systems) + Latitude 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 6 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 7 of 100 
  
Heart Failure Indication and Sudden Cardiac Death Prevention Trial Japan 
HINODE 
 
Test Device 
(continued) 
2. CRT-D (IS4 connector only, MRI conditionally safe systems) + 
Latitude 
3. PM + Latitude 
or 
CRT-P + Latitude 
All device systems are on the market in Japan, and will be implanted per 
standard of care (SOC) and BSC Instructions for Use (IFU) for the 
respective devices should be followed. 
Neither the devices nor the implant procedure are part of this study. The 
decision as to which device any subject receives is to be determined by 
the investigator and is not part of this study. 
Device system use and programming will need to follow SOC, devices 
IFUs and must follow CIP programming requirements. All devices in the 
study must be intended to be connected to the Latitude system. 
Study Design 
This is a prospective, non-randomized, multicenter, multi-cohort clinical 
outcome registry study to evaluate SOC. 
Planned 
Number of 
Subjects 
It is planned to enroll a minimum of 556 to power all primary endpoint 
for each cohort. 
As soon as a minimum of 556 eligible subjects are entered into the study 
database, the closure of enrolment can begin. The maximum number of 
followed study subjects is 950. 
The event dependent character of the study, and the calculated necessary 
minimum sample size may allow early enrollment closure of the study 
enrollment. 
Planned 
Number of 
Investigational 
Sites / Countries 
Approximately 40 investigational sites in Japan will be included. If a site 
does not enroll a subject within a 3-month time period, the site may be 
closed for enrolment and replaced at the discretion of the sponsor. 
Primary Safety 
Endpoint(s) 
Not applicable 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 7 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 8 of 100 
  
Heart Failure Indication and Sudden Cardiac Death Prevention Trial Japan 
HINODE 
 
Primary 
Effectiveness 
Endpoints 
Defibrillator Cohort (including ICD and CRT-D Cohorts): 
Composite rate of first appropriately treated ventricular arrhythmia (by 
anti-tachycardia pacing [ATP] or shock) or life-threatening symptoms 
associated to ventricular arrhythmia (defined as hemodynamic 
instability which requires treatment), whichever comes first under 
MADIT Arm B or C programming conditions in a study population 
with a majority of Japanese subjects 
PM/CRT-P Cohort: 
All-cause mortality in subjects with a maximum of 3 risk factors 
(analyzed for MADIT II data) 
Non-device Cohort (ESC Guideline 2016 Indicated but not 
implanted): 
All-cause mortality in the subject cohort with 2 to 5 predefined SCD 
driving risk factors 
Secondary 
Endpoints 
Defibrillator Cohort (including ICD and CRT-D Cohorts): 
• All-cause mortality rate 
ICD, CRT-D, and PM/CRT-P Cohorts: 
• Composite rate of HF events, which require intravenous (IV) 
treatment and/or HF related hospitalization, or which led to HF 
death 
• Therapeutic sustainability at 1 year, defined as free of qualified 
serious 
adverse 
device 
events 
(SADEs) 
post 
successful 
implantation in comparison to data from MADIT CRT, MADIT 
RIT, Optimind and Rally X4 studies 
Examples for qualified SADEs are: re-implant procedure, required 
invasive procedure related to the device system, pacing exit block, 
all-cause infection, and death due to therapy failure 
ICD, CRT-D, and Non-device Cohorts: 
• Comparison of rate of sudden cardiac death in the non-device 
cohort with the rate of appropriately treated ventricular 
arrhythmias or sudden cardiac death in the defibrillator cohort 
(including ICD and CRT-D Cohorts) 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 8 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 9 of 100 
  
Heart Failure Indication and Sudden Cardiac Death Prevention Trial Japan 
HINODE 
 
Additional 
Endpoints 
• Subject medical assessment collected pre-enrolment (post implant) 
and at Close-out: 
– 
NYHA functional classification 
– 
LVEF 
– 
QRS duration 
– 
Physician’s judgment on therapy outcome 
– 
Body mass index 
– 
Diabetes mellitus type I and II 
• Cross-over in device therapies 
• Cause of death (SCD, cardiac related, other reasons, unknown) 
• Impact of age and gender 
• MRI observations in association with reported clinical events 
• Analysis of device data coming from Latitude data reports 
• Health care utilization under Latitude 
• Standard biomarkers for heart failure and other morbidities 
Method of 
Assigning 
Patients to 
Treatment 
Subjects will be assigned to one of the 3 following Subject Cohorts 
according to device implanted: 
1. ICD: 
117 to 270 subjects 
2. CRT-D: 
95 to 250 subjects 
3. PM/CRT-P: 
172 to 200 subjects 
A fourth cohort of non-implanted subjects will also be enrolled: 
4. Non-device: 
172 to 300 subjects 
(ESC Guideline 2016 indicated but not implanted) 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 9 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 10 of 100 
  
Heart Failure Indication and Sudden Cardiac Death Prevention Trial Japan 
HINODE 
 
Follow-up 
Schedule 
Clinic visits will occur at: 
• Enrolment and Consenting Clinic Visit (Day 0, 0 to 45 days post 
implant procedure, alternative >90 days post myocardial infarction 
(MI)) (Required) 
• 6-monthly Visit (180 ± 60 days post enrolment and multiplies until 
Close-out Visit) (required) 
• Re-implant or New Device Implant post Enrolment (optional) 
• Interim Visit and Event Report (serious adverse events/SADE 
related clinical care visit) 
• Close-out Clinic Visit (see Figure 8.1-1) (Required) 
• During the trial all adverse device effects, deaths, and changes in the 
device system must be reported 
• Devices will be followed by the BSC Latitude team. Device Data as 
defined in the Clinical Investigation Plan (CIP), device alerts, and 
diagnostic data from the standard Latitude database may be collected 
and entered into the study database at any time. 
Study Duration 
Enrolment is expected to take approximately 18 months. The total study 
duration with all follow-up data collected will take up to 50 months. 
Key Inclusion 
Criteria 
General Inclusion Criteria: 
1. 
Subject is aged 20 or above 
2. 
Subject is willing and capable of providing informed consent 
3. 
Subject is willing and capable of participating in all visits associated 
with this study at an approved clinical study site and at the intervals 
defined by this CIP 
4. 
Measured Ejection fraction value obtained  by echocardiography or 
equivalent method as SOC: 
• Device cohorts: within the last 3 months prior to enrolment 
• Non-device cohort: latest available within the last 12 months 
prior to enrollment in case there was no documented HF 
decompensation, MI or revascularization, otherwise within the 
last 3 months prior to enrollment  
 
And 12 lead ECG recording available as SOC: 
• Device cohorts: pre-implant ECG maximum 45 days before 
implant; post-implant ECG 
• Non-device cohort: latest available maximum 12 months prior 
to enrollment 
 
and subject agrees in the data being used for this study 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 10 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 11 of 100 
  
Heart Failure Indication and Sudden Cardiac Death Prevention Trial Japan 
HINODE 
 
Key Inclusion 
Criteria 
Additional Inclusion Criteria for the ICD Cohort: 
1. 
De novo ICD system implanted successfully 45 days prior 
enrollment in subjects with symptomatic HF (NYHA Class II–III), 
and an LVEF ≤35% 
2. 
Subjects are on OMT ≥3 months  
3. 
Provided that the subjects are expected to survive substantially 
longer than one year with good functional status 
4. 
Subjects 
have 
ischemic 
heart 
disease 
or 
DCM 
(dilated 
cardiomyopathy) 
5. 
Subject was implanted with a BSC MRI Conditional System 
6. 
2 to 5 risk factors out of the following prior device implant: 
• LVEF ≤35% 
• NYHA Class III or IV 
• Left bundle branch block (LBBB) with QRS >130 ms or any 
QRS >150 ms 
• Renal dysfunction (blood urea nitrogen chronically [BUN] 
>26 mg/dL / ≥9.28 mmol/L) 
• Diabetes type I and II 
• Chronic atrial fibrillation (permanent or persistent according to 
ESC Guideline 201611) 
• Prior MI 
• Age >70 years 
• Smoking today or during last 5 years 
7. 
Clinical subject conditions allow programming of defibrillation 
therapy according to the principals of the MADIT RIT study 
programming 
8. 
Subjects’ devices are currently intended to be followed on Latitude 
system. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 11 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 12 of 100 
  
Heart Failure Indication and Sudden Cardiac Death Prevention Trial Japan 
HINODE 
 
Key Inclusion 
Criteria 
(continued) 
Additional Inclusion Criteria for the CRT-D Cohort: 
1. De novo CRT-D (BSC device system with IS4 connector and MRI 
conditionally safe) implanted successfully during the last 45 days 
prior enrollment in symptomatic subjects with HF 
2. A:  Sinus rhythm and one of the following conditions: 
• QRS duration ≥150 ms and LBBB QRS morphology and 
with LVEF ≤35% despite OMT 
• QRS duration ≥150 ms and non-LBBB QRS morphology 
and with LVEF ≤35% despite OMT 
• QRS duration of 130 to 149 ms and LBBB QRS morphology 
and with LVEF ≤35% despite OMT 
or 
B: CRT-D implanted subjects in atrial fibrillation with LVEF 
≤35% in NYHA Class III despite OMT and a QRS duration 
≥130 ms 
3. Subjects have 2 to 5 risk factors out of the following prior to device 
implant: 
• LVEF ≤35% 
• NYHA Class III or IV 
• LBBB with QRS >130 ms or any QRS >150 ms 
• Renal dysfunction (chronically BUN >26 mg/dL / ≥9.28 
mmol/L) 
• Diabetes type I and II 
• Chronic atrial fibrillation (permanent or persistent according to 
ESC Guideline 201611) 
• Prior MI 
• Age >70 years 
• Smoking today or during last 5 years 
4. Defibrillator therapy will be programmed following MADIT RIT 
study programming principles (e.g. cutoff rate ≥ 200 bpm or 170 
bpm with 60 seconds delayed therapy programming) 
5. Subjects’ devices are currently intended to be followed on Latitude 
system. 
Additional Inclusion Criteria for the PM/CRT-P Cohort: 
1. Subjects with a PM or CRT-P implanted during last 45 days prior 
enrollment (only BSC PG devices). 
2. Subjects who are estimated to require right ventricle (RV) 
pacing >40% 
3. PM subjects with LVEF ≤50% 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 12 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 13 of 100 
  
Heart Failure Indication and Sudden Cardiac Death Prevention Trial Japan 
HINODE 
 
Key Inclusion 
Criteria 
(continued) 
4. Paced or intrinsic QRS >90 ms, and any determined NYHA Class 
(symptoms of HF) or any previous HF admission (HF admission 
comprises the following conditions: admission to hospital because of 
HF and/or IV therapy for HF and/or upgrade of the PM/CRT-P) 
5. Subjects’ devices are currently intended to be followed on Latitude 
system. 
Additional Inclusion Criteria for the Non-device Cohort (ESC Guideline 
2016 Indicated but not implanted) 
• Subjects with symptomatic HF (NYHA Class II-III), and an 
LVEF ≤35% 
• Subjects are  on OMT ≥3 months  
• Subjects are expected to survive substantially longer than 1 year 
with good functional status 
• Subjects have ischemic heart disease or DCM (dilated 
cardiomyopathy). 
OR 
• LBBB with QRS ≥130 ms and LVEF ≤35% despite OMT  
 
or 
• QRS ≥150 ms and non-LBBB QRS morphology and LVEF 
≤35% despite OMT  
AND 
1. No present or past implanted device ICD, CRT-D, PM, or 
CRT-P 
2. 2 to 5 risk factors out of the following: 
• LVEF ≤35%  
• NYHA Class III or IV 
• LBBB with QRS > 130 ms or any QRS >150 ms 
• Renal dysfunction 
(chronically BUN >26 mg/dL / ≥9.28 mmol/L) 
• Diabetes type I and II 
• Chronic atrial fibrillation (permanent or persistent according 
to ESC Guideline 201611) 
• Prior MI 
• Age >70 years 
• Smoking today or during last 5 years 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 13 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 14 of 100 
  
Heart Failure Indication and Sudden Cardiac Death Prevention Trial Japan 
HINODE 
 
Key Exclusion 
Criteria 
General Exclusion Criteria: 
1. Subject is enrolled in any other concurrent study without prior 
written approval from BSC, with the exception of local mandatory 
governmental registries and observational studies/registries that are 
not in conflict and do not affect the following: 
• Schedule of procedures for the HINODE Study (i.e. should not 
cause additional or missed visits) 
• HINODE Study outcome 
• Conduct of the HINODE Study per Good Clinical Practice 
/International 
Standard 
Organization 
14155:2011/local 
regulations as applicable 
2. Device implant revision is scheduled due to unstable result of an 
implant <45 days prior enrolment 
3. Subjects with more than 5 of the following risk factors: 
LVEF <35%, NYHA Class III or IV, LBBB with QRS > 130 ms or 
QRS ≥150 ms, renal dysfunction (chronically BUN >26 mg/dL / 
≥9.28 mmol/L), diabetes type I and II, chronic atrial fibrillation 
(permanent or persistent according to ESC Guideline 2016), prior 
MI, age >70 years, smoking today or during last 5 years 
4. Subjects with chronic renal disease with chronic BUN ≥50mg/dL or 
creatinine ≥2.5 mg/dL 
5. Subjects with coronary artery bypass graft (CABG) surgery or 
percutaneous coronary intervention (PCI) within the past three 
calendar months prior to enrollment 
6. Subjects with enzyme-positive myocardial infarction within the past 
three calendar months prior to enrollment 
7. Subjects who are expected to survive for <1 year with good 
functional status 
8. Subject’s physician does not allow participation 
9. Subject is not willing and capable of participating in all testing or 
visits associated with this clinical study at an approved clinical 
study center and at the intervals defined by this CIP 
10. Unwilling to sign the consent for participation 
11. Women of childbearing potential who are or might be pregnant at 
the time of study enrolment 
12. ICD and CRT-D cohorts: implanted with a non-BSC device system. 
PM/CRT-P cohorts: implanted with a non-BSC PG device. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 14 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 15 of 100 
  
Heart Failure Indication and Sudden Cardiac Death Prevention Trial Japan 
HINODE 
 
Key Exclusion 
Criteria 
(continued) 
Additional Exclusion Criteria for the ICD and CRT-D Cohorts: 
1. CRT implanted in subjects with a QRS duration <130 ms 
2. Subjects who have recovered from a ventricular arrhythmia causing 
hemodynamic instability.  
3. NYHA Class IV (for ICD subjects only) 
4. Existing or previously implanted ICD, CRT-P, CRT-D, or 
pacemaker device system. 
Additional Exclusion Criteria for the PM/CRT-P Cohort: 
No additional Exclusion Criteria for the PM/CRT-P Cohort. 
Additional Exclusion Criteria for the Non-device Cohort (ESC Guideline 
2016 Indicated but not implanted): 
1. Subjects who have recovered from a ventricular arrhythmia causing 
hemodynamic instability 
2. Any ICD or CRT-D, PM or CRT-P device implanted at any time 
prior to enrollment. 
Statistical Methods  
Primary 
Statistical 
Hypothesis 
ICD Treated Subjects: 
Ventricular arrhythmia associated symptoms free-rate from implant 
through 12 months post implant is greater than the pre-specified 
performance goal of 85.0% 
Ho: π ≤85.0% 
HA: π >85.0% 
CRT-D Treated Subjects: 
Ventricular arrhythmia associated symptoms free-rate from implant 
through 12 months post implant is greater than the pre-specified 
performance goal of 87.0% 
Ho: π ≤87.0% 
HA: π >87.0% 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 15 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 16 of 100 
  
Heart Failure Indication and Sudden Cardiac Death Prevention Trial Japan 
HINODE 
 
Primary 
Statistical 
Hypothesis 
(continued) 
PM/CRT-P Treated Subjects: 
All-cause mortality free-rate (survival rate) from implant through 
12 months post implant is greater than the pre-specified performance goal 
of 80.0% 
Ho : π ≤80.0% 
HA : π >80.0% 
Non-device Subjects (ESC Guideline 2016 Indicated but not implanted) 
All-cause mortality free-rate (survival rate) from enrolment through 
12 months after enrolment is greater than the pre-specified performance 
goal of 80.0% 
Ho: π ≤80.0% 
HA: π >80.0% 
Statistical Test 
Method 
Sample Size Methodology: 
• Sample size for each primary endpoint was calculated using exact 
binomial methods for comparison of a single proportion to a 
performance goal. 
 
Analysis Methods: 
• For ICD treated subjects, the ventricular arrhythmia associated 
symptoms free-rate from implant will be calculated as the proportion 
of actively enrolled subjects without an appropriately treated 
ventricular arrhythmia associated symptom through 12 months after 
implant. The null hypothesis will be rejected and the endpoint 
considered met if the lower one-sided 97.5% confidence bound for 
the proportion of subjects with no appropriately treated ventricular 
arrhythmia associated symptoms is greater than 85.0%. 
• For CRT-D treated subjects, the ventricular arrhythmia associated 
symptoms free-rate from implant will be calculated as the proportion 
of actively enrolled subjects without an appropriately treated 
ventricular arrhythmia associated symptom through 12 months after 
implant. The null hypothesis will be rejected and the endpoint 
considered met if the lower one-sided 97.5% confidence bound for 
the proportion of subjects with no appropriately treated ventricular 
arrhythmia associated symptoms is greater than 87.0%. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 16 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 17 of 100 
  
Heart Failure Indication and Sudden Cardiac Death Prevention Trial Japan 
HINODE 
 
Statistical Test 
Method 
(continued) 
• The primary endpoints above will be performed for ICD and CRT-D 
cohorts combined (primary analysis) as well as for ICD and CRT-D 
treated subjects separately (for descriptive purpose). 
• For PM/CRT-P treated subjects, the all-cause mortality free-rate 
(survival rate) from implant will be calculated as the proportion of 
actively enrolled subjects who are alive 12 months after implant. The 
null hypothesis will be rejected and the endpoint considered met if 
the lower one-sided 97.5% confidence bound for the proportion of 
subjects with no death is greater than 80.0%. 
• For Non-device subjects (ESC Guideline 2016 Indicated but not 
implanted), the all-cause mortality free-rate (survival rate) from 
enrolment will be calculated as the proportion of actively enrolled 
subjects who are alive 12 months after enrolment. The null 
hypothesis will be rejected and the endpoint considered met if the 
lower one-sided 97.5% confidence bound for the proportion of 
subjects with no death is greater than 80.0%. 
 
