Multicenter Automatic Defibrillator Implantation Trial With Subcutaneous Implantable Cardioverter Defibrillator (MADIT S-ICD)
Phase: NA
Conditions: Tachycardia, Diabetes Mellitus, Cardiovascular Disease
Sponsor: Boston Scientific Corporation

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Multicenter Automatic Defibrillator Implantation Trial with Subcutaneous 
Implantable Cardioverter Defibrillator 
(MADIT S-ICD) 
 
CLINICAL PROTOCOL 
Version AB 
April 25, 2016  
 
 
Sponsored By 
Boston Scientific Corporation 
4100 Hamline Ave. N. 
St. Paul, MN 55112 
Tel: (800) CARDIAC 
 
Principal Investigator 
Valentina Kutyifa, MD, PhD 
University of Rochester Medical Center 
Heart Research Follow-up Program 
265 Crittenden Blvd., Room 4401 
Rochester, NY 14642 
Tel: (585) 275-5391 
 
 
 
 
 
 
 
This protocol contains confidential information for use by the Investigators and their 
designated representatives participating in this clinical investigation. The protocol should be 
held confidential and maintained in a secure location. 
Do not copy or distribute without written permission from Boston Scientific Corporation. 
 
 
NCT:02787785

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Contact Information 
Role 
Contact  
Clinical Contact 
Mary W. Brown 
University of Rochester Medical Center 
Heart Research Follow-up Program, CU 420653 
265 Crittenden Blvd. , Room 4401 
Rochester, NY, 14642 
 
E-mail address: Mary.Brown@heart.rochester.edu 
 
Coordinating Principal 
Investigator 
Valentina Kutyifa, MD, PhD 
University of Rochester Medical Center 
Heart Research Follow-up Program, CU 420653 
265 Crittenden Blvd.  
Rochester, NY, 14642 
Phone: +1-585-275-2676 
E-mail address: Valentina.Kutyifa@heart.rochester.edu  
 
Coordinating 
Co-Principal 
Investigator 
Arthur J. Moss, MD  
University of Rochester Medical Center 
Heart Research Follow-up Program, CU 420653 
265 Crittenden Blvd. , Room 4401 
Rochester, NY, 14642 
 
E-mail address: Arthur.Moss@heart.rochester.edu 
 
MADIT S-ICD 
Executive Committee 
Christopher Beck, Mary W. Brown, David Cannom, James 
Daubert, Mark Estes, Henry Greenberg, Ilan Goldenberg, Stephen 
Hammes, David Huang, Helmut Klein, Reinoud Knops, Mikhail 
Kosiborod, Valentina Kutyifa, Arthur J. Moss, Jeanne Poole, 
Claudio Schuger, Jagmeet Singh, Scott Solomon, David Wilber, 
Wojciech Zareba 
 
 
 
 

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Original Release: April 25, 2016 
Current Version: AB 
Revision History 
Revision Number 
Release Date 
Section 
Change 
Reason for Change 
AA 
NA 
NA 
NA 
Pre-release version 
      

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2. Protocol Synopsis 
Objective(s) 
The primary objective is to test the hypothesis that post-MI diabetic 
patients with relatively preserved ejection fraction of 36-50% will have a 
survival benefit from a subcutaneous implantable cardioverter defibrillator 
(S-ICD). 
Planned 
Indication(s) for 
Use  
The EMBLEM S-ICD System is intended to provide defibrillation therapy 
for the treatment of life-threatening ventricular tachyarrhythmias in patients 
who do not have symptomatic bradycardia, incessant ventricular 
tachycardia, or spontaneous, frequently recurring ventricular tachycardia 
that is reliably terminated with anti-tachycardia pacing.  
Test Device 
System 
• EMBLEM™  S-ICD Pulse Generator (Model A209) or later 
generation commercially available BSC S-ICD pulse generator1 
• EMBLEM™ S-ICD Subcutaneous Electrode (Model 3401),  Q-
TRAK Electrode (Model 3010) or later generation market approved 
BSC S-ICD electrode1 
• EMBLEM™ S-ICD Electrode Insertion Tool, (Model 4711), Q-
GUIDE Electrode Insertion Tool Model (Model 4010), or later 
generation market approved BSC electrode insertion tool1 
• EMBLEM™ S-ICD Programmer, (Model 3200) or other market 
approved programmer capable of interrogating BSC S-ICD 
Systems1 
• Additional implant accessories used in the implant procedure will 
be considered to be part of the device system. 
Control 
Conventional medical therapy (CMT). 
Study Design 
Prospective, multicenter, international, randomized, controlled trial. 
Planned 
Number of 
Subjects 
1800 subjects to be enrolled according to the sample size assumptions. 
 
 
                                                 
1 Over the course of this study, new model numbers of each device may be introduced.  The intention of 
this protocol is to allow the use of newer Boston Scientific subcutaneous implantable cardioverter 
defibrillator (S-ICD) system components that are market approved by the regulatory authorities in the 
country of the investigative site.   
 

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Planned Number 
of Sites/Countries 
Approximately 100 sites in the US, EU and Israel with a maximum of 150. 
Primary Endpoint The primary endpoint is all-cause mortality. 
Additional 
Objectives 
In all randomized subjects the following analyses will be performed: 
• All-cause mortality and sudden cardiac death  in various subgroups 
including sex, race, age continuous and dichotomized at 75 years, 
duration of diabetes, presence vs. absence of insulin therapy, 
HbA1c dichotomized at 8%, LVEF continuous and dichotomized at 
40%, and other relevant subgroups 
• Healthcare utilization assessed through adverse event reporting 
Additional Pre-
Specified 
Analyses 
In subjects randomized to S-ICD the following analyses will be performed: 
• Frequency and outcomes of S-ICD Inappropriate Shocks 
• Frequency and outcomes of S-ICD treated ventricular tachycardia 
(VT)  and ventricular fibrillation (VF) 
• Frequency and outcomes of S-ICD device complications, including 
but not limited to: infection, device malfunction and electrode 
movement 
Method of 
Assigning Patients 
to Treatment 
Subjects will be randomized 2:1 (S-ICD:CMT).  Randomization will occur 
electronically using the clinical data collection system. 
Follow-up 
Schedule 
• Screening and Consent 
• Baseline data collection 
• Implant procedure (device subjects only) 
• 1 month visit (in-clinic visit for S-ICD subjects and phone contact 
for CMT subjects) 
• 6 month phone contact (conduct annually thereafter at months 18, 
30, 42, etc.) 
• 12 month visit (conduct annually thereafter at months 24, 36, 48, 
etc.)  
o S-ICD Arm 12 Month in-clinic follow-up 
o CMT Arm 12 Month phone follow-up 
Study Duration 
The study is expected to enroll over a 48 month period with an average of 2.6 
years of follow-up. Note: the length of the study is based on the accumulation 
of endpoint events and the hazard ratio. 
Eligibility 
Criteria 
Note: The most recent evaluations, measurements or test results in the 
medical record must be used to assess inclusion and exclusion criteria. 