• Exploratory analyses for ICD and CRT-D Cohorts combined versus 
Non-Device Cohort (ESC Guideline 2016 Indicated but not 
implanted): propensity score matching comparison of all-cause 
mortality rate and composite rate of HF events between pooled 
cohorts with device (ICD and CRT-D) versus the Non-Device 
Cohort regarding 7 risk factors at baseline (NYHA Class III or IV, 
renal dysfunction [chronically BUN >26 mg/dL / ≥9.28 mmol/L], 
diabetes type I and II, chronic atrial fibrillation [permanent or 
persisting according to ESC Guideline 2016], prior MI, age >70 
years, smoking today or during last 5 years). 
Further details on analytical methods can be found in Section 12 of the 
CIP 
Sample Size 
Parameters 
ICD Treated Subjects: 
The minimum required sample size to statistically power the ventricular 
arrhythmia associated symptoms free-rate through 12 months post 
implant is 117 subjects. Sample size was calculated assuming a 95.0% 
ventricular arrhythmia associated symptoms free-rate, a performance goal 
of 85.0%, one-sided alpha level of 0.025, 90% power, and 20% attrition. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 17 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 18 of 100 
  
Heart Failure Indication and Sudden Cardiac Death Prevention Trial Japan 
HINODE 
 
Sample Size 
Parameters 
(continued) 
Although the final sample size of 117-270 for ICD treated subjects is 
higher than that required to power the primary endpoint, a sample size of 
up to 270 ensures that there will be a sufficient number of subjects to 
evaluate the primary endpoint, as well as provide ample data to 
characterize the safety, performance and efficacy profiles based on 
secondary and additional endpoints.  
CRT-D Treated Subjects: 
The minimum required sample size to statistically power the ventricular 
arrhythmia associated symptoms free-rate through 12 months post 
implant is 95 subjects. Sample size was calculated assuming a 97.0% 
ventricular arrhythmia associated symptoms free-rate, a performance goal 
of 87.0%, one-sided alpha level of 0.025, 90% power, and 20% attrition. 
Although the final adjustable sample size of 95-250 for CRT-D  treated 
subjects  is higher than that required to power the primary endpoint of the 
study arm, a sample size of up to 250 ensures that there will be a 
sufficient number of subjects to evaluate the primary endpoint, as well as 
provide ample data in the study arm to characterize the safety, 
performance and efficacy profiles based on secondary and additional 
endpoints. 
PM/CRT-P Treated Subjects: 
The minimum required sample size to statistically power the all-cause 
mortality free-rate (survival rate) through 12 months post implant is 
172 subjects. Sample size was calculated assuming a 90.0% all-cause 
mortality free-rate (survival rate), a performance goal of 80.0%, 
one-sided alpha level of 0.025, 90% power, and 20% attrition. 
Although the final sample size of 200 for PM/CRT-P treated subjects is 
higher than that required to power the primary endpoint, a sample size of 
200 ensures that there will be a sufficient number of subjects to evaluate 
the primary endpoint, as well as provide ample data to characterize the 
safety, performance and efficacy profiles based on secondary and 
additional endpoints.  
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 18 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 19 of 100 
  
Heart Failure Indication and Sudden Cardiac Death Prevention Trial Japan 
HINODE 
 
Sample Size 
Parameters 
(continued) 
Non-device Subjects (ESC Guideline 2016 Indicated but not implanted): 
The minimum required sample size to statistically power the all-cause 
mortality free-rate (survival rate) through 12 months after enrolment is 
172 subjects. Sample size was calculated assuming a 90.0% all-cause 
mortality free-rate, a performance goal of 80.0%, one-sided alpha level of 
0.025, 90% power, and 20% attrition. 
The final sample size of 300 for Non-device subjects is higher than that 
required to power the primary endpoint in order to ensure that there will 
be a sufficient number of subjects to compare the rate of sudden cardiac 
death in the non-device cohort with the rate of appropriately treated 
ventricular arrhythmias or sudden cardiac death in the defibrillator cohort 
(ICD, CRT-D).  
In case of low enrollment rates, enrollment may be closed after the 
statistically required calculated minimum sample size for each cohort. 
 
 
 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 19 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 20 of 100 
  
3. Table of Contents 
1. 
TITLE PAGE  ........................................................................................................................ 1 
2. 
SYNOPSIS ............................................................................................................................. 6 
3. 
TABLE OF CONTENTS ........................................................................................................ 20 
3.1. Table of Figures ...................................................................................................... 25 
3.2. Table of Tables ....................................................................................................... 25 
4. 
INTRODUCTION ................................................................................................................. 26 
5. 
DEVICE DESCRIPTION ....................................................................................................... 27 
6. 
STUDY OBJECTIVES .......................................................................................................... 28 
7. 
STUDY ENDPOINTS ............................................................................................................ 29 
7.1. Primary Endpoints ................................................................................................. 29 
7.2. Secondary Endpoints ............................................................................................. 29 
7.3. Additional Endpoints ............................................................................................. 30 
8. 
STUDY DESIGN .................................................................................................................. 30 
8.1. Scale and Duration ................................................................................................. 31 
8.2. Treatment Assignment .......................................................................................... 33 
8.3. Justification for the Study Design ......................................................................... 33 
9. 
SUBJECT SELECTION ......................................................................................................... 33 
9.1. Study Population and Eligibility ........................................................................... 33 
9.2. Inclusion Criteria ................................................................................................... 33 
9.2.1. 
General Inclusion Criteria .......................................................................... 34 
9.2.2. 
Inclusion Criteria for the ICD Cohort ........................................................ 35 
9.2.3. 
Inclusion Criteria for the CRT-D Cohort ................................................... 36 
9.2.4. 
Inclusion Criteria for the PM/CRT-P Cohort ............................................ 37 
9.2.5. 
Inclusion Criteria for the Non-device Cohort (ESC Guideline 2016 
Indicated but not implanted) ...................................................................... 38 
9.3. Exclusion Criteria .................................................................................................. 39 
9.3.1. 
General Exclusion Criteria ........................................................................ 39 
9.3.2. 
Exclusion Criteria for the ICD and CRT-D Cohorts ................................. 41 
9.3.3. 
Exclusion Criteria for the PM/CRT-P Cohort ........................................... 41 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 20 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 21 of 100 
  
9.3.4. 
Exclusion Criteria for the Non-device Cohort (ESC Guideline 2016 
Indicated but not implanted) ...................................................................... 41 
10. SUBJECT ACCOUNTABILITY .............................................................................................. 41 
10.1. Point of Enrolment ................................................................................................. 41 
10.2. Withdrawal ............................................................................................................. 42 
10.3. Subject Status and Classification .......................................................................... 42 
10.4. Enrolment Controls ............................................................................................... 43 
11. STUDY METHODS .............................................................................................................. 43 
11.1. Data Collection ....................................................................................................... 43 
11.2. Study Candidate Screening ................................................................................... 47 
11.3. Informed Consent .................................................................................................. 47 
11.4. Enrolment and Consenting Visit (Day 0, 0 to 45 days post implant procedure, 
alternative >90 days post MI) ............................................................................... 47 
11.5. Six-monthly Visit .................................................................................................... 52 
11.6. Re-implant, Device System Revision, Device Upgrades, or New Device 
Implant post Enrolment ........................................................................................ 53 
11.7. Interim or Unscheduled Visit and Event Report (SAE/SADE related clinical 
care visit) ................................................................................................................. 53 
11.8. Close-out Visit ........................................................................................................ 54 
11.9. Source Documents .................................................................................................. 55 
12. STATISTICAL CONSIDERATIONS ....................................................................................... 56 
12.1. Endpoints ................................................................................................................ 56 
12.1.1. Primary Endpoint for ICD Treated Subjects ............................................. 56 
12.1.1.1. Hypotheses ................................................................................ 56 
12.1.1.2. Statistical Methods .................................................................... 56 
12.1.2. Primary Endpoint for CRT-D Treated Subjects ........................................ 57 
12.1.2.1. Hypotheses ................................................................................ 57 
12.1.2.2. Statistical Methods .................................................................... 57 
12.1.3. Primary Endpoint for PM/CRT-P Treated Subjects .................................. 57 
12.1.3.1. Hypotheses ................................................................................ 58 
12.1.3.2. Statistical Methods .................................................................... 58 
12.1.4. Primary Endpoint for Non-device Subjects (ESC Guideline 2016 
Indicated but not implanted) ...................................................................... 58 
12.1.4.1. Hypotheses ................................................................................ 58 
12.1.4.2. Statistical Methods .................................................................... 59 
12.1.5. Secondary Endpoints ................................................................................. 59 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 21 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 22 of 100 
  
12.1.6. Sample Size ............................................................................................... 59 
12.2. General Statistical Methods .................................................................................. 61 
12.2.1. Analysis Sets .............................................................................................. 61 
12.2.2. Number of Subjects per Investigative Site ................................................ 61 
12.2.3. Descriptive Statistical Methods ................................................................. 61 
12.3. Data Analyses ......................................................................................................... 61 
12.3.1. Other Endpoints/Measurements ................................................................. 62 
12.3.2. Interim Analyses ........................................................................................ 62 
12.3.3. Subgroup Analyses .................................................................................... 62 
12.3.4. Justification of Pooling .............................................................................. 63 
12.3.5. Multivariable Analyses .............................................................................. 63 
12.3.6. Other Analyses ........................................................................................... 63 
12.3.7. Changes to Planned Analyses .................................................................... 63 
13. DATA MANAGEMENT ........................................................................................................ 63 
13.1. Data Collection, Processing, and Review ............................................................. 63 
13.2. Data Retention ........................................................................................................ 64 
13.3. Core Laboratories .................................................................................................. 64 
14. AMENDMENTS ................................................................................................................... 64 
15. DEVIATIONS ...................................................................................................................... 65 
16. DEVICE/EQUIPMENT ACCOUNTABILITY .......................................................................... 65 
17. COMPLIANCE ..................................................................................................................... 65 
17.1. Statement of Compliance ....................................................................................... 65 
17.2. Investigator Responsibilities ................................................................................. 65 
17.2.1. Delegation of Responsibility ..................................................................... 67 
17.3. Institutional Review Board/ Ethics Committee ................................................... 67 
17.4. Sponsor Responsibilities ........................................................................................ 67 
17.4.1. Role of Boston Scientific Representatives ................................................ 68 
17.5. Insurance ................................................................................................................. 69 
18. MONITORING ..................................................................................................................... 69 
19. POTENTIAL RISKS AND BENEFITS .................................................................................... 69 
19.1. Risks Associated with Participation in the Clinical Study ................................. 69 
19.2. Anticipated Benefits ............................................................................................... 69 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 22 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 23 of 100 
  
19.3. Risk to Benefit Rationale ....................................................................................... 69 
20. SAFETY REPORTING .......................................................................................................... 70 
20.1. Reportable Events by investigational site to Boston Scientific .......................... 70 
20.2. Definitions and Classification ............................................................................... 71 
20.3. Relationship to Devices or Procedure .................................................................. 73 
20.4. Investigator Reporting Requirements .................................................................. 74 
20.5. Boston Scientific Device Deficiencies .................................................................... 76 
20.6. Reporting to Regulatory Authorities / ECs / Investigators ................................ 76 
20.7. Subject Death Reporting ....................................................................................... 76 
20.8. Subject Death Classification ................................................................................. 77 
21. INFORMED CONSENT ......................................................................................................... 79 
22. COMMITTEES .................................................................................................................... 80 
22.1. Safety Monitoring Process ..................................................................................... 80 
22.2. Event Committee .................................................................................................... 81 
22.3. ECG experts ............................................................................................................ 81 
23. SUSPENSION OR TERMINATION ......................................................................................... 81 
23.1 Premature Termination of the Study ................................................................... 81 
23.1.1 
Criteria for Premature Termination of the Study ....................................... 81 
23.2 Termination of Study Participation by the Investigator or Withdrawal of EC 
Approval ................................................................................................................. 81 
23.3 Requirements for Documentation and Subject Follow-up ................................. 81 
23.4 Criteria for Suspending/Terminating a Study Site ............................................. 82 
24. PUBLICATION POLICY ....................................................................................................... 82 
25. BIBLIOGRAPHY .................................................................................................................. 83 
26. ABBREVIATIONS AND DEFINITIONS .................................................................................. 84 
26.1. Abbreviations ......................................................................................................... 84 
26.2. Definitions ............................................................................................................... 86 
27. APPENDICES ...................................................................................................................... 90 
27.1. Clinical Trial Organization ................................................................................... 90 
27.2. NYHA Classification .............................................................................................. 91 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 23 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 24 of 100 
  
27.3. ESC Guidelines 2016: Patterns of Atrial Fibrillation ......................................... 92 
27.4. Classification of LVEF ........................................................................................... 93 
27.5. ESC Guidelines 2016: Recommendations for cardiac resynchronization 
therapy implantation in patients with heart failure ........................................... 94 
27.6. Declaration of Helsinki .......................................................................................... 95 
 
 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 24 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 25 of 100 
  
 
3.1. Table of Figures 
Figure 3.2-1: HINODE Sample Size ...................................................................................... 29 
Figure 8.1-1: HINODE Study Design ..................................................................................... 32 
 
3.2. Table of Tables 
Table 8.2-1: General Inclusion Criteria .................................................................................. 34 
Table 8.2-2: Inclusion Criteria for the ICD Cohort ................................................................ 35 
Table 8.2-3: Inclusion Criteria for the CRT-D Cohort ........................................................... 36 
Table 8.2-4: Inclusion Criteria for the PM/CRT-P Cohort ..................................................... 37 
Table 8.2-5: Inclusion Criteria for the Non-device Cohort (ESC Guideline 2016 Indicated but 
not implanted) .................................................................................................. 38 
Table 8.3-1: General Exclusion Criteria ................................................................................. 40 
Table 8.3-2: Exclusion Criteria for the ICD and CRT-D Cohorts .......................................... 41 
Table 8.3-3: Exclusion Criteria for the Non-device Cohort (ESC Guideline 2016 Indicated 
but not implanted) ............................................................................................ 41 
Table 10.1-1: Data Collection Requirements .......................................................................... 45 
Table 10.4-1: Programming Requirements for High Rate Cutoff .......................................... 49 
Table 10.4-2: Programming Requirements for Long Delay ................................................... 49 
Table 10.4-3: ICD Programming Option 3 (if applicable for a specific device) .................... 50 
Table 10.9-1: Source Documentation Requirements .............................................................. 55 
Table 11.1-1: Endpoint Sample Size Estimates ...................................................................... 60 
Table 19.2-1: Safety Definitions ............................................................................................. 71 
Table 19.3-1: Criteria for Assessing Relationship of Study Device or Procedure to Adverse 
Event................................................................................................................. 73 
Table 19.4-1: Investigator Reporting Requirements ............................................................... 74 
Table 25.1-1: Abbreviations ................................................................................................... 84 
Table 25.2-1: Definitions ........................................................................................................ 86 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 25 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 26 of 100 
  
4. Introduction 
The prevalence of chronic heart failure (CHF) will rapidly increase in the next decades in 
many industrialized countries, including Japan1. Large cohort studies with CHF patients are 
useful for risk stratification and determination of preventive measures for the disorder. 
Large-scale, randomized treatment trials also are needed, especially in Japan, in order to 
obtain further evidence on prevention of sudden cardiac death (SCD) with defibrillation 
therapy2 and to improve the management of patients with CHF. 
The present study is intended to evaluate the risk of SCD and heart failure (HF) events in 
known high risk subject cohorts. Implantation of pacing and defibrillation devices that 
provide cardiac resynchronization therapy (CRT) is proven to be a highly effective treatment 
for selected subjects with cardiac arrhythmia and HF. However, the question remains 
whether study data from the United States (US) and Europe are fully applicable in Japan 
despite genetic and cultural differences. Implantable cardioverter-defibrillator (ICD) and 
cardiac resynchronization therapy-defibrillator (CRT-D) devices for many patients with high 
risk on SCD have not been studied in a prospective study in Japan. Therefore, this registry 
study intends to collect clinical data in defined ICD and CRT-D treatment cohorts in a study 
population with a majority of Japanese subjects so that further knowledge is added to 
improve medical device treatment options.  
An optimized ICD treatment was studied in the Automatic Defibrillator Implantation Trial 
(MADIT) Reduce Inappropriate Therapy (RIT) trial3,4 where 1500 subjects from US and 
Europe have been enrolled in 3 arms. Arm B and Arm C, with a high cut off rate of 
>200 bpm and with a prolonged delay in therapy at 170 bpm have shown a significant 
reduction in unnecessary and inappropriate treatment.4 
The mortality rate in pacemaker cohorts is usually very high and it is the question whether a 
different device therapy may help selected patient cohorts. The defined cohort in this 
HINODE study is selecting especially subjects with a heart failure background which have a 
high incidence of further progression of the disease.6 It is the question whether those subjects 
can be identified during de novo implants or during device replacement so that a different 
device therapy would have the potential to impact the progression of the disease. The 
selected cohort has at least 3 risk factors which may lead to an increased incidence of Non-
sustained ventricular tachycardia (NSVT) or other ventricular arrhythmia. The use of a risk 
score in a PM population may help to identify subjects who may benefit from CRT-P or 
CRT-D. 
The outlined risk factor MI in the HINODE study is used for subjects with one or more 
clinically documented, enzyme-positive myocardial infarctions, or clear evidence of 
pathologic Q waves or generally accepted imaging techniques. 
The rate of appropriate first treatments (anti-tachycardia pacing [ATP] or shock) will be 
considered as treatment of potential life-threatening arrhythmias. The present study will use 
the MADIT RIT ICD programming for ICD and CRT-D devices and will compare the rate of 
appropriate treatments in MADIT RIT4 with the rate observed under the same programming 
conditions in the present study. The study results will be compared with data from 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 26 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 27 of 100 
  
multicenter automatic defibrillator implantation trials (MADITs) conducted in US and 
Europe. 
In addition to the evaluation of first appropriate treatment, life-threatening ventricular 
arrhythmias, clinical HF events will be evaluated. 
Special attention will be given to known risk markers at enrolment throughout the study so 
that a risk score may be developed to provide guidance in optimized therapy decisions. 
The sample size will provide sufficient data to allow the identification of high risk 
subgroups, especially in the ICD and pacemaker (PM) cohorts. These data will also allow an 
assessment of European and US study data being transferable to the Japanese specific 
environment due to similar clinical observations. 
The selected cohort of PM subjects has an expected and unstudied elevated risk of 
developing increased HF symptoms or may be at risk of SCD. The required home monitoring 
system will allow early detection of ventricular arrhythmias and may serve as early indicator 
for left ventricular ejection fraction (LVEF) and QRS evaluation. The same LVEF and QRS 
evaluations will be associated with HF admissions (‘HF admission’ comprises the following 
conditions: admission to hospital because of HF and/or intravenous (IV) therapy of HF 
and/or upgrade of the PM/CRT-P) so that an unknown need for changed device therapy can 
be identified. CRT is recommended for subjects with HF with reduced ejection fraction 
(HFrEF; LVEF: <40%) and QRS >130 ms; ICD therapy is recommended for subjects with 
LVEF ≤35% especially if this is associated with additional risk factors e.g. prior MI, diabetes 
type I and II, etc. 
In large European registries and European diabetes guidelines, it has been described that 
diabetic post myocardial infarction (MI) patients with a mid-range LVEF of 40-49% 
(HFmrEF) have an elevated risk of SCD. Since there are no event data available for Japanese 
patients, this registry will also include a group of subjects who have combined risk factors of 
post MI, diabetes type I and II, and an LVEF ≤35% but have not received device treatment to 
collect baseline data on event rates and disease progression in a study population with a 
majority of Japanese subjects. 
5. Device Description 
Implanted subjects will receive one of 4 types of Boston Scientific (BSC) devices prior to 
enrolment in the study: 
1. ICD (only MRI conditionally safe systems) + Latitude 
2. CRT-D (IS4 connector only, MRI conditionally safe systems) + Latitude 
3. PM + Latitude 
or 
4. CRT-pacemaker (CRT-P) + Latitude 
All device systems are on the market in Japan, and will be implanted per standard of care 
(SOC) and BSC Instructions for Use (IFU) for the respective devices should be followed. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 27 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 28 of 100 
  
Neither the devices nor the implant procedure are part of this study. The decision as to which 
device any subject receives is to be determined by the investigator and is not part of this 
study. 
Device system use will need to follow SOC, devices IFUs and must follow CIP programming 
requirements. 
The programming of the devices is to be documented in the subject’s electronic Case Report 
Form (eCRF) as part of the enrolment criteria (Section 9). As part of the programming, all 
subjects must be intended to be connected to the Latitude system. 
If patients cannot be connected to Latitude more than 6 months after enrolment, a deviation 
needs to be completed and a reason needs to be given. In addition, endpoint related data can 
be uploaded into the database by the site (e.g. electrogram (EGM) for ventricular 
arrhythmias). 
A device deficiency reporting might need to be completed. 
6. Study Objectives 
The purpose of this cohort therapy study is to collect clinical event and outcome data in a 
study population with a majority of Japanese subjects on SCD, HF events, and appropriately 
treated ventricular adverse events in predefined subject cohorts. These event rates will be 
compared with available data mainly from Europe and the United States. It is the intention to 
add evidence in Defibrillator treatment and treatment with CRT-D devices. 
Selected Subject Cohorts: 
1. Selected subject cohort with of criteria for SCD (without spontaneous prior 
ventricular sustained arrhythmia) and de novo implanted Defibrillator device 
treatment (ICD). 
2. Selected subject cohort with criteria for SCD and widely accepted standard CRT 
indication who received a de novo implanted CRT-D device treatment. 
3. Selected subject cohort who are clinically expected to require >40% right ventricular 
pacing with an LVEF ≤50%, any determined New York Heart Association (NYHA) 
Class, and receiving PM or CRT-P therapy despite previous device history (de novo, 
box changes, system revisions or upgrades). 
4. Selected subject cohort with criteria for SCD fulfilling European Society of 
Cardiology (ESC) ICD or CRT-D therapy guidelines (2016) with an LVEF ≤35%, 
having 2 to 5 predefined risk factors but do not have or have had a cardiac implanted 
device ICD, CRT-D, PM, or CRT-P. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 28 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 29 of 100 
  
Figure 3.2-1: HINODE Sample Size 
 
 
7. Study Endpoints 
7.1. Primary Endpoints 
Defibrillator Cohort (including ICD and CRT-D Cohorts): 
• Composite rate of first appropriately treated ventricular arrhythmia (by ATP or shock) or 
life-threatening symptoms associated to ventricular arrhythmia (defined as hemodynamic 
instability which requires treatment), whichever comes first under MADIT Arm B or C 
programming conditions in a study population with a majority of Japanese subjects  
PM/CRT-P Cohort: 
• All-cause mortality in subjects with a maximum of 3 risk factors (analyzed for MADIT II 
data7) 
Non-device Cohort (ESC Guideline 2016 Indicated but not implanted subjects): 
• All-cause mortality in the subject cohort with 2 to 5 predefined SCD driving risk factors 
7.2. Secondary Endpoints 
• All-cause mortality rate for subjects implanted with ICD/CRT-D (= ICD cohort plus 
CRT-D cohort = defibrillator cohort) 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 29 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 30 of 100 
  
• Composite rate of HF events in ICD, CRT-D, and PM/CRT-P cohorts, which require 
IV treatment, HF related hospitalization, or led to HF death 
• Therapeutic sustainability at 1 year in ICD, CRT-D, and PM/CRT-P cohorts, defined as 
free of qualified serious adverse device events (SADEs) post successful implantation in 
comparison to data from MADIT CRT, MADIT RIT, Optimind and Rally X4 studies 
Examples for qualified SADEs: re-implant procedure, required invasive procedure related 
to the device system, pacing exit block, all-cause infection, and death due to therapy 
failure. 
• Comparison of rate of sudden cardiac death in the non-device cohort with the rate of 
appropriately treated ventricular arrhythmias or sudden cardiac death in subjects 
implanted with ICD-CRT-D (defibrillator cohort) 
7.3. Additional Endpoints 
The ancillary assessments will include: 
• Subject medical assessment collected pre-enrolment (post implant) and at Close-out: 
o NYHA functional classification 
o LVEF 
o QRS duration 
o Physician’s judgment on therapy outcome 
o Body mass index (BMI) 
o Diabetes mellitus type I and II 
• Cross-over in device therapies 
• Cause of death (SCD, Cardiac related, other reasons, unknown) 
• Incidence and development of Atrial fibrillation in different patient cohorts during the 
cause of the study 
• Impact of gender and age 
• Magnetic resonance imaging (MRI) observations in association with reported clinical 
events 
• Analysis of device data coming from Latitude data reports 
• Health care utilization under Latitude 
• Standard biomarkers for heart failure and other morbidities 
8. Study Design 
This is a prospective, non-randomized, multicenter, multi-cohort clinical outcome registry 
study to evaluate SOC. Neither the devices nor the implant procedure are part of this study. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 30 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 31 of 100 
  
Subjects will be implanted with the device per SOC within 0 to 45 days prior to enrolment in 
this study. 
The decision as to which subject gets which device is made by the implanting physician and 
is not part of this study. In addition, subjects with specified risk factors (Section 9.2.5) and 
with no device will also be enrolled. 
Devices must be programmed (considered a non-invasive procedure and SOC operation of 
the device) per protocol and according to the respective BSC IFU, and must be connected to 
the Latitude system for the duration of the trial. If this is not possible, a deviation will be 
recorded. 
The Latitude database will be reviewed by the BSC Latitude team on regular basis for all 
study subjects and inconsistencies will be discussed with the study data management. 
8.1. Scale and Duration 
As soon as a minimum of 556  eligible subjects are entered into the study database, the 
closure of enrolment can begin. After closure of enrolment, sites must obtain approval from 
the sponsor or the sponsor’s delegated representative for all remaining subjects who are 
consented but who are not yet enrolled into the study database. The maximum number of 
followed study subjects is 950. Since this is an event dependent analysis, the total number of 
subjects might be considerably lowered in all different cohorts, depending on actual number 
of events. It would allow for an early closure of the study enrollment. 
Approximately 40 investigational sites in Japan will be included. If a site does not enroll a 
sub 
ject within a 3-month time period, the site may be closed for enrolment and replaced at the 
discretion of the sponsor. 
Enrolment is expected to take approximately 18 months. The total study duration with all 
follow-up data collected will take up to 50 months. All subjects will remain in the study until 
the last subject completes his/her last visit. The maximum study duration for any subject will 
be 34 months (first subject first visit [FSFV] to last subject last visit [LSLV]); the minimum 
study duration will be the time of enrolment of the last subject enrolled (last subject first visit 
[LSFV] to LSLV) and is expected to be 16 months. Study completion and data analysis are 
anticipated in 2020. 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 31 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
Page 32 of 100 
  
Figure 8.1-1: HINODE Study Design 
 
TIME AXIS 
PERIOD OF ENROLMENT OF SUBJECTS 
1-YEAR FOLLOW-UP 
FOR ALL SUBJECTS 
ENROLLED  
CLOSE 
OUT 
VISIT 
 
6 months 
6 months 
6 months 
6 months 
6 months 
6 months 
 
 
 
 
 
 
 
 
 
FIRST  
SUBJECT 
Device implant or 
no device* 
EV  
Day 0 
1st  
6-monthly visit 
 
 
5th 
6-monthly visit 2 months 
before** 
LSLV 
until 
4 months 
LSLV 
 
 
 
 
 
 
 
FURTHER 
SUBJECTS 
Device implant or 
no device* 
EV  
Day 0 
1st 
6-monthly visit  
 
4th 
6-monthly visit 
 
 
 
FURTHER 
SUBJECTS 
 
Device implant or 
no device* 
EV 
Day 0 
1st  
3rd 
6-monthly visit 
 
 
 
  
LAST 
SUBJECT 
 
 
Device implant or 
no device* 
 
EV 
Day 0 
2nd 6-monthly 
visit 
= COV 
= LSLV ***  
 
* device is BSC device, either ICD or CRT-D or CRT-P or PM; no device = no device implanted, but indicated according to ESC 
Guideline 2016 
** if COV is done within 2 months before LSLV, the COV replaces the last 6-monthly visit 
*** LSLV will be conducted within 12 months + 60 days post enrollment 
 
Abbreviations: COV = Close out visit; EV = Enrolment visit; LSLV = last subject’s last visit 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 32 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
Page 33 of 100 
  
8.2. Treatment Assignment 
This is a non-randomized prospective registry study to collect clinical data in the real-life 
setting in Japan. Enrolled subjects will include those who have been implanted with BSC 
pacing or defibrillation devices as well as post MI subjects with preserved EF and no device 
treatment. Subjects will be assigned to one of the 3 following Subject Cohorts according to 
device implanted: 
1. ICD: 117 to 270 subjects 
2. CRT-D: 95 to 250 subjects 
3. PM/CRT-P: 172 to 200 subjects 
A fourth cohort of non-implanted subjects will also be enrolled: 
4. Non-device172 to 300 subjects  
(ESC Guideline 2016 Indicated but not implanted) 
8.3. Justification for the Study Design 
The primary objective of this study is to collect clinical event data for selected patient 
cohorts who are at risk of ventricular tachy-arrhythmias and HF events. In order to obtain 
“real world” data, the study inclusion/exclusion criteria and follow-up schedule have been 
written generally enough to allow for study site specific SOC which should accurately 
capture the clinical data in a “standard” clinical setting. Additionally, by requiring study sites 
to follow their specific SOC, risk to the subject is minimized because the treatment received 
by the subject will be similar to the treatment the subject would receive if not participating in 
the study. 
Requiring that all implanted devices be programmed per protocol and the respective BSC 
IFU, all devices must be intended to be connected to the Latitude system during study 
duration. 
The determination of sample size is provided in Section 12.1.6. 
9. Subject Selection 
9.1. Study Population and Eligibility 
Inclusion and exclusion criteria are listed in Sections 9.2 and 9.3 below. 
Subjects who are enrolled but later determined to not fulfil all inclusion and exclusion criteria 
at the time of enrolment will be considered to have incurred a Clinical Investigation Plan 
(CIP) deviation. These subjects will be withdrawn from the study immediately and will not 
be included in the planned data analysis. 
9.2. Inclusion Criteria 
All inclusion criteria apply only at the time of enrolment into the study. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 33 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
Page 34 of 100 
  
If a subject’s medical conditions change after inclusion into the study so that one or several 
of the general inclusion criteria and inclusion criteria of the pertinent cohort are no longer 
met, the subject remains in the study. 
If it turns out after enrolment into the study that one or several of the general inclusion 
criteria and inclusion criteria of the pertinent cohort were violated at the time of enrolment 
into the study, the study has to be ended in this subject. 
9.2.1. General Inclusion Criteria 
Subjects who meet all of the following criteria (Table 9.2-1) may be given consideration for 
inclusion in this clinical investigation, provided no exclusion criterion (see Section 9.3) is 
met. 
Table 9.2-1: General Inclusion Criteria 
1. Subject is aged 20 or above 
2. Subject is willing and capable of providing informed consent 
3. Subject is willing and capable of participating in all visits associated with this study 
at an approved clinical study site and at the intervals defined by this CIP 
4. Measured Ejection fraction value obtained by echocardiography or equivalent 
method as SOC: 
• Device cohorts: within the last 3 months prior to enrolment 
• Non-device cohort: latest available within the last 12 months prior to 
enrollment in case there was no documented HF decompensation, MI or 
revascularization, otherwise within the last 3 months prior to enrollment  
 
And 12 lead ECG recording available as SOC: 
• Device cohorts: pre-implant ECG maximum 45 days before implant; 
post-implant ECG 
• Non-device cohort: latest available maximum 12 months prior to 
enrollment 
 
and subject agrees in the data being used for this study. 
Abbreviations: CIP = Clinical Investigation Plan 
 
 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 34 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
Page 35 of 100 
  
9.2.2. Inclusion Criteria for the ICD Cohort 
Subjects enrolled in the ICD group must also meet all of the following inclusion criteria (in 
addition to the General Inclusion Criteria): 
Table 9.2-2: Inclusion Criteria for the ICD Cohort 
1. De novo ICD system implanted successfully 45 days prior enrollment in subjects with 
symptomatic HF (NYHA Class II–III), and an LVEF ≤35% 
2. Subjects are on OMT ≥3 months  
3. Provided that the subjects are expected to survive substantially longer than one year 
with good functional status 
4. Subjects have ischemic heart disease or DCM (dilated cardiomyopathy) 
5. Subject was implanted with a BSC MRI Conditional System 
6. Subjects have 2 to 5 risk factors out of the following prior device implant: 
• LVEF ≤35%  
• NYHA Class III or IV 
• Left bundle branch block (LBBB) with QRS >130 ms or any QRS >150 ms 
• Renal dysfunction (blood urea nitrogen chronically [BUN] >26 mg/dL) 
• Diabetes type I and II 
• Chronic atrial fibrillation (permanent or persistent according to ESC Guideline 
201611) 
• Prior MI 
• Age >70 years 
• Smoking today or during last 5 years 
7. Clinical subject conditions allow programming of defibrillation therapy according to 
the principals of the MADIT RIT study programming 
8. Subjects’ devices are currently intended to be followed on Latitude system 
Abbreviations: BSC = Boston Scientific; BUN = blood urea nitrogen; ESC = European Society of 
Cardiology; HF = heart failure; ICD = implantable cardioverter-defibrillator; LBBB = left bundle branch 
block; LVEF = left ventricular ejection fraction; MI = myocardial infarction; MRI = magnetic resonance 
imaging; NYHA = New York Heart Association; OMT = optimal medical therapy 
 
 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 35 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
Page 36 of 100 
  
9.2.3. Inclusion Criteria for the CRT-D Cohort 
Subjects enrolled in the CRT-D Cohort of the study must also meet all of the following 
inclusion criteria (in addition to the General Inclusion Criteria): 
Table 9.2-3: Inclusion Criteria for the CRT-D Cohort 
1. De novo CRT-D (BSC device system with IS4 connector and MRI conditionally 
safe) implanted successfully during last 45 days prior enrollment in symptomatic 
subjects with HF 
2. A: Sinus rhythm and one of the following conditions: 
• QRS duration ≥150 ms and LBBB QRS morphology and with LVEF ≤35% 
despite optimal medical therapy (OMT) 
• QRS duration ≥150 ms and non-LBBB QRS morphology and LVEF ≤35% 
despite OMT 
• QRS duration of 130 to 149 ms and LBBB QRS morphology and with LVEF 
≤35% despite OMT 
or 
B: CRT-D implanted subjects in atrial fibrillation with LVEF ≤35% in NYHA 
Class III despite OMT and a QRS duration ≥130 ms 
3. Subjects have 2 to 5 risk factors out of the following prior to device implant: 
• LVEF ≤35%  
• NYHA Class III or IV 
• LBBB with QRS >130 ms or any QRS >150 ms 
• Renal dysfunction (chronically BUN >26 mg/dL / >9.28 mmol/L) 
• Diabetes type I and II 
• Chronic atrial fibrillation (permanent or persistent according to ESC Guideline 
201611) 
• Prior MI 
• Age >70 years 
• Smoking today or during last 5 years 
4. ICD Defibrillation therapy will be programmed following MADIT RIT study 
programming principles (e.g. cut off rate ≥200 bpm or 170 bpm with 60 seconds 
delayed therapy programming) 
5. Subjects devices are currently intended to be followed on Latitude system. 
Abbreviations: BSC = Boston Scientific; BUN = blood urea nitrogen; CRT-D = cardiac resynchronization 
therapy-defibrillator; ESC = European Society of Cardiology; HF = heart failure; LBBB = left bundle 
branch block; LVEF = left ventricular ejection fraction; MI = myocardial infarction; MRI = magnetic 
resonance imaging; NYHA = New York Heart Association; OMT = optimal medical therapy 
 
 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 36 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
Page 37 of 100 
  
9.2.4. Inclusion Criteria for the PM/CRT-P Cohort 
Subjects enrolled in the PM/CRT-P cohort must also meet all of the following inclusion 
criteria (in addition to the General Inclusion Criteria): 
Table 9.2-4: Inclusion Criteria for the PM/CRT-P Cohort 
1. Subjects with a PM or CRT-P implanted during last 45 days prior enrollment (only 
BSC PG devices) 
2. Subjects who are estimated to require right ventricle (RV) pacing >40% 
3. PM subjects with LVEF ≤50% 
4. Paced or intrinsic QRS >90 ms, and any determined NYHA Class (symptoms of 
HF) or any previous HF admission (HF admission comprises the following 
conditions: admission to hospital because of HF and/or IV therapy for HF and/or 
upgrade of the PM/CRT-P) 
5. Subjects’ devices are currently intended to be followed on Latitude system. 
Abbreviations: BSC = Boston Scientific; CRT-P = cardiac resynchronization therapy-pacemaker; HF = 
heart failure; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; PM = 
pacemaker; RV = right ventricle 
 
 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 37 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
Page 38 of 100 
  
9.2.5. Inclusion Criteria for the Non-device Cohort (ESC Guideline 2016 Indicated 
but not implanted) 
Subjects enrolled in the Non-device cohort (ESC Guideline 2016 indicated but not 
implanted) must also meet all of the following inclusion criteria (in addition to the General 
Inclusion Criteria): 
Table 9.2-5: Inclusion Criteria for the Non-device Cohort (ESC Guideline 2016 
Indicated but not implanted) 
• Subjects with symptomatic HF (NYHA Class II-III), and an LVEF ≤35% 
• Subjects are on OMT  ≥3 months  
• Subjects are expected to survive substantially longer than 1 year with good 
functional status 
• Subjects have ischemic heart disease or DCM (dilated cardiomyopathy) 
OR 
• LBBB QRS (≥130 ms) morphology and with LVEF ≤35% despite OMT 
 
or 
• QRS duration ≥150 ms and non-LBBB QRS morphology and with LVEF 
≤35% despite OMT 
AND 
1. No present or past implant device ICD, CRT-D, PM, or CRT-P 
2. 2 to 5 risk factors out of the following: 
• LVEF ≤35%  
• NYHA Class III or IV 
• LBBB with QRS >130 ms or any QRS >150 ms 
• Renal dysfunction (chronically BUN >26 mg/dL / >9.28 mmol/L) 
• Diabetes type I and II 
• Chronic atrial fibrillation (permanent or persistent according to ESC 
Guideline 201611) 
• Prior MI 
• Age >70 years 
• Smoking today or during last 5 years. 
Abbreviations: BSC = Boston Scientific; BUN = blood urea nitrogen; CRT-D = cardiac resynchronization 
therapy-defibrillator; ESC = European Society of Cardiology; HF = heart failure; LBBB = left bundle 
branch block; LVEF = left ventricular ejection fraction; MI = myocardial infarction; NYHA = New York 
Heart Association; OMT = optimal medical therapy; PM = pacemaker 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 38 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
Page 39 of 100 
  
9.3. Exclusion Criteria 
All exclusion criteria apply only at the time of enrolment into the study.  
If a subject’s medical conditions change after inclusion into the study so that one or several 
of the general exclusion criteria and exclusion criteria of the pertinent cohort are no longer 
met, the subject remains in the study. 
If it turns out after enrolment into the study that one or several of the general exclusion 
criteria and exclusion criteria of the pertinent cohort were violated at the time of enrolment 
into the study, the study has to be ended in this subject. 
9.3.1. General Exclusion Criteria 
Subjects who meet any one of the following criteria (Table 9.3-1) are not allowed to be 
included in this clinical study. The exclusion criteria apply only at the time of enrolment into 
the study.  
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 39 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
Page 40 of 100 
  
Table 9.3-1: General Exclusion Criteria 
1. Subject is enrolled in any other concurrent study without prior written approval 
from BSC, with the exception of local mandatory governmental registries and 
observational studies/registries that are not in conflict and do not affect the 
following: 
• Schedule of procedures for the HINODE Study (i.e. should not cause 
additional or missed visits) 
• HINODE Study outcome 
• Conduct of the HINODE Study per Good Clinical Practice (GCP)/ 
International Standard Organization (ISO) 14155:2011/local regulations as 
applicable 
2. Device implant revision is scheduled due to unstable result of an implant <45 days 
prior enrolment 
3. Subjects with more than 5 of the following risk factors: LVEF ≤35%, NYHA 
Class III or IV, LBBB with QRS 130 ms or QRS >150 ms, renal dysfunction 
(chronically BUN >26 mg/dL / >9.28 mmol/L), diabetes type I and II, chronic 
atrial fibrillation (permanent or persistent according to ESC Guideline 201611), 
prior MI, age >70 years, smoking today or during last 5 years 
4. Subjects with chronic renal disease with chronic BUN ≥ 50mg/dL or creatinine ≥ 
2.5 mg/dL 
5. Subjects with coronary artery bypass graft (CABG) surgery or percutaneous 
coronary intervention (PCI) within the past three calendar months prior to 
enrollment 
6. Subjects with enzyme-positive myocardial infarction within the past three calendar 
months prior to enrollment 
7. Subjects who are expected to survive for <1 year with good functional status 
8. Subject’s physician does not allow participation 
9. Subject is not willing and capable of participating in all testing or visits associated 
with this clinical study at an approved clinical study center and at the intervals 
defined by this CIP 
10. Unwilling to sign the consent for participation 
11. Women of childbearing potential who are or might be pregnant at the time of 
study enrolment 
12. ICD and CRT-D cohorts: implanted with a non-BSC device system. PM/CRT-P 
cohorts: implanted with a non-BSC PG device. 
Abbreviations: BSC = Boston Scientific; BUN = blood urea nitrogen; CIP = Clinical Investigation Plan; 
ESC = European Society of Cardiology; GCP = Good Clinical Practice; HF = heart failure; ISO = 
International Standard Organization; LBBB = left bundle branch block; LVEF = left ventricular ejection 
fraction; MI = myocardial infarction; NYHA = New York Heart Association 
 
 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 40 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
Page 41 of 100 
  
 
9.3.2. Exclusion Criteria for the ICD and CRT-D Cohorts 
Subjects who meet any one of the following criteria (Table 9.3-2) will be excluded from the 
ICD and CRT-D cohorts of the study. 
Table 9.3-2: Exclusion Criteria for the ICD and CRT-D Cohorts 
1. CRT implanted in subjects with a QRS duration <130 ms 
2. Subjects who have recovered from a ventricular arrhythmia causing 
hemodynamic instability 
3. Subjects with NYHA Class IV (for ICD subjects) 
4. Existing or previously implanted ICD, CRT-P, CRT-D, or pacemaker device 
system. 
Abbreviations: BSC = Boston Scientific; CRT = cardiac resynchronization therapy, CRT-D = cardiac 
resynchronization therapy-defibrillator; ICD = implantable cardioverter-defibrillator 
9.3.3. Exclusion Criteria for the PM/CRT-P Cohort 
No additional Exclusion Criteria for the PM/CRT-P Cohort. 
9.3.4. Exclusion Criteria for the Non-device Cohort (ESC Guideline 2016 Indicated 
but not implanted) 
Subjects who meet any one of the following criteria (Table 9.3-3) will be excluded from the 
Non-device cohort (ESC Guideline 2016 indicated but not implanted) of the study. 
Table 9.3-3: Exclusion Criteria for the Non-device Cohort (ESC Guideline 2016 
Indicated but not implanted) 
1. Subjects who have recovered from a ventricular arrhythmia causing hemodynamic 
instability 
2. Subject with any ICD or CRT-D, PM or CRT-P device implanted at any time prior 
to enrollment. 
 