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Key Inclusion 
Criteria 
• Age ≥ 65 years on date of consent 
• Diabetes mellitus treated with oral hypoglycemic agents, non-insulin 
injectable and/or insulin for the past 3 calendar months or longer prior to 
consent date 
• LV ejection fraction (LVEF) of 36-50% documented by imaging 
(preferably by MRI or echocardiographic methods), within 12 calendar 
months before consent date and at least 3 calendar months after most 
recent MI, PCI or CABG  
• One or more clinically documented, enzyme-positive myocardial 
infarctions, more than 3 calendar months prior to consent date*.  
o If enzyme information and clinical documentation is not available, 
there must be a clear evidence of prior silent myocardial infarction 
identified as either new pathologic Q waves on ECG or imaging 
documentation of an infarcted area (left ventricular angiography/ 
nuclear scan/ MRI)*  
* MI qualification based on the Universal Definition of MI1   
• Qualifying 12-lead ECG within 6 calendar months before consent date and 
at least 3 calendar months after most recent MI, PCI or CABG  
* The qualifying ECG can be sinus rhythm or atrial fibrillation 
(patients with persistent or permanent atrial fibrillation should have a 
controlled ventricular response <100 bpm on consent date) 
*QRS duration on the qualifying ECG >90 msec 
• Passing S-ICD Screening ECG performed per applicable user’s manual on 
or after the consent date that identifies one or more qualifying S-ICD 
sensing vectors 
Key Exclusion 
Criteria 
• Ejection fraction >50% or <36% within 12 calendar months prior to 
consent date and at least 3 calendar months after the most recent MI, PCI 
or CABG  
• Existing guideline based indication for an ICD, pacemaker, CRT, or CRT-
D therapy  
• Existing or previously implanted ICD, CRT, CRT-D, or pacemaker device 
system 
• Active infection at the time of consent  
• Contraindication for S-ICD implantation according to the S-ICD pulse 
generator (PG) User’s Manual 
• Hemodialysis and/or peritoneal dialysis at the time of enrollment  
• New York Heart Association Class IV in the past 3 calendar months prior 
to or at the time of consent date 
• Coronary artery bypass graft surgery or percutaneous coronary 
intervention (balloon and/or stent angioplasty) within 3 calendar months 
prior to the consent date 
• Enzyme-positive myocardial infarction or silent myocardial infarction 
diagnosed within 3 calendar months prior to the consent date  

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• Unstable angina with need for outpatient treatment or hospitalization 
(change/addition of anti-anginal medication and/or coronary 
revascularization), within 3 calendar months prior to the consent date 
• Angiographic evidence of coronary disease in a patient that is a candidate 
for coronary revascularization and is likely to undergo CABG or PCI in 
the next 3 calendar months  
• High risk for arterial embolism (e.g. presence of mobile left ventricular  
• thrombus) 
• Hemodynamically significant congenital heart disease, aortic valvular 
heart disease, or amyloid heart disease 
• Baseline body mass index > 45 kg/m2 
• On a heart transplant list or likely to undergo heart transplant within one 
calendar year 
• Presence of any other disease, other than the subject’s cardiac disease, that 
in the opinion of the investigator is likely to significantly reduce the 
patient’s likelihood of survival for the duration of the trial (e.g. cancer, 
liver failure). 
• Unwillingness or inability to cooperate with the protocol 
• Resides at such a distance from the enrolling site so travel to follow-up 
visits would be unusually difficult  
• Reversible causes of heart disease (e.g. viral myocarditis or tachycardia 
induced cardiomyopathy) 
• Participation in other clinical trials (observational registries are allowed 
with approval from the CDC) 
• Does not anticipate residing in the vicinity of the enrolling site for the 
duration of the trial 
• Unwillingness to sign the consent for participation 
 
Statistical Methods  
Primary 
Statistical 
Hypothesis 
Post-MI diabetes patients with a relatively preserved left ventricular ejection 
fraction will have reduced mortality from S-ICD as compared to CMT. 
Statistical Test 
Method 
Wang-Tsiatis group sequential design based on monitoring the log-rank 
statistic for time-to-death, with stochastic curtailment based on conditional 
power and sample size re-estimation based on overall recruitment, withdrawal, 
and event rates.  
Sample Size 
Parameters 
1800 patients are expected to yield a maximum of 454 deaths, which provides 
80% power at a two-sided significance level of 5% to detect a HR of 0.75.  
 
 
 

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3. Table of Contents 
1. 
TITLE PAGE  ........................................................................................................................ 1 
2. 
PROTOCOL SYNOPSIS .......................................................................................................... 4 
3. 
TABLE OF CONTENTS .......................................................................................................... 8 
4. 
INTRODUCTION ................................................................................................................. 15 
5. 
TEST DEVICE DESCRIPTION (TREATMENT ARM ONLY) ................................................. 17 
5.1. Device Description .................................................................................................. 17 
5.1.1. EMBLEM S-ICD Pulse Generator ....................................................................... 18 
5.1.2. EMBLEM S-ICD Subcutaneous Electrode ......................................................... 19 
5.1.3. EMBLEM S-ICD Electrode Insertion Tool (EIT) .............................................. 19 
5.1.4. EMBLEM S-ICD Programmer ............................................................................ 20 
5.1.5. S-ICD System Indication ....................................................................................... 20 
6. 
OBJECTIVES ...................................................................................................................... 21 
6.1. Primary Study Objective ....................................................................................... 21 
6.2. Secondary Study Objective ................................................................................... 21 
6.3. Tertiary Study Analyses ........................................................................................ 21 
7. 
ENDPOINTS ........................................................................................................................ 22 
7.1. Primary Endpoint .................................................................................................. 22 
8. 
DESIGN .............................................................................................................................. 22 
8.1. Scale and Duration ................................................................................................. 22 
8.2. Treatment Assignment........................................................................................... 23 
8.2.1. Treatment and Control .......................................................................................... 23 
8.3. Justification for the Study Design ......................................................................... 24 
9. 
SUBJECT SELECTION ......................................................................................................... 25 
9.1. Study Population and Eligibility ........................................................................... 25 
9.2. Inclusion Criteria ................................................................................................... 27 
9.3. Exclusion Criteria .................................................................................................. 27 