Abbreviations: CRT-D = cardiac resynchronization therapy-defibrillator; CRT-P = cardiac 
resynchronization therapy-pacemaker; ICD = implantable cardioverter-defibrillator; PM = pacemaker 
 
10. Subject Accountability 
10.1. Point of Enrolment 
Subjects will only be enrolled in this registry study if they meet all eligibility criteria and 
provide written informed consent. If a subject is found not to meet all applicable eligibility 
criteria, the subject will be withdrawn from the study; any points of ineligibility must be 
clearly documented in the enrolment/screening log. These subjects will be considered 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 41 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
Page 42 of 100 
  
consent ineligible as discussed in Section 10.3, and will not count towards the enrolment 
ceiling. Any subject that signs consent and meets all inclusion criteria and does not meet any 
Exclusion Criteria will be enrolled in the study. Any reportable events, as defined in Section 
20 of this CIP, must be collected after written informed consent is obtained. 
 
Subjects enrolled under protocol version C deviating from eligibility criteria of protocol 
version D will be withdrawn from the study. Other subjects previously not meeting eligibility 
criteria of protocol version C, but now meeting eligibility criteria of protocol version D, will 
be accepted under protocol version D and no protocol deviation will need to be documented 
in the eCRF. 
10.2. Withdrawal 
All subjects enrolled in this registry 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 
study, 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. 
All applicable eCRFs should be completed up to the point of subject withdrawal. Subjects 
who are “lost-to-follow-up” should have 3 documented failed phone call attempts to contact 
the subject as well as a certified letter sent to the subject without a response prior to study 
withdrawal or termination. A death note will need to be provided together with the serious 
adverse event (SAE) event description on the Adverse Event (AE) form. Additional data may 
no longer be collected after the point at which a subject has been withdrawn from the study 
or withdraws his/her consent, for whatever reason. All open AEs should be closed or 
documented as chronic or continuing at the end of the study. Data collected up to the point of 
subject withdrawal may be used. A Study Withdrawal eCRF page should be completed at 
this time. A retrospective cancelling of subject data collection should be expressed explicitly 
by the subject so that all data can be removed from the database. 
10.3. Subject Status and Classification 
Consent ineligible subject 
A study subject who has signed informed consent but is found to not meet eligibility criteria 
will be considered a consent ineligible subject and will not count towards the enrolment 
ceiling. There are no follow-up or AE reporting requirements for consent ineligible subjects. 
The original signed informed consent must be maintained in the center’s administrative file 
as original or e-copy as part of the hospital patient chart. 
Active enrolled subject 
A study subject who meets the eligibility criteria as per Section 9.2 and Section 9.3 and has 
signed and dated the subject informed consent form (ICF) is considered actively enrolled in 
the study. These subjects are followed in accordance with the CIP follow-up schedule and 
included in the foreseen study analysis. The original signed subject ICF and any applicable 
documentation must be maintained in the center’s subject paper or electronic file. All 
applicable electronic Case Report Form (eCRFs) per the CIP must be completed. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 42 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
Page 43 of 100 
  
10.4. Enrolment Controls 
Centers are allowed to enroll up to 20% of subjects in each of the 4 defined Subject Cohorts. 
This translates into the following allowed maximum subject numbers per center: 
• ICD:23 to 54 subjects* 
• CRT-D: 19 to 50 subjects* 
• PM/CRT-P:34 to 40 subjects 
• Non-device:34 to 60 subjects 
(ESC Guideline 2016 Indicated but not implanted) 
* Variable; depending on the total number of enrolled subjects in this study cohort. 
If a center wishes to exceed these limits, the center must obtain prior approval from the 
sponsor or sponsor’s delegated representative. 
As soon as a minimum of 556 eligible subjects are entered into the study database, the 
closure of enrolment can begin. All sites will be informed that enrolment has closed. After 
closure of enrolment has been communicated, sites must obtain approval from the sponsor or 
the sponsor’s delegated representative for all remaining subjects who are consented but who 
are not yet enrolled into the study database. 
A maximum of 950 subjects will be allowed to be followed and entered into the study 
database. 
11. Study Methods 
11.1. Data Collection 
Details for data collection are shown in Table 11.1-1. Data collection will take place at the 
following time points: 
• Enrolment and Consenting Clinic Visit (Day 0, 0 to 45 days post implant procedure, 
alternative minimum > 3months post MI, PCI, or CABG required). The date of signature 
on the informed consent form is the time point of enrolment. 
• Six-monthly Visit (180 ± 60 days post enrolment and multiplies until Close-out Visit) 
(required) 
• Re-implant or new device implant post enrolment (optional) 
• Interim Visit and Event Report (SAE/SADE related clinical care visit) (Following study 
site specific SOC, optional) 
• Close-out Clinic Visit (see table 8.1-1) (required) 
All clinic visits that occur outside the specified protocol visit window will be classified as 
“Unscheduled CIP Visits”. Unscheduled visits triggered by a specific event (e.g. adverse 
event, Latitude alert, patient request etc.) and not by standard routine control (e.g. device 
check-up standard by the institution, wound check, standard echo or ECG, blood analysis 
etc.) must be documented. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 43 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
Page 44 of 100 
  
CIP defined visits that occur outside the specified visit window will be documented as a CIP 
deviation. 
All data collected according to the Data Collection Requirements (Table 11.1-1) and 
specified in Sections 11.2 to 11.9 are to be appropriately noted in the eCRF. 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 44 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
Page 45 of 100 
  
Table 11.1-1: Data Collection Requirements 
Procedure/Assessment 
Enrolment and 
Consenting Clinic Visit 
Day 0 
(required) 
(0 to 45 days post implant 
procedure, or minimum 
≥3 months post MI, PCI, or 
CABG) 
Follow-Up Visits 
6-monthly Visit 
(required) 
(180 ± 60 days post 
enrolment and 
multiplies until 
Close-out Visit)  
Re-implant 
or New 
Device 
Implant post 
Enrolment 
(optional) 
Interim/ 
Unscheduled 
Visit and Event 
Report 
(optional) 
(SAE/SADE related 
clinical care visit)  
Close-out 
Clinic Visit 
(required) 
(see figure 8.1-1) 
Informed consent form, including informed 
consent signature and date 
X 
-- 
-- 
-- 
-- 
Inclusion criteria / exclusion criteria 
X 
-- 
-- 
-- 
-- 
Demographic data 
X 
-- 
-- 
-- 
-- 
Clinical assessment 
X 
-- 
X 
-- 
X 
Medical history/co-morbidities 
X 
-- 
X 
-- 
-- 
LVEF, intrinsic or paced 
X 
SOC 
SOC 
-- 
SOC 
QRS, intrinsic 
X 
-- 
-- 
-- 
-- 
QRS, intrinsic or paced 
-- 
-- 
-- 
-- 
X 
Current concomitant medications  
X 
-- 
X 
-- 
X 
Documentation of implanted devices 
X 
-- 
X 
-- 
-- 
ECG recording pre-implant upload 
SOC 
-- 
SOC 
-- 
-- 
ECG recording post implant (paced) upload 
SOC 
 
SOC 
-- 
SOC 
Echocardiography data collection 
SOC 
SOC 
SOC 
-- 
SOC 
Device assessment/Interrogation (for devices) 
SOC 
SOC 
SOC 
-- 
SOC 
Standard Biomarkers for heart failure+ other 
SOC 
-- 
-- 
-- 
SOC 
Adverse events assessment review 
-- 
X 
X 
X 
X 
Adverse events reporting (SAE, SADE, ADE, 
DD information) 
X 
X 
X 
X 
X 
Latitude device data collection (for subjects 
implanted with a device) 
X 
X 
X 
X 
X 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 45 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
Page 46 of 100 
  
Procedure/Assessment 
Enrolment and 
Consenting Clinic Visit 
Day 0 
(required) 
(0 to 45 days post implant 
procedure, or minimum 
≥3 months post MI, PCI, or 
CABG) 
Follow-Up Visits 
6-monthly Visit 
(required) 
(180 ± 60 days post 
enrolment and 
multiplies until 
Close-out Visit)  
Re-implant 
or New 
Device 
Implant post 
Enrolment 
(optional) 
Interim/ 
Unscheduled 
Visit and Event 
Report 
(optional) 
(SAE/SADE related 
clinical care visit)  
Close-out 
Clinic Visit 
(required) 
(see figure 8.1-1) 
MRI scan information  
SOC 
SOC 
SOC 
SOC 
SOC 
Physician’s judgment on therapy status / 
outcome / CRT therapy delivery / defibrillator 
therapy 
X 
X 
X 
-- 
X 
Risk factor assessment 
X 
X 
X 
X 
X 
Protocol deviations 
X 
X 
X 
X 
X 
SOC = according to standard of care; X = required; -- = not required 
Abbreviations: ADE = adverse device effect; CRT = cardiac resynchronization therapy; DD = device deficiency; ECG = electrocardiogram; LAT = Latitude 
reporting system; LSLV = last subject last visit; LVEF = Left ventricular ejection fraction; MI = myocardial infarction; MRI = magnetic resonance imaging; NYHA 
= New York Heart Association; SADE = serious adverse device effect; SAE = serious adverse events; SOC = required if center’s standard of care; X = required; --
 = not required.  
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 46 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 47 of 100 
 
11.2. Study Candidate Screening 
After approval by the investigator’s Ethics Committee (EC) and the sponsor or delegated 
representative, the investigator will follow SOC practices to screen subjects for inclusion in 
the study. 
11.3. Informed Consent 
During the Enrolment and Consenting Visit (Section 11.4), a qualified center representative 
will review the consent with a potential subject. The subject will be encouraged to ask any 
questions about the study. All questions from the subject should be addressed prior to the 
subject signing the informed consent. If the subject signs the informed consent, a signed copy 
should be provided to the subject and the original should be filed in the electronic or paper 
medical records. Documentation of the consent process by the person obtaining consent 
should be filed in the subject study file. No study-specific data collection of any procedure 
should be conducted prior to consent. 
11.4. Enrolment and Consenting Visit (Day 0, 0 to 45 days post implant procedure, 
alternative >90 days post MI) 
Prior to initiating any study procedures, the investigator must ensure that appropriate 
informed consent has been signed and dated (Section 21). Subjects will sign and date the ICF 
post successful implant or minimum 3 months post MI, PCI, or CABG. 
Subjects who meet all of the entry criteria and consent to the evaluation are eligible. The 
enrolment for this registry will occur up to 45 calendar days after the device system 
implantation. 
Subjects are considered enrolled after they have met all inclusion criteria, none of the 
exclusion criteria, and provided written informed consent in accordance with applicable 
regulatory agency and EC requirements. 
The data collection at enrolment includes: demographic data, clinical assessment, medical 
history and co-morbidities, subject information and medical history; subject status and 
clinical assessment per SOC; and details on previously/currently implanted devices. 
Subject information and medical history 
• Demographic data: age at time of consent; gender. 
• Clinical assessment: weight, height, BMI, blood pressure, NYHA Class. 
• Medical history / co-morbidities: 
o Subject etiology: ischemic cardiomyopathy; idiopathic cardiomyopathy; 
valvular cardiomyopathy; hypertrophic cardiomyopathy; congenital heart 
disease; infiltrative disease; neuromuscular disease (including myotonic 
dystrophy and Kearns-Sayre syndrome). 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 47 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 48 of 100 
 
o Associated diseases/risk factors: previous MI; previous hospitalization for 
HF; hypertension; diabetes type I and II; renal disease (BUN); chronic 
pulmonary disease; smoking in the last 5 years, peripheral artery disease; 
other known malignancies (tumor, lymphoma or leukemia); other chronic 
diseases. 
o Additional rhythm disease: information will be collected on additional 
relevant rhythm diseases: AV block; sinus node dysfunction; paroxysmal, 
chronic, persistent atrial fibrillation; chronotropic incompetence. 
o Other subject history: previous stroke; shock; previous ablation (AV node, 
atrial fibrillation or atrial flutter). 
• LVEF: measured or estimated within the last 12 months and documented in the 
subject’s medical file: fully preserved (≥50%); partially preserved (40%-49%); 
reduced (<40%). 
• QRS: intrinsic 
• Current/concomitant cardiac medication: documentation of the following 
current/concomitant medication classes being administered: Angiotensin Converting 
Enzyme (ACE)-inhibitor/Angiotensin II (ATII) receptor antagonist; antiarrhythmic; 
anticoagulant; antiplatelet; Aldosterone-antagonist; beta-blocker; Digitalis; diuretics; 
statins; calcium antagonists. 
Documentation of implanted devices 
• ICD, CRT-D, PM/CRT-P, etc. data: Implant date, number of days implanted, 
model, serial number 
• Pacing lead data: cardiac chamber (atrial and ventricular), number of days implanted 
and lead model (serial number) and manufacturer 
Some subjects received a device system for the first time whereas others received a 
replacement procedure of existing systems (usually pulse generator due to battery depletion 
but may also include lead extractions due to lead failure or other reasons for system 
component replacement). Data (implant date, number of years implanted, model and 
manufacturer) for previous device systems will also be collected. 
Defibrillator therapy for all ICD and CRT-D devices in the protocol must be programmed 
according to the specifications provided in Table 11.4-1, Table 11.4-2 and Table 11.4-3, 
respectively. 
Any deviation from protocol requirements for medical reasons will need to be documented as 
an adverse event and as a deviation from the protocol. The programming is considered non-
invasive; specifications are provided to ensure that the devices are operated per BSC IFU. 
Any programming not per the specifications below will be considered a CIP violation. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 48 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 49 of 100 
 
Table 11.4-1: Programming Requirements for High Rate Cutoff 
Parameters 
Programming 
Ventricular Tachy Therapy Zones  
2 and one optional high rate zone 
Zone 1 (VT) Rate Cutoff  
170 bpm 
Zone 1 (VT) Zone Rate Therapy  
Monitor Only (No Therapy)  
 
 
Zone 2 (VF) Zone Rate Cutoff 
200 bpm 
Zone 2 (VF) Zone Duration 
2.5 seconds or longer 
Zone 2 (VF) Zone Therapy 
Defibrillator therapy (ATP (optional) + Shock) 
 
Zone 3 (VF) 
>200 bpm 
Optional programming for all parameters 
 
Table 11.4-2: Programming Requirements for Long Delay 
Parameters 
Programming 
Ventricular Tachy Therapy Zones 
3 
Zone 1 (VT-1) Zone Rate Cutoff 
170 bpm 
Zone 1 (VT-1) Zone Duration 
60 seconds 
Rhythm Detection Enhancements (Rhythm ID): ON; Program Passive and Active Methods ON 
with Fallback LRL 
AF Threshold 
170 bpm 
Stability 
20 ms 
Post-Shock Detection: 
ON 
SRD 
OFF 
Zone 1 (VT-1) Zone Therapy 
Defibrillator therapy (ATP (optional) + Shock) 
Redetection Duration 
Nominal 
 
 
Zone 2 (VT) Zone Rate Cutoff 
200 bpm 
Zone 2 (VT) Zone Duration 
12 seconds 
Rhythm Detection Enhancements (Rhythm ID): ON, Same as VT-1 Zone 
Zone 2 (VT) Zone Therapy 
Defibrillator therapy (Shock + ATP (Optional)) 
Redetection Duration 
Nominal 
 
 
Zone 3 (VF) Zone Rate Cutoff 
250 bpm 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 49 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 50 of 100 
 
Table 11.4-2: Programming Requirements for Long Delay 
Parameters 
Programming 
Zone 3 (VF) Zone Duration 
2.5 seconds 
Zone 3 (VF) Zone Therapy 
Defibrillator therapy (ATP (optional) or Shock) 
Other parameters may be programmed following physician’s discretion 
 
Table 11.4-3: ICD Programming Option 3 (if applicable for a specific device) 
Conditional Shock Zone 
200 bpm 
Shock Zone 
250 bpm 
 
Baseline subject status and clinical assessment data collection from if 
performed as standard of care 
All uploaded data must be anonymous and de-identified to assure data 
confidentiality 
• 12-lead ECG recording pre and post implant and at close-out (data collection 
and document upload in e.g. pdf format) as SOC: date (pre-implant maximum 45 
days before implant; latest available maximum 12 months prior to enrollment for non-
device cohort); rhythm (normal sinus rhythm, junctional rhythm, atrial fibrillation, 
paced); resting heart rate; intrinsic or paced QRS width; PR interval, QT interval; 
QRS morphology (normal, right bundle branch block, LBBB, other conduction 
disorders).  
• Echocardiography or equivalent method as SOC: will be used to determine basic 
measures: LVEF, diastolic diameters, volumes (Implant criteria and therapy efficacy 
data).  
o Device cohorts: data obtained within the last 3 months prior to enrolment are 
to be provided 
o Non-device cohort: latest data obtained within the last 12 months prior to 
enrollment in case there was no documented HF decompensation, MI or 
revascularization, otherwise within the last 3 months prior to enrollment are to 
be provided 
• MRI scan: data on actual number of MRI scans performed according to center’s 
SOC since the implant procedure, including information about scanned body parts, 
will be collected. 
• Physician’s judgment: judgment on therapy status / outcome / CRT therapy delivery 
(success yes/no) / defibrillator therapy (ATP/Shock delivered: yes/no). 
• Biomarkers for heart failure: parameters as routinely evaluated  prior to device 
implant or as part of standard visit for non-device subjects will be documented by the 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 50 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 51 of 100 
 
site teams in the eCRF including name of parameter, date of analysis, result, and 
normal range according to local lab.  
Collected standard biomarkers are: amino-terminal pro-peptide B-type natriuretic 
peptide (NT-proBNP), BNP, Troponin T, Troponin I, creatinine, BUN, and estimated 
glomerular filtration rate (eGFR) 
Optional additional biomarkers collected from SOC diagnostics are: CK-MB, C-
reactive protein, TNF-alpha, galectin-3 (Gal-3), parathyroid hormone (pTH), CA125, 
ST2 
However, the identification of laboratory parameters as biomarkers for heart failure is 
left to the discretion of each individual investigator. 
Risk factor assessment 
The following risk marker will need to be assessed (at all FU scheduled and 
unscheduled): 
1. Myocardial infarction status 
2. Last available EF status (value/ date) 
3. Atrial fibrillation 
4. Smoking 
5. QRS morphology and width 
6. Renal function 
7. Diabetes type I and II 
8. NYHA assessment 
9.  Age of subject 
• Therapy judgment: appropriate, inappropriate, both, unclear 
• CRT only: V-V timing of programmed vector 
• MRI scan done during last 6 months observational period: yes/no 
• Reason for MRI scan documented as related to diagnostics or related to a known SAE 
• After any MRI, appropriate pacing and sensing need to be verified and documented as 
an unscheduled visit. In case of an increased pacing threshold or inappropriate 
sensing or any other device abnormality, an event report must be completed. 
Latitude 
All Latitude alerts related to ventricular episodes and heart failure (if applicable) must be 
programmed on. All other alerts can be programmed on the physician’s discretion or 
following hospital routine. If Latitude is available for a device, the device should be 
programmed ensuring that a Latitude report is created bi-weekly or at a higher frequency so 
that Latitude reports can be collected timely to corresponding clinical events. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 51 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 52 of 100 
 
Subjects will have their device performance and diagnostic data downloaded remotely into 
the Latitude database. The Latitude BSC team will collect device reports in the following 
cases: 
• After all ventricular treatment Latitude alerts 
• After all heart failure related Latitude alerts (if available) 
• After the center reported serious adverse (device) events if these were related to 
ventricular episodes or heart failure events 
• After the center reported SADE or ADE, including all inappropriate device treatments 
The collected and anonymized Latitude reports will be uploaded into the study database for 
analysis. 
If for any reason patients cannot be connected to Latitude, endpoint related data can be 
uploaded into the database by the site (e.g. electrogram (EGM) for ventricular arrhythmias). 
11.5. Six-monthly Visit 
Subjects will be visited every 6 months from enrolment (Day 0) until Close-out Visit. During 
the 6-monthly follow-up visit, device assessment/interrogation should be performed 
according to SOC practices. Details on the occurrence of any adverse device effects (ADEs), 
SAEs, SADEs, and device deficiency (DD), which have occurred since enrolment (Day 0), 
are to be recorded. 
Echocardiography or equivalent method according to center’s SOC will be used to determine 
basic measures: LVEF, diastolic diameters, and volumes. If the echo is not done per SOC, no 
deviation will be recorded. 
Data on actual number of MRI scans performed according to center’s SOC since the 
enrolment, including information about scanned body parts, reason for scan, etc., will be 
collected. 
Subjects will have their device performance, all Latitude alerts on. Latitude report is 
requested every 14 days, and diagnostic data are downloaded remotely by the Latitude BSC 
team as Latitude report during this visit timeframe. 
Latitude remote device interrogation is requested to be programmed every 2 weeks or more 
frequent. 
Subjects that receive re-implant, repositioning, device upgrade or new device implant post 
enrolment, as determined by the investigator, will continue to follow same initial procedures 
and schedules as described for Day 0 at the initial enrolment. The reason for re-implant/ 
revision is to be documented as an Adverse Event in the eCRF. 
Physician’s judgment on therapy and risk factor assessment will be collected on standard 
follow-up CRF as planned at enrolment. In addition to the Re-implant CRF, the form for 
unscheduled visits will be used for event reporting. 
If there were any protocol deviations since the last study visit, they have to be recorded. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 52 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 53 of 100 
 
11.6. Re-implant, Device System Revision, Device Upgrades, or New Device Implant 
post Enrolment 
The Re-implant or New Device Implant post Enrolment visit is optional and needs to be 
performed only if re-implant (invasive procedure towards the evaluated therapy system), 
device system revision, device upgrade, or new device implant occurs while subjects are in 
the study. 
Subjects that receive re-implant or new device implant post enrolment, as determined by the 
investigator, will undergo the same procedures as described for Day 0. The reason for 
re-implant/revision is to be documented in the eCRF. 
Details on the occurrence of any adverse device effects (ADEs), SAEs, SADEs, and DD are 
to be recorded. 
If there were any protocol deviations since the last study visit, they have to be recorded. 
11.7. Interim or Unscheduled Visit and Event Report (SAE/SADE related clinical 
care visit) 
The Interim Visit is optional and should be performed according to the SOC at the center. 
This visit can be completed in person at the clinic or over the phone at any time other than 
study scheduled visits. 
All clinic visits that occur outside the specified protocol visit window will be classified as 
“Unscheduled CIP Visits”. Unscheduled visits triggered by a specific event (e.g. adverse 
event, Latitude alert, patient request etc.) and not by standard routine control (e.g. device 
check-up standard by the institution, wound check, standard echo or ECG, blood analysis 
etc.) must be documented. 
During this follow-up visit, details on the occurrence of any SAEs, SADEs, and DDs, which 
have occurred since the last visit, are to be recorded. 
Events which already have been reported as part of an unscheduled visit do not need to be 
reported again during a CIP defined visit. 
Data on actual number of MRI scans performed according to center’s SOC since the last 
visit, including information about scanned body parts, will be collected. 
Subjects will have their device performance, nominal alerts, and diagnostic data downloaded 
remotely from the Latitude BSC team during this visit. Risk factor assessment will be 
collected. 
It is possible that more than one Interim Visit may occur if the SOC at the center requires 
more than one visit throughout the visit window. Any additional Interim Visits should be 
conducted similarly. 
If there were any protocol deviations since the last study visit, they have to be recorded. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 53 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 54 of 100 
 
11.8. Close-out Visit 
All subjects will remain in the study until the last subject completes his/her last visit. The 
maximum study duration for any subject will be 34 months (FSFV to LSLV). For the last 
subject enrolled, the study duration is 12 months. 
As soon as the last subject was enrolled, planning of Close-out Visits for all subjects starts. 
All close out visits will be documented on a specific Close out CRF. The time window for 
the Close-out Visits of all subjects starts 2 months before the last subject enrolled has 
completed 12 months and ends 4 months after the last subject enrolled has completed 12 
months. 
In case the time window for the Close-out Visits does not follow SOC, for HF subjects in a 
hospital, any follow-up appointment after 6 months which is closest to the study window 
might be defined as Close-out Visit. 
During the Close-out Clinic Visit, a clinical assessment/physical exam should be performed 
in order to document the health status of the subject in addition to any ADEs, SA(D)Es, and 
DDs that may have occurred since the last visit. The physician’s judgment on therapy 
outcome will be recorded. Current medication classes prescribed as well as a device 
assessment/interrogation should also be performed according to SOC practices. 
The duration of QRS, intrinsic or paced, will be collected. 
Full ECG recording is required at this visit if it is SOC of the center and data should be 
uploaded to the study database. 
If Echocardiography or equivalent method is SOC of the center, it will be used to determine 
basic measures: LVEF, diastolic diameters, volumes. 
Data on actual number of MRI scans performed according to site’s SOC since the last visit, 
including information about scanned body parts, will be collected. 
Subjects will have their device performance, nominal alerts and diagnostic data downloaded 
remotely from the Latitude BSC team during this visit timeframe. 
Available results for heart failure related and other SOC biomarkers that were generated 
within the last 4 months prior each subject’s individual close-out visit will be documented in 
the eCRF including name of parameter, date of analysis, result, and normal range according 
to local lab. 
Once the subject completes the Close-out Clinic Visit, participation in this registry study has 
been completed. In case of premature termination of the study, data collection will stop 
accordingly. As this is an observational study, subjects will be managed according to center 
SOC following termination/completion of the study. 
If a device-related event (unanticipated SADE [USADE], SADE, ADE) is ongoing at the 
time of study completion, the subject may be asked to remain enrolled in the study and 
provide additional information regarding the event until the event is resolved. The physician 
will provide treatment for any ongoing events according to SOC regardless of whether the 
subject agrees to continue participating in the study. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 54 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 55 of 100 
 
Physician’s judgment on therapy and risk factor assessment will be done. Device therapy will 
be documented on an event form as well as all device deficiencies including false positive 
Latitude Alerts. 
If there were any protocol deviations since the last study visit, they have to be recorded. 
11.9. 
Source Documents 
Table 11.9-1 summarizes all source data requirements for this CIP. Most source documents 
will be filed in the subject’s hospital chart since all procedures will follow SOC. All source 
documents should be filed in the subject hospital chart since all procedures will follow SOC. 
Some source documents (ECG strips, Echo imaging, and Latitude recordings) may be stored 
electronically on a secured study database. 
Only a copy of the subject consent will be kept in the administrative study binder and no 
subject study binder will be generated. 
All personal information should be removed from all documents prior uploading into the 
study database and replaced by the study ID. In case this is not possible the database 
administrator will anonymize data as required. 
Table 11.9-1: Source Documentation Requirements 
Requirement 
Disposition 
Subject Consent Form 
1-Retain subject file, 2 administrative study binder, 
3-Subject copy 
Enrolment and Baseline Data 
Retain in subject hospital file 
Implant Measurement  
Retain in subject hospital file 
Implant Procedure Medical Records 
Retain in subject hospital file, 
6-monthly Clinic Visit Data 
Retain in subject hospital file 
Interim /Unscheduled CIP Visit Data 
Retain in subject hospital file 
Close-out Clinic Visit Data 
Retain in subject hospital file 
Adverse Events and Device Event Data 
Retain in subject hospital file 
CIP Deviation  
Report in Study Database 
Study Withdrawal Data 
Retain in subject hospital file 
ECG e-Recording  
Retain in subject hospital file and copy upload to 
study database 
Echocardiographic Imaging e-Recording 
Retain in subject hospital file  
Device Interrogation Printouts 
Retain in subject hospital file 
MRI pictures, videos, and reports 
Retain in subject hospital file 
Latitude device and alert data  
Retain in subject hospital file 
Latitude database and copy of the Latitude report 
upload into study database 
Abbreviations: CIP = Clinical Investigation Plan; ECG = electrocardiogram; MRI = magnetic resonance 
imaging 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 55 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 56 of 100 
 
 
12. Statistical Considerations 
12.1. Endpoints 
12.1.1. Primary Endpoint for ICD Treated Subjects 
The primary endpoint for ICD treated subjects is: 
• Composite rate of first appropriately treated ventricular arrhythmia (by ATP or shock) or 
life-threatening symptoms associated to ventricular arrhythmia (defined as hemodynamic 
instability which requires treatment), whichever comes first under MADIT Arm B or C 
programming conditions in a study population with a majority of Japanese subjects 
Based on the MADIT RIT study4, we estimate that 5% of the ICD treated subjects will 
present an appropriately treated first ventricular arrhythmia associated symptom (by ATP or 
shock) within one year. 
12.1.1.1. Hypotheses 
The null and alternative hypotheses are as follows: 
H0: The ventricular arrhythmia associated symptoms free-rate from 0-12 months ≤85.0% 
HA: The ventricular arrhythmia associated symptoms free-rate from 0-12 months >85.0% 
The null hypothesis (H0) will be rejected if the lower one-sided 97.5% confidence bound for 
the ventricular arrhythmia associated symptoms free-rate is greater than the performance goal 
of 85.0%. 
12.1.1.2. Statistical Methods 
When the final study subject reaches the final CIP required follow-up visit, the primary 
analysis will be performed based on the Kaplan-Meier method for the estimation of the 
12-month ventricular arrhythmia associated symptoms free-rate, including the lower 97.5% 
confidence bound (computed based on log-log methodology). This Kaplan-Meier analysis 
will begin at the time of implant. Subjects that withdraw consent or are lost-to-follow-up 
prior to the 12-month endpoint evaluation will be censored at their date of last contact. All 
subjects actively enrolled will be included in the endpoint analysis. 
The null hypothesis will be rejected and the endpoint considered met if the lower 97.5% 
confidence bound for the ventricular arrhythmia associated symptoms free-rate at 12 months 
is greater than 85.0%. 
Additionally, a Kaplan-Meier survival time-to-event curve along follow-up will be provided. 
The primary analysis above will be performed for CRT-D and ICD cohorts combined as well 
as for ICD treated subjects separately. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 56 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 57 of 100 
 
12.1.2. Primary Endpoint for CRT-D Treated Subjects 
The primary endpoint for CRT-D treated subjects is: 
• Composite rate of first appropriately treated ventricular arrhythmia (by anti-tachycardia 
pacing [ATP] or shock) or life-threatening symptoms associated to ventricular arrhythmia 
(defined as hemodynamic instability which requires treatment), whichever comes first 
under MADIT Arm B or C programming conditions in a study population with a majority 
of Japanese subjects 
Based on the MADIT RIT study4, we estimate that 3% of the CRT-D treated subjects will 
present a first appropriately treated ventricular arrhythmia associated symptom (by ATP or 
shock) within one year. 
12.1.2.1. Hypotheses 
The null and alternative hypotheses are as follows: 
H0: The ventricular arrhythmia associated symptoms free-rate from 0-12 months ≤87.0% 
HA: The ventricular arrhythmia associated symptoms free-rate from 0-12 months >87.0% 
 
The null hypothesis (H0) will be rejected if the lower one-sided 97.5% confidence bound for 
the ventricular arrhythmia associated symptoms free-rate is greater than the performance goal 
of 87.0%. 
12.1.2.2. Statistical Methods 
When the final study subject reaches the final CIP required follow-up visit, the primary 
analysis will be performed based on the Kaplan-Meier method for the estimation of the 
12-month ventricular arrhythmia associated symptoms free-rate, including the lower 97.5% 
confidence bound (computed based on log-log methodology). This Kaplan-Meier analysis 
will begin at the time of implant. Subjects that withdraw consent or are lost-to-follow-up 
prior to the 12-month endpoint evaluation will be censored at their date of last contact. All 
subjects actively enrolled will be included in the endpoint analysis. 
The null hypothesis will be rejected and the endpoint considered met if the lower 97.5% 
confidence bound for the ventricular arrhythmia associated symptoms free-rate at 12-months 
is greater than 87.0%. 
Additionally, a Kaplan-Meier survival time-to-event curve along follow-up will be provided. 
The primary analysis above will be performed for CRT-D and ICD cohorts combined as well 
as for CRT-D treated subjects separately. 
12.1.3. Primary Endpoint for PM/CRT-P Treated Subjects 
The primary endpoint for PM/CRT-P treated subjects is: 
• All-cause mortality in subjects with a maximum of 3 risk factors (analyzed for MADIT II 
data7) 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 57 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 58 of 100 
 
Based on previous CARE-HF study8, we estimate that 10% of the PM/CRT-P treated 
subjects will present an all-cause mortality within one year. 
12.1.3.1. Hypotheses 
The null and alternative hypotheses are as follows: 
H0: The all-cause mortality free-rate (survival rate) from 0-12 months ≤80.0% 
HA: The all-cause mortality free-rate (survival rate) from 0-12 months >80.0% 
 
The null hypothesis (H0) will be rejected if the lower one-sided 97.5% confidence bound for 
the all-cause mortality free-rate is greater than the performance goal of 80.0%. 
12.1.3.2. Statistical Methods 
When the final study subject reaches the final CIP required follow-up visit, the primary 
analysis will be performed based on the Kaplan-Meier method for the estimation of the 
12-month all-cause mortality free-rate (survival rate) including the lower 97.5% confidence 
bound (computed based on log-log methodology). This Kaplan-Meier analysis will begin at 
the time of implant. Subjects that withdraw consent or are lost-to-follow-up prior to the 
12-month endpoint evaluation will be censored at their date of last contact. All subjects 
actively enrolled will be included in the endpoint analysis. 
The null hypothesis will be rejected and the endpoint considered met if the lower 97.5% 
confidence bound for the all-cause mortality free-rate (survival rate) at 12 months is greater 
than 80.0%. 
Additionally, a Kaplan-Meier survival time-to-event curve along follow-up will be provided. 
12.1.4. Primary Endpoint for Non-device Subjects (ESC Guideline 2016 Indicated but 
not implanted) 
The primary endpoint for Non-device subjects (ESC Guideline 2016 Indicated but not 
implanted) is: 
• All-cause mortality in the subject cohort with 2 to 5 predefined SCD driving risk factors. 
Based on the MADIT II study2, we estimate that 10% of the Non-device subjects (ESC 
Guideline 2016 Indicated but not implanted) will present an all-cause mortality within one 
year. 
12.1.4.1. Hypotheses 
The null and alternative hypotheses are as follows: 
H0: The all-cause mortality free-rate (survival rate) from 0-12 months ≤80.0% 
HA: The all-cause mortality free-rate (survival rate) from 0-12 months >80.0% 
The null hypothesis (H0) will be rejected if the lower one-sided 97.5% confidence bound for 
the all-cause mortality free-rate is greater than the performance goal of 80.0%. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 58 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 59 of 100 
 
12.1.4.2. Statistical Methods 
When the final study subject reaches the final CIP required follow-up visit, the primary 
analysis will be performed based on the Kaplan-Meier method for the estimation of the 
12-month all-cause mortality free-rate (survival rate) including the lower 97.5% confidence 
bound (computed based on log-log methodology). This Kaplan-Meier analysis will begin at 
the time of enrolment. Subjects that withdraw consent or are lost-to-follow-up prior to the 
12-month endpoint evaluation will be censored at their date of last contact. All subjects 
actively enrolled will be included in the endpoint analysis. 
The null hypothesis will be rejected and the endpoint considered met if the lower 97.5% 
confidence bound for the all-cause mortality free-rate (survival rate) at 12 months is greater 
than 80.0%. 
Additionally, a Kaplan-Meier survival time-to-event curve along follow-up will be provided. 
12.1.5. Secondary Endpoints 
• The secondary endpoint for subjects implanted with CRT-D/ICD is: 
o All-cause mortality rate 
• The secondary HF endpoints for subjects with device implanted include: 
o Composite rate of HF events in ICD, CRT-D, and PM/CRT-P cohorts, which require 
IV treatment, HF related hospitalization, or led to HF death 
o Therapeutic sustainability at 1 year in ICD, CRT-D, and PM/CRT-P cohorts, defined 
as free of qualified SADEs post successful implantation, such as re-implant 
procedure, required invasive procedure related to the device system, pacing exit 
block, all-cause infection, and death due to therapy failure in comparison with data 
from MADIT CRT, MADIT RIT, Optimind, and Rally X4 studies. 
• The secondary endpoint for subjects implanted with CRT-D/ICD and non-device subjects 
is: 
o Comparison of rate of sudden cardiac death in the non-device cohort with the rate of 
appropriately treated ventricular arrhythmias or sudden cardiac death in the 
defibrillator cohort (ICD cohort and CRT-D cohort) 
Secondary analyses will be descriptive and exploratory. Detailed statistical methods for these 
endpoints will be presented in a Statistical Analysis Plan (SAP). 
12.1.6. Sample Size 
The pre-specified primary endpoints sample sizes are outlined in Error! Reference source 
not found.. The minimum required sample sizes to sufficiently power each primary endpoint 
at 90% and account for up to 20% attrition are lower than the final sample sizes.  
The final sample sizes for the device cohorts (ICD: 117 to 270 subjects; CRT-D: 95 to 250 
subjects; PM/CRT-P: 172 to 200 subjects) will ensure that there will be a sufficient number 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 59 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 60 of 100 
 
of subjects to evaluate each primary endpoint, as well as provide ample data to characterize 
the safety, performance and efficacy profiles based on secondary and additional endpoints. 
The final sample size for the non-device cohort (Non-device [ESC Guideline 2016 Indicated 
but not implanted]: 172 to 300 subjects) will ensure that there will be a sufficient number of 
subjects to compare the rate of sudden cardiac death in the non-device cohort with the rate of 
appropriately treated ventricular arrhythmias or sudden cardiac death in the defibrillator 
cohort (ICD, CRT-D). 
In case of low enrollment rates, enrollment may be closed after the statistically required 
calculated minimum sample size was completed. 
Table 12.1-1: Endpoint Sample Size Estimates 
Endpoint 
Measurement 
Performance Goal 
Hypotheses1 
Expected 
Performance2 Power 
Number of Subjects 
Needed 
for 
Analysis 
Required 
Minimum 
Sample size 
Enrolled 
for ≤20% 
Attrition 
Primary 
Endpoint for 
ICD Treated 
Subjects 
Ventricular 
arrhythmia3 
associated symptoms 
free-rate from 0 to 12 
months 
H0: Rate ≤ 85.0% 
HA: Rate > 85.0% 
95.0% 
90% 
93 
117 
Primary 
Endpoint for 
CRT-D 
Treated 
Subjects 
Ventricular 
arrhythmia3 
associated symptoms 
free-rate from 0 to 12 
months 
H0: Rate ≤ 87.0% 
HA: Rate > 87.0% 
97.0% 
90% 
76 
95 
Primary 
Endpoint for 
PM/CRT-P 
Treated 
Subjects 
All-cause mortality 
free-rate (survival 
rate) from 0 to 12 
months 
H0: Rate ≤ 80.0% 
HA: Rate > 80.0% 
90.0% 
90% 
137 
172 
Primary 
Endpoint for 
Non-device 
Subjects (ESC 
Guideline 
2016 Indicated 
but not 
implanted) 
All-cause mortality 
free-rate (survival 
rate) from 0 to 12 
months 
H0: Rate ≤ 80.0% 
HA: Rate > 80.0% 
90.0% 
90% 
137 
172 
1Hypothesis test based on a one-sided alpha level of 0.025; clinically accepted delta of 10%, subtracted from 
expected performance 
2 Determined from prior comparable studies 
3 Appropriately treated 
CRT-D = cardiac resynchronization therapy-defibrillator; ICD = implantable cardioverter-defibrillator; 
PM = pacemaker; CRT-P = cardiac resynchronization therapy-pacemaker. 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 60 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 61 of 100 
 