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10. SUBJECT ACCOUNTABILITY .............................................................................................. 29 
10.1. Pre-Enrollment Screening ..................................................................................... 29 
10.2. Point of Enrollment ................................................................................................ 29 
10.3. Withdrawal ............................................................................................................. 29 
10.4. Subject Status and Classification .......................................................................... 29 
10.5. Implant Status and Classification ......................................................................... 30 
10.6. Enrollment Controls .............................................................................................. 30 
10.7. End-of-Study Action Plan ..................................................................................... 30 
11. STUDY METHODS .............................................................................................................. 31 
11.1. Study Flow .............................................................................................................. 31 
11.2. Data Collection ....................................................................................................... 32 
11.3. Screening Process ................................................................................................... 34 
11.3.1. 
WIN-Her Initiative .................................................................................. 34 
11.4. MADIT S-ICD Screening Data and Consent....................................................... 35 
11.5. Randomization and Baseline Data (Enrollment) ................................................ 36 
11.6. Implant Data/Visit .................................................................................................. 36 
11.6.1. 
Implant Procedure ................................................................................... 36 
11.6.2. 
Conversion Testing .................................................................................. 37 
11.6.3. 
Implant Visit............................................................................................. 38 
11.6.4. 
Protocol Required Programming ........................................................... 39 
11.7. One Month Follow-up Visit ................................................................................... 39 
11.8. Six Month Follow-up Visit (Phone contact)/ Medical Record Review .............. 40 
11.9. Annual Follow-up Visit .......................................................................................... 40 
11.9.1. 
CMT (Control) Group Annual Follow-up Requirements .................... 40 
11.9.2. 
S-ICD (Treatment) Group Annual Follow-up Requirements ............. 41 
11.9.3. 
Additional Non-Visit Related Data Collection ...................................... 42 
11.10. 
Device Status Change (S-ICD treatment group) ................................... 43 
11.10.1. 
System Revision ....................................................................................... 43 
11.10.2. 
PG/Electrode Replacement ..................................................................... 43 
11.10.3. 
PG/Electrode Explant without Replacement ........................................ 44 
11.10.4. 
Out of Service Device(s) .......................................................................... 44 

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11.10.5. 
Cardiac Implantable Electronic Device Information (Non-study 
device implantation) ................................................................................ 45 
11.11. 
Study Completion Visit ........................................................................... 45 
11.11.1. 
Subject Withdrawal Prior to Study Completion or Study 
Termination ............................................................................................. 45 
11.12. 
Source Documents ................................................................................... 48 
11.13. 
Overall Study Completion Requirements ............................................. 48 
12. STATISTICAL CONSIDERATIONS ....................................................................................... 49 
12.1. Endpoints ................................................................................................................ 49 
Primary Endpoint ..................................................................................................... 49 
12.1.1.1. Hypotheses ................................................................................ 49 
12.1.1.2. Sample Size ............................................................................... 49 
12.1.1.3. Statistical Methods .................................................................... 49 
12.2. General Statistical Methods .................................................................................. 57 
12.2.1. 
Analysis Sets ............................................................................................. 57 
12.2.2. 
Control of Systematic Error/Bias ........................................................... 57 
12.2.3. 
Number of Subjects per Investigative Site ............................................ 57 
12.3. Data Analyses ......................................................................................................... 58 
12.3.1. 
Other Objectives/Measurements ............................................................ 58 
12.3.2. 
Interim Analyses ...................................................................................... 59 
12.3.3. 
Subgroup Analyses .................................................................................. 59 
12.3.4. 
Justification of Pooling ............................................................................ 60 
12.3.5. 
Multivariable Analyses ............................................................................ 60 
12.3.6. 
Other Analyses ......................................................................................... 60 
12.3.7. 
Changes to Planned Analyses ................................................................. 61 
13. DATA MANAGEMENT ........................................................................................................ 61 
13.1. Data Collection, Processing, and Review ............................................................. 61 
13.2. Data Retention ........................................................................................................ 62 
14. STUDY ORGANIZATION ..................................................................................................... 62 
14.1. University of Rochester.......................................................................................... 63 
14.2. Data Safety and Monitoring Board ...................................................................... 63 
14.3. Mortality Events Committee ................................................................................. 64 

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15. AMENDMENTS ................................................................................................................... 64 
16. DEVIATIONS ...................................................................................................................... 64 
17. COMPLIANCE ..................................................................................................................... 65 
17.1. Statement of Compliance ....................................................................................... 65 
17.2. Investigator Responsibilities ................................................................................. 65 
17.2.1. 
Delegation of Responsibility .................................................................... 68 
17.3. Institutional Review Board/ Ethics Committee ................................................... 68 
17.4. Sponsor Responsibilities ........................................................................................ 69 
17.4.1. 
Role of Boston Scientific Representatives .............................................. 70 
17.5. Insurance ................................................................................................................. 71 
18. MONITORING ..................................................................................................................... 73 
19. POTENTIAL RISKS AND BENEFITS ASSOCIATED WITH THE S-ICD SYSTEM ................... 74 
19.1. Anticipated Adverse Events .................................................................................. 74 
19.2. Anticipated Adverse Device Effects ...................................................................... 75 
19.3. Risks associated with Participation in the Clinical Study .................................. 75 
19.4. Risk Minimization Actions .................................................................................... 75 
19.5. Anticipated Benefits ............................................................................................... 75 
19.6. Risk to Benefit Rationale ....................................................................................... 76 
20. SAFETY REPORTING .......................................................................................................... 76 
20.1. Reportable Study Events ....................................................................................... 76 
20.2. Definitions and Classification ............................................................................... 77 
20.3. Relationship to Study Device(s) ............................................................................ 79 
20.4. Investigator Reporting Requirements .................................................................. 81 
20.5. Boston Scientific Device Deficiencies .................................................................... 82 
20.6. Reporting to Regulatory Authorities / IRBs / ECs / Investigators .................... 83 
20.7. Subject Death Reporting ....................................................................................... 83 
21. INFORMED CONSENT......................................................................................................... 84 
22. ADDITIONAL SAFETY MONITORING ................................................................................. 86 
22.1. Safety Monitoring Process ..................................................................................... 86 

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23. SUSPENSION OR TERMINATION ........................................................................................ 86 
23.1 Premature Termination of the Study by the Sponsor ........................................ 86 
23.1.1 
Criteria for Premature Termination of the Study by the Sponsor .............. 87 
23.2 Termination of Study Participation by the Investigator or Withdrawal of 
IRB/ EC Approval .................................................................................................. 87 
23.3 Criteria for Suspending/Terminating an Individual Study Center by the 
CDC/Sponsor .......................................................................................................... 88 
24. PUBLICATION POLICY ....................................................................................................... 88 
25. REIMBURSEMENT AND COMPENSATION FOR SUBJECTS .................................................. 89 
25.1. Subject Reimbursement......................................................................................... 89 
25.2. Compensation for Subject’s Health Injury ......................................................... 89 
26. ABBREVIATIONS AND DEFINITIONS .................................................................................. 89 
26.1. Abbreviations ......................................................................................................... 89 
26.2. Definitions ............................................................................................................... 90 
27. APPENDICES ...................................................................................................................... 91 
27.1. MADIT-S-ICD Executive Committee Members ................................................. 91 
27.2. MADIT-S-ICD Mortality Events Committee ...................................................... 92 
27.3. Statistical Considerations ...................................................................................... 94 
27.4. Hinkle- Thaler Criteria.......................................................................................... 97 
27.5. MADIT S-ICD Conversion Testing Protocol ...................................................... 98 
27.6. Bibliography ........................................................................................................... 99 
 
 
 

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List of Figures 
Figure 9-1: Enrollment Process .............................................................................................. 26 
Figure 11-1: Study Visit Flow Chart ...................................................................................... 31 
Figure 12-1: Stopping and Decision Boundaries for the Design ............................................ 50 
Figure 14-1:  Study Organization ........................................................................................... 63 
 
List of Tables 
Table 9.2-1: Inclusion Criteria ................................................................................................ 27 
Table 9.3-1: Exclusion Criteria ............................................................................................... 28 
Table 11.2-1 CMT Cohort Data Collection Schedule ............................................................ 32 
Table 11.2-2 S-ICD Cohort Data Collection Schedule ........................................................... 33 
Table 11.4-1: Screening Source Documentation .................................................................... 35 
Table 11.5-1: Baseline Data Collection .................................................................................. 36 
Table 11.6.3-1: Implant Data Collection ................................................................................ 38 
Table 11.6.4-1: Required S-ICD Programming ...................................................................... 39 
Table 11.7-1: One Month Follow-Up Visit Data Collection .................................................. 39 
Table 11.8-1: Six Month Follow-Up Visit Data Collection ................................................... 40 
Table 11.9.2-1: Annual Follow-Up Visit Data Collection ...................................................... 42 
Table 11.10.1-1. System Revision Data Collection ................................................................ 43 
Table 11.10.2-1 PG/Electrode Replacement Data Collection ................................................ 44 
Table 11.10.4-1 Out of Service Data Collection..................................................................... 45 
Table 11.11.1-1 Study Completion Data Collection ............................................................... 47 
Table 12.1-1: Coordinates of the Upper and Lower Stopping Boundaries ............................. 51 
Table 12.1-2 Alternative Scales for the Upper and Lower Stopping Boundaries: Score 
Statistic and MLE of HR .................................................................................. 52 
Table 12.1-3 Simulation Results Using a Conditional Power Threshold of 0.0001% ........... 55 
Table 12.1-4: Characteristics of the Study Design ................................................................. 56 
Table 12.1-5: Assuming 45 ppm throughout (1800 pts in 40 months) ................................... 57 
Table 12.1-6: Assuming 30 ppm throughout (1800 pts in 60 months) ................................... 57 
Table 19.1-1 Potential Adverse Events for Implantation of the S-ICD System ..................... 74 
Table 20.2-1: Safety Reporting Definitions ............................................................................ 77 

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Table 20.3-1: Criteria for Assessing Relationship of Study Device/Study procedure to 
Adverse Event .................................................................................................. 80 
Table 20.4-1: Investigator Reporting Requirements ............................................................... 81 
Table 20.7-1 Death Narrative Summary Required Components ............................................ 83 
Table 26.1-1: Abbreviations ................................................................................................... 89 
Table 26.2-1: Definitions ........................................................................................................ 90 
Table 27.3-1: Monthly Projections and Accounting for the Study Design............................. 94 
 
 
 

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4. Introduction 
Implantable cardioverter defibrillators (ICD)2  and more recently the subcutaneous ICD 
(S-ICD)3-6  have been shown to be effective in preventing sudden cardiac death in high-
risk cardiac patients. The MADIT II trial previously demonstrated a significant reduction 
in all-cause mortality with an ICD implantation compared to optimal medical therapy 
(hazard ratio 0.69; 95% CI 0.51 to 0.93; two-sided P=0.016) in high-risk cardiac patients 
with prior myocardial infarction and severely impaired left ventricular ejection fraction 
(LVEF  ≤ 30%).2 
However, patients with severely impaired LVEF represent only a minority of patients at 
risk for sudden cardiac death (SCD)7. Other cohorts at high risk for SCD who could 
potentially benefit from an ICD include patients following a coronary event, especially 
those with other clinical risk factors, such as age or diabetes mellitus (DM). 
Diabetes mellitus has been shown to be associated with increased risk for SCD following 
a myocardial infarction, independent of the infarct size and LVEF, but is not currently 
used in the indication for ICD implantation8. Data from a substudy of the VALIANT 
trial9, which enrolled 11,000 subjects (3, 095 diabetics), indicate that diabetes was 
associated with a 37% higher risk of all-cause mortality, independent of LVEF, (adjusted 
hazard ratio of 1.37, 95% CI 1.25-1.51) compared to non-diabetics.  The mortality risk in 
diabetic patients with LVEF >39% was similar to the mortality risk in non-diabetic 
patients with LVEF in the 30% range.10 This observation was further supported by 
another large clinical study, the Candesartan in Heart Failure – Assessment of Reduction 
in Mortality and Morbidity (CHARM) program11, and by smaller single and multicenter 
studies12, 13. The large multi-center study assessing 3276 post infarction patients from 
Germany and Finland showed that the incidence of SCD was significantly higher in 
diabetic versus non-diabetic patients with an LVEF >35% (HR 3.8 (95% CI 2.4-5.8; 
p<0.001), and the incidence of SCD in diabetic patients with LVEF >35% was similar to 
the incidence in non-diabetic patients with an LVEF ≤ 35% (4.1% vs 4.9%, 
respectively)13. 