Sample sizes for primary endpoints were calculated employing exact binomial methods in 
nQuery + nTerim 3.0. 
12.2. General Statistical Methods 
12.2.1. Analysis Sets 
All subjects actively enrolled in the study (i.e. who meet all eligibility criteria at the time of 
enrolment into the study and who have given written informed consent) will be included in 
the primary endpoints analyses. 
12.2.2. Number of Subjects per Investigative Site 
Approximately 40 investigational sites in Japan will enroll a minimum of 556 to power all 
primary endpoint for each cohort and a maximum of 900 eligible subjects. If a site does not 
enroll a subject within a 3-month time period, the site may be replaced at the discretion of the 
sponsor. 
12.2.3. Descriptive Statistical Methods 
Descriptive statistical methods will be used to summarize the data from this study, with 
hypothesis testing performed for the primary endpoints. Unless otherwise stated, all 
statistical testing will be one-sided and will be performed using a significance (alpha) level of 
0.025. 
Continuous variables as a minimum will be described by number of non-missing 
observations (n), arithmetic mean (Mean), SD, minimum (Minimum), median (Median), and 
maximum (Maximum). One additional decimal point for mean and median and 2 additional 
decimal points for SD will be used. 
Categorical variables will be presented using the number of non-missing observations (n) or 
the number of subjects in the population (N) as applicable and percentages (%). Percentages 
will be rounded to one decimal place. Unless otherwise stated, two-sided 95% confidence 
intervals (CIs) will be provided when relevant. The two-sided 95% CI will be presented as it 
provides the one-sided 97.5% lower (resp. upper) limit when the upper (resp. lower) bound is 
ignored to assess superiority. 
12.3. Data Analyses 
Exploratory analyses for the pooled ICD and CRT-D Cohorts versus Non-Device Cohort 
(ESC Guideline 2016 Indicated but not implanted) will be performed using propensity score 
matching method in order to compare the all-cause mortality rate and the composite rate of 
HF events between the pooled ICD and CRT-D Cohorts versus the Non-Device Cohort 
regarding 7 risk factors at baseline (age >70 years, smoking today or during last 5 years, prior 
MI, diabetes type I and II, chronic atrial fibrillation, renal dysfunction, NYHA Class III or 
IV). 
A propensity matching score will be generated for each subject by logistic regression where 
the ‘device’ variable (device implantation Yes/No) is the dependent variable and the 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 61 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 62 of 100 
 
covariates are the 7 risk factors in the model. Each subject in the pooled ICD and CRT-D 
Cohorts will be matched to a subject in the Non-Device Cohort based on the closest 
propensity score. 
Subjects in the pooled ICD and CRT-D Cohorts will then be compared to those in the Non-
Device Cohort before propensity score matching and after propensity score matching for 
each of the 7 risk factors using the Chi-square test. This technique enables evaluation of the 
success of propensity matching. 
Finally, the all-cause mortality rate and the composite rate of HF events (outcomes) will be 
compared between the pooled ICD and CRT-D Cohorts and the Non-Device Cohort using 
the Chi-square test. 
The detailed statistical method for propensity score matching will be presented in an SAP. 
12.3.1. Other Endpoints/Measurements 
The ancillary assessments will include: 
• Subject medical assessment collected pre-enrolment (post implant) and at Close-out: 
o NYHA functional classification 
o LVEF 
o QRS duration 
o Physician’s judgment on therapy outcome 
o BMI 
o Diabetes mellitus type I and II 
• Cross-over in device therapies 
• Cause of death (SCD, cardiac related, other reasons, unknown) 
• Impact of gender and age 
• MRI observations in association with reported clinical events 
• Analysis of device data coming from Latitude data reports 
• Health care utilization under Latitude 
• Selected Biomarkers for heart failure and other morbidities 
Additional analyses will be descriptive and exploratory. Detailed statistical methods for these 
endpoints will be presented in an SAP. 
12.3.2. Interim Analyses  
No interim analyses are planned. 
12.3.3. Subgroup Analyses 
Not applicable. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 62 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 63 of 100 
 
12.3.4. Justification of Pooling 
The poolability of data by investigational site will be tested. This analysis will be performed 
to determine whether there are differences from center-to-center. 
The center-to-center heterogeneity will be assessed for each primary endpoint by performing 
a random effects logistic regression analysis. Centers enrolling 10 subjects or fewer will be 
combined into pooled sites of 11 or more subjects for the purpose of this pooling analysis. 
Investigational center will be added into the model as a random effect. Centers will be 
deemed to be heterogeneous if the variance of the random center effect is found to 
significantly differ from zero. A significance level of 10% will be used for each test. 
12.3.5. Multivariable Analyses 
Not applicable. 
12.3.6. Other Analyses 
Descriptive statistics of subject demographics and baseline characteristics will be presented. 
A list of potential baseline variables is categorized below: 
• Demographics: age (numeric and % ≤70 years/ % >70 years), gender (%) 
• Clinical: NYHA Class, chronic atrial fibrillation (%), paroxysmal atrial fibrillation (%), 
atrioventricular block (%), QRS morphology, intrinsic or paced QRS width, LVEF 
(numeric and % normal, fully preserved [≥ 50%]/ % partially preserved [40%-49%]/ % 
reduced [<40%]), blood pressure, BMI, heart rate 
• Medical history/co-morbidities: single/multiple MI, hypertension, diabetes type I and II, 
current smoking, renal dysfunction 
• Current medications: ACE-inhibitor, Angiotensin II receptor antagonist, antiarrhythmic, 
anticoagulant, antiplatelet, aldosterone-antagonist, beta-blocker, digitalis, diuretics, 
statins, calcium antagonists, oral hypoglycemic agent, non-insulin injectable, insulin. 
12.3.7. Changes to Planned Analyses 
Any changes to the planned statistical analyses made prior to database lock will be 
documented in an amended SAP approved prior to database lock. Changes from the planned 
statistical methods after database lock will be documented in the clinical study report along 
with a reason for the deviation. 
13. Data Management 
13.1. Data Collection, Processing, and Review 
Subject data will be recorded in a limited access secure electronic data capture (EDC) 
system. The time periods for recording of study data (enrolment, implant data, etc.) are 
specified in the site guidelines. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 63 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 64 of 100 
 
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 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. 
All echographic imaging (DICO format) and ECG readings (pdf format) should be uploaded 
to the study database. 
All personal information must be removed prior to the upload. 
13.2. Data Retention 
The Principal Investigator or his/her designee or investigational site will maintain, at the 
investigative site, all essential study documents and source documentation that support the 
data collected on the study subjects in compliance with ICH/GCP guidelines. Documents 
must be retained for at least 2 years after the 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 Principal Investigator or his/her designee will take measures to ensure that these 
essential documents are not accidentally damaged or destroyed. If for any reason the 
Principal Investigator or his/her designee withdraws responsibility for maintaining these 
essential documents, custody must be transferred to an individual who will assume 
responsibility and BSC must receive written notification of this custodial change. Sites are 
required to inform Boston Scientific in writing where paper or electronic files are maintained 
in case files are stored off site and are not readily available. 
13.3. Core Laboratories 
There will be no core laboratories involved in this registry. 
14. Amendments  
If a CIP revision is necessary which affects the rights, safety or welfare of the subject or 
scientific integrity of the data, an amendment is required. Appropriate approvals (e.g., EC / 
Competent Authority) of the revised CIP must be obtained prior to implementation. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 64 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 65 of 100 
 
15. Deviations 
An Investigator must not make any changes or deviate from this CIP, except to protect the 
life and physical well-being of a subject in an emergency. An investigator shall notify the 
sponsor and the reviewing EC of any deviation from the investigational plan to protect the 
life or physical well-being of a subject in an emergency, and those deviations which affect 
the scientific integrity of the clinical investigation. Such notice shall be given as soon as 
possible, but no later than 5 working days after the emergency occurred, or per prevailing 
local requirements, if sooner than 5 working days.  
All deviations from the CIP, with the reason for the deviation and the date of occurrence, 
must be documented and reported to the sponsor using the eCRF. Sites may also be required 
to report deviations to the EC, per local guidelines and government regulations.  
Deviations will be reviewed and evaluated on an ongoing basis and, as necessary, appropriate 
corrective and preventive actions (including notification, site re-training, or site 
discontinuation/termination) will be put into place by the sponsor. 
16. Device/Equipment Accountability 
Not applicable. 
17. Compliance 
17.1. Statement of Compliance 
This study will be conducted in accordance with the relevant parts of the ICH Guidelines for 
GCP, ethical principles that have their origins in the Declaration of Helsinki, and pertinent 
individual country laws and regulations. The study shall not begin until the required 
approval/favorable opinion from the EC and/or regulatory authority has been obtained, if 
appropriate. Any additional requirements imposed by the EC or regulatory authority shall be 
followed, if appropriate. 
17.2. Investigator Responsibilities 
The Principal Investigator of an investigational site is responsible for ensuring that the study 
is conducted in accordance with the Clinical Study Agreement, the CIP/, ISO 14155, ethical 
principles that have their origins in the Declaration of Helsinki, any conditions of approval 
imposed by the reviewing EC, and prevailing local and/or country laws and/or regulations, 
whichever affords the greater protection to the subject. 
All centers in Japan are asked to follow the recommended Ethics Guideline for Clinical 
Research on Human Subjects. 
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.   
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 65 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 66 of 100 
 
• Provide his/her qualifications and experience to assume responsibility for the proper 
conduct of the study and that of key members of the site team through up-to-date 
curriculum vitae or other relevant documentation and disclose potential conflicts of 
interest, including financial, that may interfere with the conduct of the clinical study or 
interpretation of results. 
• Make no changes in or deviate from this CIP, except to protect the life and physical well-
being of a subject in an emergency; document and explain any deviation from the 
approved CIP 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 
AE as applicable per the CIP and observed device deficiency. 
• Report to sponsor, per the CIP requirements, all SAEs and device deficiencies that could 
have led to a SADE and potential/USADE or UADE. 
• Report to the 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 CIP or by the EC, and supply BSC with any additional requested 
information related to the safety reporting of a particular event. 
• Allow the sponsor to perform monitoring and auditing activities, and be accessible to the 
clinical research monitor or auditor and respond to questions during monitoring visits or 
audit(s). 
• Allow and support regulatory authorities and the EC when performing auditing activities. 
• Ensure that informed consent is obtained in accordance with applicable laws, this CIP 
and local EC requirements. 
• Provide adequate medical care to a subject during and after a subject’s participation in a 
clinical study in the case of AEs, as described in the ICF. 
• Inform the subject of the nature and possible cause of any AEs 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. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 66 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 67 of 100 
 
• Ensure that clinical medical records are clearly marked to indicate that the subject is 
enrolled in this clinical study. 
• Ensure that, if appropriate, subjects enrolled in the clinical investigation are provided 
with some means of showing their participation in the clinical investigation, together with 
identification and compliance information for concomitant treatment measures (contact 
address and telephone numbers shall be provided). 
• Inform, with the subject’s approval or when required by national regulations, the 
subject’s personal physician about the subject’s participation in the clinical investigation. 
• Make all reasonable efforts to ascertain the reason(s) for a subject’s premature 
withdrawal from clinical investigation while fully respecting the subject’s rights. 
• Ensure that an adequate investigation site team and facilities exist and are maintained and 
documented during the clinical investigation. 
17.2.1. Ensure that maintenance and calibration of the equipment relevant for the 
assessment of the clinical investigation is appropriately performed and 
documented, where applicable.Delegation of Responsibility 
When specific tasks are delegated by an investigator, including but not limited to conducting 
the informed consent process, the Principal Investigator is responsible for providing 
appropriate training and adequate supervision of those to whom tasks are delegated. The 
investigator is accountable for regulatory violations resulting from failure to adequately 
supervise the conduct of the clinical study. 
17.3. Institutional Review Board/ Ethics Committee 
Prior to gaining Approval-to-Enroll status, the investigational site will provide to the sponsor 
documentation verifying that their 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 EC and/or competent authority approval of the CIP (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 EC approval and renewals will be obtained throughout the duration of the study as 
required by local/country or EC requirements. Copies of the Investigator’s reports and the EC 
continuance of approval must be provided to the sponsor. 
17.4. Sponsor Responsibilities 
Boston Scientific will serve as the sponsor of this clinical investigation. A sponsor is defined 
as individual or organization taking responsibility and liability for the initiation or 
implementation of a clinical investigation. It is the responsibility of BSC as the sponsor to 
ensure proper monitoring of the investigation and to see that all clinical requirements are 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 67 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 68 of 100 
 
met. In addition, BSC representatives may participate in the conduct of the trial to the extent 
described in the following section that describes the role of the BSC representatives. BSC 
personnel may or may not be blinded to the study results. Participation in the study’s conduct 
will be limited to BSC personnel who are appropriately qualified and trained such as those 
personnel with an engineering, technical or nursing degree or equivalent training, or who 
have significant experience in cardiology, electrophysiology or the implantable 
cardiovascular device industry. All personnel will be aware of general clinical study 
regulations and guidelines for medical device trials. 
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 and publication.. 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. Information received during the study 
will not be used to market to subjects; subject names will not be placed on any mailing lists 
or sold to anyone for marketing purposes.  
17.4.1. Role of Boston Scientific Representatives 
Boston Scientific personnel can provide technical support to the investigator and other health 
care personnel (collectively HCP) as needed during implant, testing required by the CIP, and 
follow-ups. Support and assistance may include HCP training, addressing HCP questions, or 
providing clarifications to HCPs. Operation of BSC equipment/devices (including 
programmers, analyzers, and other support equipment) is not allowed per Japanese 
regulation. 
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 CIP 
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 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 68 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 69 of 100 
 
17.5. Insurance 
Where required by local/country regulation, proof and type of insurance coverage by BSC for 
subjects in the study will be obtained. 
18. Monitoring 
Monitoring will be performed during the study to assess continued compliance with the CIP 
and applicable regulations. In addition, the clinical research monitor verifies that study 
records are adequately maintained, that data are reported in a satisfactory manner with 
respect to timeliness, adequacy, and accuracy, and that the Principal Investigator continues to 
have sufficient staff and facilities to conduct the study safely and effectively. The Principal 
Investigator/institution guarantees direct access to original source documents by BSC 
personnel, their designees, and appropriate regulatory authorities. 
The study may also be subject to a quality assurance audit by BSC or its designees, as well as 
inspection by appropriate regulatory authorities. It is important that the Principal Investigator 
and relevant study personnel are available during on-site monitoring visits or audits and that 
sufficient time is devoted to the process. 
19. Potential Risks and Benefits 
19.1. Risks Associated with Participation in the Clinical Study 
This is a registration study and will therefore not increase the risks for the subject; after 
enrolment procedures are either SOC or eCRF documentation from Latitude uploads or the 
occurrence of any AEs. 
Neither the device nor the implant procedure are part of this study; programming of the 
device has been specified as part of this study, but this is non-invasive and is specified to 
ensure compliance with the BSC device IFU. All subjects receive device as part of the SOC 
treatment, therefore there are no additional procedural risks to the subject for being included 
in this study. 
19.2. Anticipated Benefits 
There may be no benefit to the subject for being in this study. However, results from the data 
collected during this registry study may improve the medical device treatment options in the 
future, therefore the subjects enrolled in this registry may also benefit at a later stage. 
Because device programming has been specified, it is ensured that the devices will be 
operated per BSC IFU. 
19.3. Risk to Benefit Rationale 
Subjects enrolled in the HINODE study will not be exposed to any additional testing, visits 
or risks as compared to subjects who are routinely implanted with any clinically approved 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 69 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 70 of 100 
 
pulse generator (PG) system and not enrolled in this study. Standard device interrogation and 
testing that will be performed in the present study are part of routine procedures that occurs 
for each subject implanted with a PG who is followed up under standard clinical practice. 
Even if electronic devices such as PG are subject to random component failures that cannot 
be predicted, those risks are not affected by this CIP and would be equally applicable to all 
subjects implanted with a market released PG system. Risks can be minimized through 
adherence to the guidelines for subject selection, implementing BSC programming as 
specified by the CIP, close monitoring of the subject's physiologic status during visits and by 
promptly supplying BSC with all pertinent information required by this CIP. 
20. Safety Reporting 
20.1. Reportable Events by investigational site to Boston Scientific 
It is the responsibility of the investigator to assess and report to BSC any event which occurs 
in any of following categories: 
• All Serious Adverse Events 
• All Device Deficiencies 
• Unanticipated Adverse Device Effects/Unanticipated Serious Adverse Device Effects 
• All Adverse Device Effects  
• All ventricular episodes not followed by defibrillator therapy (ATP or Shock) but 
which have been associated to serious clinical symptoms (especially if medical 
intervention was necessary) must be documented as Adverse Event. 
• All Cardiac Related AEs, including worsening in severity or frequency of pre-existing 
cardiac events and new onset of cardiac events (i.e. new onset Atrial Fibrillation) 
o For ICD/CRT-D - All ventricular arrhythmia which received therapy must be 
reported as an event. 
o Multiple ventricular arrhythmias on the same calendar day should be captured 
as a single event. 
o A pacemaker logbook on ventricular arrhythmias will be reviewed at any in 
clinic follow-up by the investigational center. 
o The Latitude database will be reviewed on ventricular arrhythmias at least 
annually. In case of arrhythmias that are not already reported by the study 
center, data management will query to add the arrhythmia as SAE. 
When possible, the medical diagnosis should be reported as the Event Term instead of 
individual symptoms. 
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 AE and/or device 
deficiency. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 70 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 71 of 100 
 
Any AE event required by the CIP, experienced by the study subject after informed consent 
and once considered enrolled in the study (as defined in study subject classification section), 
whether during or subsequent to the procedure, must be recorded in the eCRF. 
Underlying diseases are not reported as AEs unless there is an increase in severity of 
frequency during the course of the investigation. Death should not be recorded as an AE, but 
should only be reflected as an outcome of ONE (1) specific SAE (see Table 20.2-1 for AE 
definitions). 
20.2. Definitions and Classification 
Definitions are provided in Table 20.2-1 as reference only. Reportable events per this CIP are 
listed in the section above. Administrative edits were made on the definition of serious AEs 
from ISO 14155 and MEDDEV 2.7/4 for clarification purposes. 
Table 20.2-1: Safety Definitions 
Term 
Definition 
Adverse Event (AE) 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/4 
 
 
Any untoward medical occurrence, unintended disease or injury, or any 
untoward clinical signs (including an abnormal laboratory finding) in 
subjects, users or other persons, whether or not related to the investigational 
medical device.  
NOTE 1: This includes events related to the investigational medical device 
or comparator. 
NOTE 2: This definition includes events related to the procedures involved. 
NOTE 3: For users or other persons, this definition is restricted to events 
related to the investigational medical device.  
Adverse Device Effect (ADE) 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/4 
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 2.7/4 
Note: This definition meets the reporting objectives and requirements of ISO 
14155 and MEDDEV 2.7/4. 
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. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 71 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 72 of 100 
 
Table 20.2-1: Safety Definitions 
Term 
Definition 
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 2.7/4 
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 
 
Ref: MEDDEV 2.7/4 
 
 
Serious adverse device effect which by its nature, incidence, severity, or 
outcome has not been identified in the current version of the risk analysis 
report. 
NOTE 1: Anticipated serious adverse device effect (ASADE) is an effect 
which by its nature, incidence, severity or outcome has been identified in the 
risk analysis report. 
Device Deficiency 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/4 
An inadequacy of an investigational medical device-related to its identity, 
quality, durability, reliability, safety or performance. This may include 
malfunctions, use error, or inadequacy in the information supplied by the 
manufacturer. 
 