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These data indicate that post-MI diabetic patients have a significant risk for SCD even 
with a relatively preserved LVEF, and present a population with a significant unmet need 
that could potentially be addressed with an expanded ICD indication. This may have an 
important global health impact and clinical implications. Diabetes is currently one of the 
most prevalent, major health issues in the United States and throughout the world.  It is 
estimated that DM affects nearly 29 million people in the United States alone and claims 
more than 250,000 lives annually, with higher mortality risk in those older than 60 years 
of age; furthermore, the prevalence of diabetes is expected to increase dramatically in the 
US and worldwide in the near future. 14, 15   
 
Therefore, the MADIT S-ICD study was designed to prospectively test the hypothesis 
that post-MI diabetic patients with a relatively preserved left ventricular ejection fraction 
(LVEF 36-50%) will demonstrate a lower rate of all-cause mortality with an S-ICD than 
in those who do not receive an S-ICD.  The S-ICD was chosen for this study design due 
to device system characteristics that could potentially provide advantages in diabetic 
patients who may otherwise be at a higher risk for device-related infections16-18.   
  
 
 

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5. Test Device Description (Treatment Arm Only) 
5.1. Device Description 
The following information is a brief summary of the EMBLEM S-ICD System and its 
principle of operation.  Refer to the applicable User’s Manuals for additional information. 
The EMBLEM S-ICD System is an implantable defibrillator system that treats 
ventricular tachyarrhythmias using a subcutaneous pulse generator and a subcutaneous 
electrode.  The full EMBLEM S-ICD System consists of four devices that comprise the 
study device system: 
• EMBLEM™ S-ICD Pulse Generator (Model A209) or later generation market 
approved BSC S-ICD pulse generator 
• EMBLEM™ S-ICD Subcutaneous Electrode (Model 3401), Q-TRAK Electrode 
(Model 3010) or later generation market approved BSC S-ICD electrode 
• EMBLEM™ S-ICD Electrode Insertion Tool, (Model 4711), Q-GUIDE Electrode 
Insertion Tool Model (Model 4010), or later generation market approved BSC 
electrode insertion tool 
• EMBLEM™ S-ICD Programmer, (Model 3200) or other market approved 
programmer capable of interrogating BSC S-ICD Systems 
Note: Additional commercially available implant accessories used in the implant 
procedure are considered to be part of the test device system. 
Over the course of this study, new model numbers of each device may become approved 
for use.  The intention of this protocol is to allow the use of newer Boston Scientific 
subcutaneous implantable cardioverter defibrillator (S-ICD) system components that are 
market approved by the regulatory authorities in the country of the study center.   
 
 
 

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The EMBLEM S-ICD System is designed to work with the following accessories: 
• Programmer telemetry wand; 
• Magnet; 
• Suture sleeve; 
• Torque wrench; 
• SD memory card 
  
The EMBLEM S-ICD System also involves the use of a surface ECG screening tool, 
which is used to determine the adequacy of sensing in potential candidates for an S-ICD.  
Any new screening tools or methods that are market approved by the regulatory 
authorities in the country of the study center may be used. 
5.1.1. EMBLEM S-ICD Pulse Generator 
The EMBLEM S-ICD pulse generator comprises an inner structure of discrete electrical 
components, interconnected hybrid assemblies, batteries, and high energy capacitors.  
The inner assembly is enclosed in a hermetically sealed can with a pre-molded 
polyurethane header for electrode connection.  The header contains a single port for 
connection of the subcutaneous electrode to accommodate sensing, pacing, and 
defibrillation.  The EMBLEM S-ICD pulse generator is designed to provide high energy 
defibrillation shocks using a constant tilt biphasic waveform and is capable of delivering 
bradycardia demand pacing for a period up to thirty seconds following defibrillation 
therapy.  Future generations of the BSC S-ICD pulse generator market approved by the 
appropriate regulatory bodies may be included in the study. 
 
 

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5.1.2. EMBLEM S-ICD Subcutaneous Electrode 
The EMBLEM S-ICD subcutaneous electrode features one high voltage defibrillation 
coil for the purpose of providing defibrillation energy.  It is constructed using multifilars 
of metallic wire formed into a coil.  Two sense electrodes (proximal and distal) are used 
for sensing.  These sense electrodes are electrically insulated from the shock electrode by 
a multi-lumen polymeric tube. 
Electrical connectivity to the pulse generator is provided using multiple strands of 
insulated metallic cable inserted into the same multi-lumen polymeric tube.  This tube 
comprises the body of the subcutaneous electrode and is subcutaneously implanted from 
the device pocket along the rib margin to the sternum.  The proximal termination 
comprises a multi-pole connector to plug into the header of the BSC S-ICD pulse 
generator.  The connector is designed to be compatible with the BSC S-ICD pulse 
generators only. Future generations of the BSC subcutaneous electrode market approved 
by the appropriate regulatory authorities may be included in the study. 
5.1.3. EMBLEM S-ICD Electrode Insertion Tool (EIT) 
The EMBLEM S-ICD EIT is a single use, disposable subcutaneous tunneling tool that is 
used to facilitate predictable placement of the subcutaneous electrode.  The EIT is 
designed to create an appropriately sized subcutaneous sinus for the subcutaneous 
electrode such that the electrode will fit securely and not loosely in the subcutaneous 
sinus.  The tip of the EIT and the tip of the subcutaneous electrode are equipped with 
suture holes which enable the two devices to be temporarily sutured together during the 
implant procedure.  Once the two devices are sutured together, the EIT can be used to 
pull the subcutaneous electrode through a subcutaneous sinus.  Future generations of the 
BSC subcutaneous electrode insertion tool market approved by the appropriate regulatory 
bodies may be included in the study. 