Abbreviations: ADE = Adverse Device Effect; AE = Adverse Event, ASADE = anticipated serious adverse 
device effect; EC=Ethics Committee; ISO = International Standard Organization, MEDDEV = medical device 
guidance; SAE = Serious Adverse Event; USADE = Unanticipated Serious Adverse Device Effect 
 
Underlying diseases are not reported as AEs unless there is an increase in severity or 
frequency during the course of the investigation. Death should be recorded as an SAE, and 
should include a detailed description of circumstances and expected cause. 
Any AE experienced by the study subject after informed consent, whether during or 
subsequent to the procedure, must be recorded in the eCRF. 
In case of shock or ATP treatment is noted by the subject or site, an SAE should be 
documented (life-threatening arrhythmia and corrective action is ATP or shock). Several 
shocks or ATP treatments on the same day are to be reported as one SAE. The event will be 
recorded as related to an arrhythmia. All events of shock will be captured by the Latitude 
system. If an event of shock is captured by the Latitude system, but has not been documented 
as an AE, the site will be asked to provide the documentation. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 72 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 73 of 100 
 
Any ATP treatment or shock that was inappropriate is to be documented as device 
deficiency. Multiple inappropriate ATP treatments or shocks on one day can be summarized 
in one device deficiency report. 
Refer to the BSC Physician’s Lead Manual for the known risks associated with the study 
devices. 
All device-related AEs will be evaluated at least monthly during the trial and might be 
extracted from the database in order to pool those data with other available data sets (e.g. 
trials). Pooling of those datasets on product performance on a broader sample size will be 
done especially to support safety aspects of all medical devices in this trial. 
20.3. Relationship to Devices or Procedure 
The Investigator must assess the relationship of the AE to the device or procedure. See 
criteria in Table 20.3-1:  
 
Table 20.3-1: Criteria for Assessing Relationship of Study Device or Procedure to 
Adverse Event 
Classification 
Description 
Not Related 
Relationship to the device or procedures can be excluded when: 
- the event is not a known side effect of the product category the device belongs to or 
of similar devices and procedures; 
- the event has no temporal relationship with the use of the investigational device or 
the procedures; 
- the serious event does not follow a known response pattern to the medical device (if 
the response pattern is previously known) and is biologically implausible; 
- the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible – and reintroduction of its use (or 
increase of the level of activation/exposure), do not impact on the serious event; 
- the event involves a body-site or an organ not expected to be affected by the device 
or procedure; the serious event can be attributed to another cause (e.g. an underlying 
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 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 73 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 74 of 100 
 
Table 20.3-1: Criteria for Assessing Relationship of Study Device or Procedure to 
Adverse Event 
Classification 
Description 
event cannot reasonably explained by another cause, but additional information may 
be obtained. 
Causal Relationship 
The serious event is associated with the investigational device or with procedures 
beyond reasonable doubt when: 
- the event is a known side effect of the product category the device belongs to or of 
similar devices and procedures; 
- the event has a temporal relationship with investigational device use/application or 
procedures; 
- the event involves a body-site or organ that 
o the investigational device or procedures are applied to; 
o the investigational device or procedures have an effect on; 
- the serious event follows a known response pattern to the medical device (if the 
response pattern is previously known); 
- the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible); 
- other possible causes (e.g. an underlying or concurrent illness/ clinical condition 
or/and an effect of another device, drug or treatment) have been adequately ruled out; 
- harm to the subject is due to error in use; 
- the event depends on a false result given by the investigational device used for 
diagnosis, when applicable; 
- In order to establish the relatedness, not all the criteria listed above might be met at 
the same time, depending on the type of device/procedures and the serious event. 
 
20.4. Investigator Reporting Requirements 
The communication requirements for reporting to BSC are as shown in Table 20.4-1. 
Table 20.4-1: Investigator Reporting Requirements 
Event Classification 
Communication Method 
Communication Timeline post-
market studies 
(MEDDEV 2.12/2 :  
GUIDELINES ON A 
MEDICAL DEVICE 
VIGILANCE SYSTEM) 
Unanticipated Adverse Device 
Effect / Unanticipated Serious 
Adverse Device Effect  
 
Complete AE eCRF page with 
all available new and updated 
information. 
 
• Within 1 business day of first 
becoming aware of the event. 
• Terminating at the end of the 
study 
Provide all relevant source 
documentation (unidentified) for 
reported event. 
• At request of sponsor. 
Serious Adverse Event  
Complete AE eCRF page with 
• Within 10 business days after 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 74 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 75 of 100 
 
Table 20.4-1: Investigator Reporting Requirements 
Event Classification 
Communication Method 
Communication Timeline post-
market studies 
(MEDDEV 2.12/2 :  
GUIDELINES ON A 
MEDICAL DEVICE 
VIGILANCE SYSTEM) 
all available new and updated 
information.  
becoming aware of the event 
or as per local/regional 
regulations. 
• Reporting required through 
end of the study 
Provide all relevant source 
documentation (unidentified) for 
reported event upon request of 
the sponsor 
• When documentation is 
available 
Serious Adverse Device Effects 
Complete AE eCRF page with 
all available new and updated 
information. 
• Within 2 business days of 
first becoming aware of the 
event or as per local/regional 
regulations. 
• Reporting required through 
the end of the study 
Provide all relevant source 
documentation (unidentified) for 
reported event 
• When documentation is 
available 
• At sponsor request. 
Device Deficiencies (including 
but not limited to failures, 
malfunctions, and product 
nonconformities) 
Note:  Any Investigational 
Device Deficiency that might 
have led to a serious adverse 
event if a) suitable action had not 
been taken or b) intervention had 
not been made or c) if 
circumstances had been less 
fortunate is considered a 
reportable event. 
 
Complete AE eCRF page with 
all available new and updated 
information.  
• Within 2 business days of 
first becoming aware of the 
event. Reporting required 
through the end of the study 
Adverse Event including 
Adverse Device Effects 
Complete AE eCRF page, which 
contains such information as 
date of AE, treatment of AE 
resolution, assessment of 
seriousness and relationship to 
the device 
Provide all relevant source 
documentation (unidentified) for 
reported event upon request of 
the sponsor 
• In a timely manner (e.g. 
recommend within 30 
business days) after 
becoming aware of the 
information 
• Reporting required through 
end of study 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 75 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 76 of 100 
 
Table 20.4-1: Investigator Reporting Requirements 
Event Classification 
Communication Method 
Communication Timeline post-
market studies 
(MEDDEV 2.12/2 :  
GUIDELINES ON A 
MEDICAL DEVICE 
VIGILANCE SYSTEM) 
Abbreviations: AE=adverse event; CRF=case report form; IDE=Investigational Device Exemption; 
UADE=unanticipated adverse device effect 
20.5. Boston Scientific Device Deficiencies 
All device deficiencies (including but not limited to failures, malfunctions, use errors, 
product nonconformities, and inadequacy in the information supplied by the manufacturer) 
will be documented and reported to BSC. If possible, the device(s) should be returned to 
BSC for analysis. If it is not possible to return the device, the investigator should document 
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 to be reported in the eCRF but are not AEs. However, an AE that 
results from a device failure or malfunction would be recorded as an AE on the appropriate 
eCRF. 
Any Device Deficiency that might have led to a serious AE 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. 
Device deficiencies are to be reported from the study site to BSC or the study database within 
2 business days of investigator awareness. Device deficiencies will be evaluated at routine 
intervals during the trial and might be extracted from the study database in order to pool 
those data with other available data sets (e.g. trials). Pooling of datasets on product 
performance on a broader sample size will be done especially to support safety aspects of all 
medical devices in this trial. 
20.6. Reporting to Regulatory Authorities / ECs / Investigators 
BSC is responsible for reporting AE information to all participating Principal Investigators 
and regulatory authorities, as applicable. 
The Principal Investigator is responsible for informing the EC, and regulatory authorities of 
UADE and SAE as required by local/regional regulations. 
20.7. Subject Death Reporting 
A subject death during the study should be reported to BSC as soon as possible and, in any 
event, within 10 calendar days of site notification. The site’s EC must be notified of any 
death in accordance with that site’s EC policies and procedures. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 76 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 77 of 100 
 
Upon subject death, Death should not be recorded as an AE, but should only be reflected as 
an outcome of ONE (1) specific SAE. 
An “End of Study” form must be completed for all deceased subjects, as well as the “Death 
CRF”. 
20.8. Subject Death Classification 
The following definitions of each category, along with the Epstein article,12 are to be used by 
the investigator when completing the Death Information section in the EDC. 
I. Primary Organ Cause – The root problem that initiated the terminal event if multiple 
factors were involved, e.g., HF –primary, renal failure – secondary. 
A. Cardiac 
1. Arrhythmic 
2. Pump Failure - Death occurring in a subject with severe heart failure, 
refractory to medical therapy, in whom death is anticipated within days to 2 
months. Often such patients are referred for hospice care, comfort care is 
provided and aggressive treatment is curtailed. The terminal event could be 
sudden and may be arrhythmic. This does not change the non-sudden, non-
arrhythmic course that preceded the terminal event. 
3. Ischemic 
a. Acute MI – Symptoms compatible with an acute coronary syndrome (chest 
pain, acute dyspnea etc.), with evidence of myocardial necrosis as defined 
by: 
i. 
creatinine kinase (CK) ≥2x upper limit of normal (ULN) and CK-MB 
isoenzyme percent > ULN 
ii. 
troponin level ≥2x ULN 
Subjects with an acute coronary syndrome and diagnostic ST-T wave 
changes (>2 mm ST elevation in 2 contiguous leads) are included if 
death occurs prior to enzyme confirmation 
b. 
No Acute MI – Subject has not met the enzymatic or electrocardiographic 
criteria for an acute myocardial infarction. The testing was done and came 
back negative. For example, a patient who survives an unstable angina 
episode long enough to provide documentation that they did NOT have an 
MI, e.g., cardiac enzyme confirmation. 
c. 
MI Unknown – Myocardial infarction suspected but data to prove or 
disprove are not available. Used to capture the subject who is suspected of 
having probable MI but dies prior to the MI being documented. For 
example, chest pain >20 minutes, or chest pain with a non-diagnostic ECG 
(LBBB), or chest pain of unknown duration. 
4. Other Cardiac 
5. Unknown 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 77 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 78 of 100 
 
B. Noncardiac 
C. Unknown 
II. Temporal Course 
A. Sudden – death that occurred within one hour of onset of symptoms 
B. Non-Sudden – death that occurred greater than one hour of onset of symptoms 
C. Unknown/Presumed Sudden – This category should be used for subjects who 
were not expected to die of other causes, and were not witnessed at the time of 
death. There must be documentation of the subject’s condition within 24 hours 
prior to the event and there should be no acute change in the subject’s condition or 
circumstances leading up to the event. An example would be a stable subject who 
dies in his sleep. Subjects can have worsening heart failure prior to the event and 
be included in this category, as long as the severity of heart failure does not fit the 
definition of death due to pump failure. 
D. Unknown 
III. Antecedent Worsening Heart Failure – Patients with signs or symptoms of 
worsening heart failure within 2 weeks prior to death or the event that led to death 
(e.g. cardiac arrest and hypoxic encephalopathy from which the subject does not 
recover). In order to avoid recall bias, there must be documentation of a clinical 
evaluation documenting worsening signs or symptoms or a change in medication 
recommended for symptoms of worsening heart failure. 
A. N/A (Not Applicable) 
B. Yes 
C. No 
D. Unknown – Insufficient information to determine state of heart failure at time of 
the event 
IV. Death Witnessed – Someone witnessed the death event (in the same room or within 
earshot) 
A. Yes 
B. No 
C. Unknown 
V. Monitored – The subject’s rhythm at the onset of the terminal event (just prior to 
death) was documented. This may or may not be related to the actual cause of death. 
A. Yes 
1. Ventricular Tachyarrhythmia 
2. Bradyarrhythmia 
a. Sinus bradyarrhythmia 
b. High degree AV block with slow ventricular response 
c. Asystole 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 78 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 79 of 100 
 
3. PEA (Pulseless Electrical Activity) 
4. Other (AF, SVT, sinus tachycardia, normal sinus rhythm) 
5. Unknown 
B. No 
C. Unknown 
VI. Pulse Generator Related – includes events associated with pulse generator’s ability 
to detect and treat an arrhythmia. 
A. Yes 
B. No – including events where initiating event was non-arrhythmic 
C. Unknown 
D. N/A 
21. Informed Consent 
Subject participation in this clinical study is voluntary.  Informed Consent is required from 
each subject. The Investigator is responsible for ensuring that Informed Consent is obtained 
prior to the 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 EC, or central EC, 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 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 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, 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 79 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 80 of 100 
 
• use native language that is non-technical and understandable to the subject or his/her 
legal representative, 
• provide ample time for the subject to consider participation and ask questions if 
necessary, 
• ensure important new information is provided to new and existing subjects throughout the 
clinical study.  
The ICF shall always be signed and personally dated by the subject 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 as original or as e-copy as part of the hospital 
patient chart 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. Any violations of the informed consent process must be 
reported as deviations to the sponsor and local regulatory authorities (e.g. 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, CIP, a change of the Principal Investigator, administrative changes, or 
following annual review by the EC. The new version of the ICF must be approved by the EC. 
Acceptance by Boston Scientific is required if changes to the revised ICF are requested by 
the site’s EC. The EC will determine the subject population to be re-consented. 
The ICF will note that the transmission of confidential subject data, such as copies of source 
documents, will be required and that by signing the consent, the subject gives permission for 
his/her confidential subject data to be transmitted to the sponsor. 
22. Committees 
22.1. Safety Monitoring Process 
To promote early detection of safety issues and consistent coding across projects, an internal 
BSC Event Review Team (Technical Services, Clinical Cardiac Rhythm Management [a 
business division of BSC], Medical Safety, and assigned persons from ICON Plc) will 
provide routine and ongoing review and an overview of all events reported in the study 
database.  
Review and event classification will be done to support device hazard analysis and 
monitoring of event rates. This process requires dynamic collection (as soon as the event is 
reported) of unmonitored data. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 80 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 81 of 100 
 
During scheduled monitoring visits, clinical research monitors and locally responsible BSC 
Technical Science Liaison will support the dynamic reporting process through their review of 
source document information. 
22.2. Event Committee 
The event committee will centrally assess events that are relevant for the primary endpoints 
(onset / treatment of all ventricular events and classifying those events towards endpoint 
relevance) of the study. The scope and the procedures to be followed will be defined in a 
separate document. 
22.3. ECG experts 
Experts will centrally assess the ECGs to determine whether subjects met ECG-related 
criteria for inclusion and exclusion at the time of enrolment. 
23. Suspension or Termination 
23.1Premature 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 ECs, and regulatory authorities, as 
applicable, will be notified in writing in the event of study termination. 
23.1.1Criteria for Premature Termination of the Study 
Possible reasons for premature study termination include, but are not limited to, the 
following. 
• The occurrence of USADE or unusual trends of SAEs or SADEs that present a significant 
or unreasonable risk to subjects enrolled in the study. 
• An enrolment rate far below expectation that prejudices the conclusion of the study. 
• A decision on the part of BSC to suspend or discontinue development of the device. 
23.2Termination of Study Participation by the Investigator or Withdrawal of EC Approval 
Any investigator or EC in the HINODE Study may discontinue participation in the study or 
withdrawal approval of the study, respectively, with suitable written notice to BSC. 
Investigators, associated ECs, and regulatory authorities, as applicable, will be notified in 
writing in the event of these occurrences. 
23.3Requirements 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 BSC. The EC and 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 81 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 82 of 100 
 
regulatory authorities, as applicable, will be notified. Detailed information on how enrolled 
subjects will be managed thereafter will be provided.  
In the event an EC terminates participation in the study, participating investigators, 
associated 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 BSC. 
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 BSC. 
The Principal Investigator or his/her designee must return all study-related documents and 
investigational product to BSC, unless this action would jeopardize the rights, safety, or 
welfare of the subjects. 
23.4Criteria 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 3 months after site initiation, or if the site has multiple or severe CIP 
violations/noncompliance without justification and/or fails to follow remedial actions. 
In the event of termination of site participation, all study devices and testing equipment, as 
applicable, will be returned to BSC unless this action would jeopardize the rights, safety or 
well-being of the subjects. The EC and regulatory authorities, as applicable, will be notified. 
All subjects enrolled in the study at the site will continue to be followed according to SOC of 
the center. The Principal Investigator at the site must make provision for these follow-up 
visits unless BSC notifies the investigational site otherwise. 
24. Publication Policy 
BSC requires disclosure of its involvement as a sponsor or financial supporter in any 
publication or presentation relating to a BSC study or its results. BSC will submit study 
results for publication (regardless of study outcome) following the conclusion or termination 
of the study. Boston Scientific Corporation adheres to the Contributorship Criteria set forth in 
the Uniform Requirements of the International Committee of Medical Journal Editors 
(ICMJE; http://www.icmje.org). In order to ensure the public disclosure of study results in a 
timely manner, while maintaining an unbiased presentation of study outcomes, BSC 
personnel may assist authors and investigators in publication preparation provided the 
following guidelines are followed. 
• All authorship and contributorship requirements as described above must be followed. 
• BSC involvement in the publication preparation and the BSC Publication Policy should 
be discussed with the Coordinating Principal Investigator(s) and/or Executive/Steering 
Committee at the onset of the project. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 82 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 83 of 100 
 
• The First and Senior authors are the primary drivers of decisions regarding publication 
content, review, approval, and submission.  
25. Bibliography 
1. Nobuyuki Shiba and Hiroaki Shimokawa, Chronic Heart Failure in Japan: 
Implications of the CHART Studies. Vasc Health Risk Manag 2008; 4(1): 103-13. 
2. Moss AJ et al., Prophylactic implantation of a defibrillator in patients with 
myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877-
83. (MADIT II Trial) 
3. Schuger C, Daubert JP, Brown MW, Cannom D, Estes NA 3rd, Hall WJ et al. 
Multicenter automatic defibrillator implantation trial: reduce inappropriate therapy 
(MADIT-RIT): background, rationale, and clinical protocol. Ann Nonivasive 
Electrocardiol. 2012;17:176-85. 
4. Moss AJ et al., Reduction in Inappropriate Therapy and Mortality through ICD 
Programming. N Engl J Med 2012;367:2275-83. (MADIT RIT Trial) 
5. Moss AJ et al., Reduction in the risk of heart failure events with preventive cardiac 
resynchronization therapy N Engl J Med 
6. Biffi M, Pelargonio G, Havlicek A, Rossi P, Melissano D, Kaltofen G, et al. 
Pacemaker Programming, Physiologic Pacing Settings, and Clinical Outcomes in 
Real-world Practice: Results from the OPTI-MIND Clinical Study. The Journal of 
Innovations in Cardiac Rhythm Management 2016; 7:2229-2237. 
7. Goldenberg I, Vyas AK, Hall WJ, et al., Risk Stratification for Primary 
Implantation of a Cardioverter-Defibrillator in Patients With Ischemic Left 
Ventricular Dysfunction. J Am Coll Cardiol 2008;51(3):288-296. 
8. Cleland J, Daubert JC, Erdmann E, et al., For the Cardiac Resynchronization-Heart 
Failure (CARE-HF) Study Investigators. The Effect of Cardiac Resynchronization 
on Morbidity and Mortality in Heart Failure. N Engl J Med 2005;352:1539-49. 
9. Junttila MJ et al., Sudden Cardiac Death After Myocardial Infarction in Patients 
With Type 2 Diabetes. Heart Rhythm Society 2010;7:1396-1403. 
10. Ponikowski P et al., 2016 ESC Guidelines for the diagnosis and treatment of acute 
and chronic heart failure. European Heart Journal 2016; 37(27):2129-2200. 
http://dx.doi.org/10.1093/eurheartj/ehw128; 
http://eurheartj.oxfordjournals.org/content/37/27/2129 
11. Kirchhof P et al., 2016 ESC Guidelines for the management of atrial fibrillation 
developed in collaboration with EACTS. European Heart Journal, 
http://dx.doi:10.1093/eurheart/ehw210 
12. Epstein AE, Carlson MD, Fogoros RN, Higgins SL, Venditti FJ Jr., Classification 
of death in antiarrhythmia trials. J Am Coll Cardiol 1996,27:433-442. 
 