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5.1.4. EMBLEM S-ICD Programmer 
The programmer is a completely self-contained, non-sterile, non-implantable, 
lightweight, easily portable computer that does not allow general purpose computing.  It 
implements a graphical user interface (GUI) design which gathers user input via touch 
screen and/or keyboard.  Communication between the pulse generator and the 
programmer is accomplished through an RF telemetry wand.  The radio link operates in 
the Medical Implant Communication Service band specified in EN 301 839-1:2002 and 
complies with applicable FCC regulations.  The programmer is capable of recognizing 
multiple pulse generators, but active communication is permitted with only one pulse 
generator at a time.  Communication between the programmer and a printer is based on a 
standard Bluetooth piconet. 
The programmer application consists of multiple screens from which online (active 
communication with the pulse generator) and offline modes may be commanded.  
Programmer functionality includes: 
• Scan for devices, resulting in a display of pick list of pulse generators 
• Establishment and termination of communication link 
• Display of a real-time S-ECG  
• Selection of programmable parameters  
• Review of subject event history 
• Induction ECG capability 
Future generations of the BSC programmer market approved by the appropriate 
regulatory bodies may be included in the study. 
5.1.5. S-ICD System Indication 
For US clinical sites, the S-ICD Device system indications for the MADIT S-ICD study 
are consistent with the indications documented in current and future S-ICD User’s 
Manuals that are market approved by the FDA. For clinical sites in countries accepting 
devices with CE Mark, the study protocol will follow the CE-marked instructions for use.   

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6. Objectives 
6.1. Primary Study Objective 
The primary objective is to test the hypothesis that post-MI diabetic patients with 
relatively preserved ejection fraction of 36-50% will have a survival benefit from a 
subcutaneous implantable cardioverter defibrillator (S-ICD). 
6.2. Secondary Study Objective 
The secondary objective of the study is to evaluate the effects of the S-ICD on all-cause 
mortality in various subgroups and on sudden cardiac death. 
The pre-specified subgroups include but are not limited to: gender, race, age continuous 
and dichotomized at 75 years, duration of diabetes, presence versus absence of insulin 
therapy, HbA1c dichotomized at 8%, LVEF continuous and dichotomized at 40% and 
MADIT II risk score sub-groups (MADIT II risk score: New York Heart Association 
functional class > II, age > 70 years, BUN > 26 mg/dl, QRS duration > 120 ms, and atrial 
fibrillation). 
6.3. Tertiary Study Analyses 
Pre-specified tertiary analyses include the following: 
• Frequency and outcomes of S-ICD treated episodes of ventricular tachycardia 
(VT)  and ventricular fibrillation (VF), 
• Frequency and outcomes of S-ICD  inappropriate shocks, 
• Frequency of S-ICD device complications, including but not limited to: infection, 
device malfunction and electrode movement and, 
• Healthcare utilization assessed through adverse event reporting. 

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7. Endpoints 
7.1. Primary Endpoint  
The primary endpoint will be all-cause mortality. All-cause mortality is defined as death 
by any cause during the duration of the trial. 
8. Design 
MADIT S-ICD is a prospective, multicenter, international, randomized (2:1), controlled 
clinical trial.  Subjects (n=1800) will be enrolled at approximately 100 study sites and 
randomized  to receive conventional medical therapy plus an S-ICD or conventional 
medical therapy alone in a 2:1 ratio, respectively. The trial uses a group sequential design 
with 18 pre-specified interim analyses. The sample size was chosen to detect a hazard 
ratio of 0.75 with 80% power (1-β), two-sided 5% significance level (α) and accounts for 
an estimated dropout rate of 10%. This trial will be conducted under an investigational 
device exemption (IDE) in the United States and as a post-market study in Europe and 
Israel. 
8.1. Scale and Duration 
The investigation will be initiated in the U.S., Europe, and Israel, at approximately 100 
sites with a maximum of 150 centers. Other geographies may be added over the course of 
the study. An average of 40-60 subjects per month, once all sites are approved to enroll, 
is expected to result in up to 1800 subjects enrolled within a 48 month period. The 
recruitment rate will be closely monitored. If the monthly recruitment rate is less than the 
projected average of 40-60 subjects per month, or a lower rate of events is observed, the 
study duration may be prolonged or additional subject enrollment beyond 1800 may be 
required. Subjects must be followed per this investigational protocol for the duration of 
the study, unless the investigator is notified by the Coordination Data Center (CDC) or 
sponsor to the contrary.   
• Study initiation will begin approximately 3-6 months post IDE approval 
• Estimated first enrollment is 6 months post IDE approval. 

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• The number of enrollments per month is estimated at 40-60, once all sites are 
approved to enroll. 
• The estimated date to complete enrollment is 48 months after the first enrollment. 
• The estimated date to complete follow-up is dependent on the events accumulated 
during the study and the hazard ratio. 
• The study report will be submitted to the appropriate regulatory bodies no later 
than 6 months after the study has been completed. 
 
8.2. Treatment Assignment 
Treatment assignments are generated from a pre-determined randomization schedule and 
administered from the electronic data capture system when a new subject is entered and 
confirmed as meeting study eligibility criteria. Randomization will be blocked and 
stratified by enrolling site. 
8.2.1. Treatment and Control 
Subjects randomized to the control arm of the trial will continue to receive conventional 
medical therapy alone (CMT) and will continue to be treated per standard of care by their 
current physician. Follow-up data in the CMT arm will be collected by the enrolling site 
study team through phone follow-up and chart review.  Subjects in the control arm will 
not receive any investigational treatments or devices as a part of their participation. 
Subjects randomized to the device arm of the trial will receive conventional medical 
therapy (per standard of care) plus a subcutaneous implantable defibrillator (see Section 
5.0) and will be followed primarily by the enrolling site study team. 
It is strongly recommended that subjects in both randomized arms receive standard of 
care treatment consistent with the American Diabetes Association (ADA) 2015 
Guidelines19, the 2013 ACCF/AHA guideline for the management of heart failure20,  the 
ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 201221 

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and the ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases from 
201322 and other guidelines as they come into effect over the course of the study.   
All subjects will be followed in the randomly assigned arm regardless of the actual 
medical treatments administered during the study (intention to treat). 
 