 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 83 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 84 of 100 
 
26. Abbreviations and Definitions  
26.1. Abbreviations 
Abbreviations are shown in Table 26.1-1. 
Table 26.1-1: Abbreviations 
Abbreviation/Acronym 
Term 
ACE 
Angiotensin Converting Enzyme 
ADE 
Adverse Device Effect 
AE  
Adverse Event 
ATP 
Anti-tachycardia pacing 
AV 
Atrioventricular 
BSC 
Boston Scientific 
BMI 
Body mass index  
BUN 
Blood urea nitrogen 
CA125 
Carcinoma antigen 125 
CABG 
Coronary artery bypass grafting 
CHF 
Chronic heart failure 
CI 
Confidence interval 
CIP 
Clinical Investigation Plan 
CRT 
Cardiac Resynchronization Therapy 
CRT-D 
CRT-Defibrillator 
CRT-P 
CRT-Pacemaker 
CRO 
Contract Research Organization 
CRM 
Cardiac Rhythm Management (a business division of Boston Scientific) 
DCM 
Dilated cardiomyopathy 
DD 
Device deficiency 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EF 
Ejection fraction 
eGFR 
Estimated glomerular filtration rate 
ESC 
European Society of Cardiology 
FSFV 
First subject first visit 
GCP 
Good Clinical Practice 
HCP 
Health Care Professional 
HF 
Heart Failure 
HFmrEF 
Heart failure with mid-range ejection fraction  
HFrEF 
Heart failure with reduced ejection fraction 
ICD 
Implantable Cardioverter-Defibrillator 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IFU 
Instructions for Use 
ISO 
International Standard Organization 
IV 
intravenous 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 84 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 85 of 100 
 
Table 26.1-1: Abbreviations 
Abbreviation/Acronym 
Term 
LAT 
Latitude reporting system 
LBBB 
Left bundle branch block 
LSFV 
Last subject first visit 
LSLV 
Last subject last visit 
LV 
Left ventricle/ventricular 
LVEF 
Left ventricular ejection fraction 
MADIT 
Automatic Defibrillator Implantation Trial 
MEDDEV 
Medical Device Guidance 
MI 
Myocardial infarction 
MRI 
Magnetic resonance imaging 
ms 
milli seconds 
NYHA 
New York Heart Association 
OMT 
Optimal medical therapy 
PCI 
Percutaneous coronary intervention 
PG 
Pulse generator 
PM 
Pacemaker 
PSA 
Pacing System Analyzer 
pTH 
Parathyroid hormone 
RBBB 
Right bundle branch block 
RIT 
Reduce Inappropriate Therapy 
RV 
Right ventricle/ventricular 
s 
seconds 
SADE 
Serious Adverse Device Effect 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SCD 
Sudden cardiac death 
SD 
Standard deviation 
SOC 
Standard of care 
TNF 
Tumor necrosis factor 
US 
United States 
USADE 
unanticipated serious adverse device effect 
 
 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 85 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 86 of 100 
 
26.2. Definitions 
Terms are defined in Table 26.2-1.  
Table 26.2-1: Definitions 
Term 
Definition 
Cardiac Perforation 
Penetration of the lead tip through the myocardium to the pericardium or 
beyond (including micro-perforation), either clinically suspected by 
chest x-ray, fluoroscopy or, intra-cardiac electrogram and/or confirmed 
by echocardiogram, CT or visually at operation.  
Cardiac Tamponade 
Also known as pericardial tamponade is an acute type of pericardial 
effusion in which hemodynamic compromise results and urgent 
intervention is required. This will be considered a SADE.  
Complication 
An adverse event that resulted in: death, serious injury, a correction 
using invasive intervention, or permanent loss of device functions. 
Conductor Fracture/Lead 
Fracture 
A mechanical break/disruption within the lead conductor (includes 
connectors, coils and/or electrodes) observed visually, electrically or 
radiographically. 
Device-related 
Complication 
A complication (an AE that resulted in death, serious injury, a correction 
using invasive intervention, or permanent loss of device functions) 
assessed as related to the device. 
Elevated Pacing 
Thresholds 
At implant, pacing thresholds for the permanently programmed 
electrode that are greater than 3.0 volts and at follow-up pacing 
thresholds for the permanently programmed electrode that are either: (1) 
An observed increase of 2-fold over the first chronic threshold; or (2) 
An observed threshold greater than 3.5 volts. Please note that these 
elevations in pacing threshold values may be physiologic, pathologic or 
device-related. 
Extra-cardiac Stimulation 
(e.g., phrenic, 
diaphragm) 
Clinical observation of inadvertent muscle/nerve stimulation other than 
cardiac muscle. 
Hematoma 
If a hematoma requires invasive intervention to evacuate the hematoma, 
it will be considered a SAE. 
Hemodynamic instability 
A state requiring pharmacological or mechanical support to maintain a 
normal blood pressure or adequate cardiac output. 
High Pacing Impedance 
Pacing impedance is considered abnormal based on lead model and 
measurement range of the device. 
High Shock Impedance 
Shock impedance is considered abnormal based on lead model and 
measurement range of the device. 
High Shock Impedance 
when attempting to 
deliver a shock 
High shock impedance is considered abnormal based on lead model and 
measurement range of the device when attempting to deliver a shock. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 86 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 87 of 100 
 
Table 26.2-1: Definitions 
Term 
Definition 
Inappropriate shock due 
to over-sensing 
Shock delivered due to over-sensing resulting from either physiologic or 
non-physiologic causes. 
Inappropriate shock 
Shock 
delivered 
by 
the 
device 
which 
is 
not 
appropriate 
therapy/treatment per the device programming. 
Infection 
If oral antibiotics are prescribed for treatment of an infection, it will be 
considered as an adverse event. If IV antibiotics are required for 
treatment of the infection, then it will be considered a SAE. 
Any confirmed pocket sepsis or lead endocarditis requiring device 
system (generator and lead) extraction will be considered a SAE. 
Intermittent Sensing 
Intermittent loss of sensing or failure to detect intended intrinsic cardiac 
signals (atrial or ventricular) during non-refractory periods at 
programmed sensitivity settings. 
Lead Abrasion 
Upon returned product analysis, leads are analyzed for abrasion. Known 
examples of lead abrasion occur 1) proximal abrasions associated with 
lead-on-lead or lead-on-PG contact in the pocket; 2) mid-lead insulation 
damage caused by clavicle flex-fatigue or crush, suture or suture sleeve, 
insulation wear in the area of vein insertion and 3) distal region wear 
due to lead-on-lead (intra-cardiac), lead-on-heart valve or lead-on-
another anatomy contact. 
Lead Insulation Breach 
A disruption or break in lead insulation observed visually, electrically or 
radiographically. 
Lead 
Migration/Dislodgment 
Radiographic and electrical evidence of electrode displacement from the 
original implant site or electrode displacement that adversely affects 
pacing and/or lead performance. Micro-dislodgement is not included. 
Lead 
Revision/Reposition 
An invasive procedure that involves manipulation of the lead(s) to 
modify the anatomical implanted location of the intra-thoracic portion of 
the lead.  
Loss-of-Capture 
Intermittent or complete failure to stimulate cardiac stimulation (atrial or 
ventricular) at programmed output delivered outside of the cardiac 
refractory period. 
Low Pacing Impedance 
Pacing impedance is considered abnormal based on lead model and 
measurement range of the device. 
Low Shock Impedance 
Shock impedance is considered abnormal based on lead model and 
measurement range of the device. 
Low shock impedance 
when attempting to 
deliver a shock 
Low shock impedance is considered abnormal based on lead model and 
measurement range of the device) when attempting to deliver a shock. 
Normal Battery 
Depletion 
For pulse generators , the condition when a) a device is returned with no 
associated complaint and the device has reached its elective replacement 
indicator(s) with implant time that meets or exceeds the nominal (50 
percentile) predicted longevity at default (labelled) settings, or b) the 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 87 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 88 of 100 
 
Table 26.2-1: Definitions 
Term 
Definition 
device is returned and the device has reached it elective replacement 
indicator(s) with implant time exceeding 75% of the expected longevity 
using the longevity calculation tool available at the time of product 
introduction, calculated using the device’s actual use conditions and 
settings. 
Other, Lead related 
Specific proprietary attributes of a lead, such as sensors which affect a 
leads ability to perform as designed and remain in service. 
Other, Pulse 
Generator/Header related 
Specific proprietary attributes of a pulse generator/header, which affect 
a device’s ability to perform as designed and remain in service. 
Over-sensing 
The occurrence of cardiac or noncardiac events being misinterpreted as 
cardiac depolarization, (e.g., T waves, multiple counting, skeletal 
muscle potentials and extra-cardiac electromagnetic interference (EMI)). 
Pacing Impedance 
Changes 
Pacing impedance changes are considered clinically significant if the 
value changes by more than a 2:1 ratio from the previous value. 
Pain 
A pain requiring oral medication is not considered serious. Pain 
requiring IV analgesics or results in prolonged hospitalization will be 
considered a complication. 
Pneumothorax 
Is a collection of air in the pleural space, causing the lung to collapse. It 
will be considered a SAE if invasive intervention is needed for 
treatment. 
Pocket Revision 
Assuming that the subject continues to participate in the study, a pocket 
revision is an invasive procedure that involves modification in some 
manner to the extra-thoracic device pocket and/or lead(s) therein. There 
is no repositioning of the lead(s) tip in the heart. 
Possible Malfunction 
May be considered if neither of the 2 listed below occurred. 
a) Malfunction with compromised therapy, PG – The condition when 
a device is found to have “malfunctioned” in a manner that 
compromised pacing or defibrillation therapy (including complete loss 
or partial degradation) while implanted and in service. Therapy is 
considered to have been compromised if no therapy is available or 
critical subject protective pacing or defibrillation therapy is not available 
b) Malfunction without compromised therapy, PG - The condition 
when a device is found to have “malfunctioned” in a manner that did not 
compromise pacing or defibrillation therapy while implanted and in 
service. Therapy is not compromised as long as critical subject 
protective pacing or defibrillation therapies are available. Changes in 
device setting that occur as intended by design (i.e. Power-on-reset) that 
do not result in loss of critical subject protective therapies but are 
reported as reasons for explant shall be classified as malfunctions 
without compromised therapy. 
Shock Impedance 
Changes 
Shock impedance changes are considered clinically significant if the 
value changes by more than a 2:1 ratio from the previous value. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 88 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 89 of 100 
 
Table 26.2-1: Definitions 
Term 
Definition 
Significant r-wave 
amplitude decrease over 
2 weeks or less 
A decrease in r-wave value is considered clinically significant if the 
value changes by more than a 2:1 ratio over the course of 2 (2) weeks or 
less. 
Source Data 
All information in original records of clinical findings, observations, or 
other activities in a clinical investigation, necessary for the 
reconstruction and evaluation of the clinical study (original records or 
certified copies including electronic patient charts). 
Source Document 
Printed, optical or electronic document containing source data. 
Examples: Hospital records, laboratory notes, device accountability 
records, radiographs, records kept at the investigation site, and at the 
laboratories involved in the clinical study. 
Suspected Lead Fracture 
May be manifested by abnormal device measurements (i.e. RV lead 
impedance, thresholds, inappropriate shocks) which may be caused as a 
result of conductor/lead fracture. Investigators are requested to complete 
a through lead assessment; confirm through visual, radiographic and 
electrical analysis, and are strongly recommended to return the lead to 
for analysis. 
Suspected Lead Abrasion 
May be manifested by abnormal device measurements (i.e. RV lead 
impedance, thresholds) which may be as a result of unknown lead 
abrasion type (which are not already defined above). Investigators are 
requested to complete a through lead assessment; and strongly 
recommended to return the lead to for analysis. 
Twiddler’s Syndrome 
A complication of pacemaker treatment, in which repeated torsional 
pocket forces applied to the generator cause rotation and, by a ratchet 
mechanism, lead retraction. This may potentially result in lead 
displacement and loss of device function. 
Under sensing 
Complete or intermittent loss of sensing or failure to detect the intended 
intrinsic cardiac signals (atrial or ventricular) during non-refractory 
periods at programmed sensitivity. 
Abbreviations are defined in Table 26.1-1: Abbreviations 
 
 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 89 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 90 of 100 
 
27. Appendices 
27.1. Clinical Trial Organization 
CRO 
ICON Clinical Research Limited 
South Country Business Park 
Leopardstown 
Dublin 18 
Ireland 
 
STUDY SITES 
In Japan will be documented and available upon request on a separate document. 
 
COORDINATING PRINCIPAL INVESTIGATOR 
Professor Kazutaka Aonuma 
Ibaraki  
Japan 
 
 
 
 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 90 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 91 of 100 
 
 
27.2. NYHA Classification 
NYHA Class 
Symptoms 
I 
No limitations of physical activity. Ordinary physical activity does not 
cause undue fatigue, palpitation, or dyspnea. 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary 
physical activity results in fatigue, palpitation, or dyspnea. 
III 
Marked limitation of physical activity. Comfortable at rest, Less than 
ordinary activity causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms 
of HF may be present even at rest. If any physical activity is undertaken, 
discomfort is increased. 
Source: Heart Failure Society of America. NYHA Classification: The Stages of Heart Failure. March 2012. 
Available at: http://www.abouthf.org/questions stages.htm. 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 91 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 92 of 100 
 
27.3. ESC Guidelines 2016: Patterns of Atrial Fibrillation 
 
Source: 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. 
European Heart Journal, doi: 10.1093/eurheart/ehw210 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 92 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 93 of 100 
 
 
27.4. Classification of LVEF 
 
Source: 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure, European Heart Journal, doi: 10.1093/eurheart/ehw128 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 93 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 94 of 100 
 
27.5. ESC Guidelines 2016: Recommendations for cardiac resynchronization therapy implantation in patients with heart 
failure 
 
Source: 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure, European Heart Journal, doi: 10.1093/eurheart/ehw128 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 94 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 95 of 100 
 
 
27.6. Declaration of Helsinki 
DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI - 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended 
by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Preamble 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving 
human subjects to adopt these principles. 
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health 
of my patient will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A physician shall act in the patient's best interest when providing medical 
care.” 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research. The physician's knowledge 
and conscience are dedicated to the fulfilment of this duty. 
5. Medical progress is based on research that ultimately must include studies involving 
human subjects. 
6. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best proven 
interventions must be evaluated continually through research for their safety, effectiveness, 
efficiency, accessibility and quality. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 95 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 96 of 100 
 
7. Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
8. While the primary purpose of medical research is to generate new knowledge, this goal 
can never take precedence over the rights and interests of individual research subjects. 
9. It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. The responsibility for the protection of research subjects 
must always rest with the physician or other health care professionals and never with the 
research subjects, even though they have given consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable international 
norms and standards. No national or international ethical, legal or regulatory requirement 
should reduce or eliminate any of the protections for research subjects set forth in this 
Declaration. 
11. Medical research should be conducted in a manner that minimises possible harm to the 
environment. 
12. Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications. Research on 
patients or healthy volunteers requires the supervision of a competent and appropriately 
qualified physician or other health care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14. Physicians who combine medical research with medical care should involve their patients 
in research only to the extent that this is justified by its potential preventive, diagnostic or 
therapeutic value and if the physician has good reason to believe that participation in the 
research study will not adversely affect the health of the patients who serve as research 
subjects. 
15. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
Risks, Burdens and Benefits  
16. In medical practice and in medical research, most interventions involve risks and 
burdens. 
Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the risks and burdens to the research subjects. 
17. All medical research involving human subjects must be preceded by careful assessment 
of predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected by 
the condition under investigation. 
Measures to minimise the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher.  
18. Physicians may not be involved in a research study involving human subjects unless they 
are confident that the risks have been adequately assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive 
proof of definitive outcomes, physicians must assess whether to continue, modify or 
immediately stop the study. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 96 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 97 of 100 
 
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive to 
the health needs or priorities of this group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to benefit from the knowledge, 
practices or interventions that result from the research. 
Scientific Requirements and Research Protocols 
21 Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal experimentation. 
The welfare of animals used for research must be respected. 
22. The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, potential conflicts 
of interest, incentives for subjects and information regarding provisions for treating and/or 
compensating subjects who are harmed as a consequence of participation in the research 
study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This committee 
must be transparent in its functioning, must be independent of the researcher, the sponsor and 
any other undue influence and must be duly qualified. It must take into consideration the 
laws and regulations of the country or countries in which the research is to be performed as 
well as applicable international norms and standards but these must not be allowed to reduce 
or eliminate any of the protections for research subjects set forth in this Declaration.  
The committee must have the right to monitor ongoing studies. The researcher must 
provide monitoring information to the committee, especially information about any serious 
adverse events. No amendment to the protocol may be made without consideration and 
approval by the committee. After the end of the study, the researchers must submit a final 
report to the committee containing a summary of the study’s findings and conclusions.  
Privacy and Confidentiality 
24. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
Informed Consent  
25. Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members or 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 97 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 98 of 100 
 
community leaders, no individual capable of giving informed consent may be enrolled in a 
research study unless he or she freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, any 
possible conflicts of interest, institutional affiliations of the researcher, the anticipated 
benefits and potential risks of the study and the discomfort it may entail, post-study 
provisions and any other relevant aspects of the study. The potential subject must be 
informed of the right to refuse to participate in the study or to withdraw consent to participate 
at any time without reprisal. Special attention should be given to the specific information 
needs of individual potential subjects as well as to the methods used to deliver the 
information. 
After ensuring that the potential subject has understood the information, the physician or 
another appropriately qualified individual must then seek the potential subject’s freely-given 
informed consent, preferably in writing. If the consent cannot be expressed in writing, the 
non-written consent must be formally documented and witnessed. 
All medical research subjects should be given the option of being informed about the 
general outcome and results of the study. 
27. When seeking informed consent for participation in a research study the physician must 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent must be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
28. For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. These 
individuals must not be included in a research study that has no likelihood of benefit for them 
unless it is intended to promote the health of the group represented by the potential subject, 
the research cannot instead be performed with persons capable of providing informed 
consent, and the research entails only minimal risk and minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent is 
able to give assent to decisions about participation in research, the physician must seek that 
assent in addition to the consent of the legally authorised representative. The potential 
subject’s dissent should be respected. 
30. Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition that 
prevents giving informed consent is a necessary characteristic of the research  group. In such 
circumstances the physician must seek informed consent from the legally authorised 
representative. If no such representative is available and if the research cannot be delayed, 
the study may proceed without informed consent provided that the specific reasons for 
involving subjects with a condition that renders them unable to give informed consent have 
been stated in the research protocol and the study has been approved by a research ethics 
committee. Consent to remain in the research must be obtained as soon as possible from the 
subject or a legally authorised representative. 
31. The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 98 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 99 of 100 
 
32. For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek informed 
consent for its collection, storage and/or reuse. There may be exceptional situations where 
consent would be impossible or impracticable to obtain for such research. In such situations 
the research may be done only after consideration and approval of a research ethics 
committee. 
Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; 
or 
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention is 
necessary to determine the efficacy or safety of an intervention and the patients who receive 
any intervention less effective than the best proven one, placebo, or no intervention will not 
be subject to additional risks of serious or irreversible harm as a result of not receiving the 
best proven intervention.  
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34. In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention 
identified as beneficial in the trial. This information must also be disclosed to participants 
during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have a 
duty to make publicly available the results of their research on human subjects and are 
accountable for the completeness and accuracy of their reports. All parties should adhere to 
accepted guidelines for ethical reporting. Negative and inconclusive as well as positive 
results must be published or otherwise made publicly available. Sources of funding, 
institutional affiliations and conflicts of interest must be declared in the publication. Reports 
of research not in accordance with the principles of this Declaration should not be accepted 
for publication. 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with 
informed consent from the patient or a legally authorised representative, may use an 
unproven intervention if in the physician's judgement it offers hope of saving life, re-
establishing health or alleviating suffering. This intervention should subsequently be made 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 99 of 100

Study Reference Number: C2076 
 
Form/Template 92120219 Rev/Ver A 
Confidential 
HINODE Study, Clinical Investigation Plan, Version D 29 March 2018 
 
 
Page 100 of 100 
 
the object of research, designed to evaluate its safety and efficacy. In all cases, new 
information must be recorded and, where appropriate, made publicly available. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
92082863 D.3
Protocol Hinode Study
Page 100 of 100