8.3. Justification for the Study Design 
Diabetic patients with prior myocardial infarction are at an increased risk for all-cause 
mortality and sudden cardiac death.  There is abundant data from prior literature 
suggesting that the incidence of sudden cardiac death in post-infarction patients with 
diabetes  and an LVEF >35% is similar to non-diabetic patients with an LVEF  ≤ 35%9,  
supporting the concept that a prophylactic implantable cardioverter defibrillator 
implantation could improve survival in post MI diabetes patients with an LVEF < 35% 
unless contraindicated.   
Furthermore the S-ICD was chosen for this study because it utilizes a non-vascular 
electrode, minimizing the risks associated with device related system infections that 
might be especially relevant in diabetic patients who have previously shown to be at 
higher risk of device related infections16-18. Although direct comparison of infection rates 
with the S-ICD vs transvenous ICD are lacking, we hypothesize that the non-vascular 
electrode in the S-ICD system could minimize the likelihood of device-related systemic 
infection and endocarditis in diabetic patients, since it avoids the central cardiovascular 
system and the heart. 
The MADIT S-ICD study was designed to assess if post-MI diabetic patients with a 
relatively preserved LVEF derive a survival benefit from implantation of an S-ICD in 
addition to conventional medical therapy. 
 
 

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9. Subject Selection  
9.1. Study Population and Eligibility  
Subjects will be screened for recruitment by the clinical study team within each enrolling 
site.  Screening information will be recorded by each enrolling site on a screening log and 
entered into the electronic data capture system. Reasons for exclusion will also be 
documented.  Subjects who met the criteria will be approached for participation. Figure 
9-1 represents the enrollment process for the study. 

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Figure 9-1: Enrollment Process  
 
Approach patient 
for participation
Pre-Enrollment Process:
Screening Visit
Step 1: Obtain patient consent
Step 2: Reconfirm Inclusion/exclusion criteria 
Step 3: Perform S-ICD Screening ECG
Randomize patient
Enrollment 
Complete
Screening Failure
Withdraw from 
participation
(Does not count toward 
enrollment ceiling)
S-ICD ECG Screening 
Pass?
NO
YES
S-ICD Arm
(Device)
Conventional 
Medical Therapy
(No-Device)
Does Patient Meet Eligibility Criteria?
 (with exception of S-ICD ECG Screening Success)
YES
NO
Pre-Screening Failure
Patient does not qualify 
do not approach for 
study.
Pre-Screening
Identify potential patients
(Treated Diabetes Mellitus over 3 months, prior MI, age 65 or greater and preserved EF of 36-50%)
 
 

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9.2. Inclusion Criteria 
Subjects who meet all of the inclusion criteria listed in Table 9.2-1 and none of the exclusion 
criteria listed in Table 9.3-1 may be considered for enrollment. The most recent evaluations, 
measurements or test results in the medical record must be used to assess inclusion criteria. 
Table 9.2-1: Inclusion Criteria 
Clinical 
Inclusion 
Criteria 
• Age ≥ 65 years on date of consent 
• Diabetes mellitus treated with oral hypoglycemic agents, non-insulin injectable 
and/or insulin for the past 3 calendar months or longer prior to consent date 
• LV ejection fraction (LVEF) of 36-50% documented by imaging (preferably by 
MRI or echocardiographic methods), within 12 calendar months before consent 
date and at least 3 calendar months after most recent MI, PCI or CABG.  
• One or more clinically documented, enzyme-positive myocardial infarctions, more 
than 3 calendar months prior to consent date*.  
o If enzyme information and clinical documentation is not available, there 
must be a clear evidence of prior silent myocardial infarction identified as 
either new pathologic Q waves on ECG or imaging documentation of an 
infarcted area (left ventricular angiography/ nuclear scan/ MRI)*  
* MI qualification based on the Universal Definition of MI1   
• Qualifying 12-lead ECG within 6 calendar months before consent date and at least 
3 calendar months after most recent MI, PCI or CABG  
* The qualifying ECG can be sinus rhythm or atrial fibrillation (patients with 
persistent or permanent atrial fibrillation should have a controlled ventricular 
response <100 bpm on consent date) 
*QRS duration on the qualifying ECG >90 msec 
• Passing S-ICD Screening ECG performed per applicable user’s manual on or after 
the consent date that identifies one or more qualifying S-ICD sensing vectors.  
Abbreviations: MRI=Magnetic Resonance Imaging; MI=Myocardial Infarction; PCI=Percutaneous Coronary 
Intervention; CABG=Coronary Artery Bypass Graft; ECG=Electrocardiogram; S-ICD=Subcutaneous Implantable 
Cardioverter Defibrillator 
 
9.3. Exclusion Criteria 
Subjects who meet any one of the criteria listed in Table 9.3-1 will be excluded from this 
clinical study. The most recent evaluations, measurements or test results in the medical 
record must be used to assess exclusion criteria. 

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Table 9.3-1: Exclusion Criteria 
Clinical 
Exclusion 
Criteria 
• Ejection fraction >50% or <36% within 12 calendar months prior to consent date 
and at least 3 calendar months after the most recent MI, PCI or CABG  
• Existing guideline based indication for an ICD, pacemaker, CRT, or CRT-D therapy  
• Existing or previously implanted ICD, CRT, CRT-D, or pacemaker device system 
• Active infection at the time of consent  
• Contraindication for S-ICD implantation according to the S-ICD pulse generator 
(PG) User’s Manual 
• Hemodialysis and/or peritoneal dialysis at the time of enrollment  
• New York Heart Association Class IV in the past 3 calendar months prior to or at the 
time of consent date 
• Coronary artery bypass graft surgery or percutaneous coronary intervention (balloon 
and/or stent angioplasty) within 3 calendar months prior to the consent date 
• Enzyme-positive myocardial infarction or silent myocardial infarction diagnosed 
within 3 calendar months prior to the consent date  
• Unstable angina with need for outpatient treatment or hospitalization 
(change/addition of anti-anginal medication and/or coronary revascularization), 
within 3 calendar months prior to the consent date 
• Angiographic evidence of coronary disease in a patient that is a candidate for 
coronary revascularization and is likely to undergo CABG or PCI in the next 3 
calendar months  
• High risk for arterial embolism (e.g. presence of mobile left ventricular  thrombus) 
• Hemodynamically significant congenital heart disease, aortic valvular heart disease, 
or amyloid heart disease 
• Baseline body mass index > 45 kg/m2 
• On a heart transplant list or likely to undergo heart transplant within one calendar 
year 
• Presence of any other disease, other than the subject’s cardiac disease, that in the 
opinion of the investigator is likely to significantly reduce the patient’s likelihood of 
survival for the duration of the trial (e.g. cancer, liver failure). 
• Unwillingness or inability to cooperate with the protocol 
• Resides at such a distance from the enrolling site so travel to follow-up visits would 
be unusually difficult  
• Reversible causes of heart disease (e.g. viral myocarditis or tachycardia induced 
cardiomyopathy) 
• Participation in other clinical trials (observational registries are allowed with 
approval from the CDC) 
• Does not anticipate residing in the vicinity of the enrolling site for the duration of 
the trial 
• Unwillingness to sign the consent for participation 
Abbreviations: ICD=Implantable Cardioverter-Defibrillator; CRT=Cardiac Resynchronization Therapy;  CRT-
D=Cardiac Resynchronization Therapy Defibrillator;  CABG=Coronary Artery Bypass Graft; PCI=Percutaneous 
Coronary Intervention, CDC=Coordination Data Center, S-ICD=Subcutaneous ICD, MI=Myocardial Infarction 

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10. Subject Accountability 
10.1. Pre-Enrollment Screening 
All subjects will be screened prior to enrollment, any subjects who sign the consent and 
fail to pass the screening ECG or do not meet all criteria will be considered screening 
failures and the reason for failure will be documented. Subjects who do not pass the pre-
enrollment screening will not count toward the enrollment ceiling. 
10.2. Point of Enrollment 
Subjects will be considered enrolled in the trial once they have signed the consent and 
been randomized. Subjects who are consented but expire prior to randomization or 
otherwise fail to be randomized will not be considered enrolled in the trial and will not 
count toward the enrollment ceiling. All subjects enrolled in the clinical study (including 
those withdrawn from the clinical study or lost to follow-up) shall be accounted for and 
documented.  
10.3. Withdrawal 
If a randomized subject withdraws from the clinical investigation, the reason(s) shall be 
reported (refer to Section 11.11). A subject will be considered lost to follow-up and 
withdrawn after18 calendar months following the last point of contact (i.e. phone follow-
up or in-clinic visit) and at least 3 documented attempts to contact the patient.  Attempted 
contact should be documented in the subject’s medical record.  
10.4. Subject Status and Classification 
Subject status will be defined as follows: 
Screen Failure (Consented, not randomized) is defined as completing the consent 
process (refer to Section 21, but not receiving a randomization assignment (for reasons 
such as withdrawal of consent, failure to pass S-ICD screening ECG, etc.).  
Enrolled is defined as completing the consent process and being randomized. 

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10.5. Implant Status and Classification 
For subjects randomized to the treatment (S-ICD) arm, the following additional 
definitions will be applied: 
Intent is defined as a subject randomized to the treatment (S-ICD) arm that does not 
undergo an S-ICD implant procedure.2   
Attempted implant  is defined as a subject randomized to the treatment (S-ICD) arm who 
undergoes an S-ICD implant procedure,2 but does not go on to receive the full S-ICD 
system within 30 calendar days of the initial implant procedure. 
Implant is defined as a subject randomized to the treatment (S-ICD) arm that undergoes 
an S-ICD implant procedure2 and is discharged with an S-ICD system. 
 
10.6. Enrollment Controls 
The number of subjects meeting enrollment criteria will be managed by the CDC through 
randomization assignments issued through the electronic data capture (EDC) system.  
Once the enrollment limit has been met, the EDC will cease to issue randomization 
assignments and the CDC will communicate to the enrolling sites. 
10.7. End-of-Study Action Plan 
At the conclusion of the study, subjects implanted with an S-ICD system will need to 
continue to have the device checked at their physicians’ office, in accordance with their 
physicians’ instructions, per standard of care, as long as they remain implanted with the 
device. Subjects who are not implanted with an S-ICD system will continue medical 
treatments in consultation with his/her physician. Implantation of an S-ICD in the CMT 
arm is left to the discretion of the physician.  
                                                 
2 A subject is considered to have undergone an S-ICD implant procedure once anaesthesia is administered in 
preparation for implant. 

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11. Study Methods 
11.1.  Study Flow 
Figure 11-1: Study Visit Flow Chart 
Randomized to 
S-ICD
Randomized to 
CMT 
(No Device)
Implantation
Within 14 days of randomization
One Month Visit
In-clinic 
(Occurs at one calendar month post-
randomization  +/- 3 calendar weeks)
Collects: Any adverse events, device 
deficiencies, episodes required per the protocol, 
includes a review of the subject chart
6 Month telephone contact
(Occurs at 6, 18, 30, 42, 54 months from 
randomization +/- 1 calendar month)
Collects: Any adverse events, device 
deficiencies, episodes required per the protocol, 
includes a review of the subject chart
Note: may be conducted in-clinic
Baseline/Randomization Visit
-Randomization Obtained
-Enrollment data collection (collect: eligibility, medication, 
demographic and medical history data, etc)
Annual In-Clinic Follow-up Visit 
(Occurs at 12, 24, 36, 48, 60 months from 
randomization +/- 1 calendar month)
Collects: Any adverse events, device 
deficiencies, episodes, medication, (HbA1c and 
NYHA, if available), S-ICD Final Summary 
Report, and a review of the subject chart
One Month Visit
Telephone contact
(Occurs at one calendar month post-
randomization +/- 3 calendar weeks)
Collects: Any adverse events, required per the 
protocol, includes a review of the subject chart
6 Month telephone contact
(Occurs at 6, 18, 30, 42, 54 months from 
randomization +/- 1 calendar month)
Collects: Any adverse events required per the 
protocol, includes a review of the subject chart
Annual Follow-up Visit 
(Telephone contact or in-clinic)
(Occurs at 12, 24, 36, 48, 60 months from 
randomization +/- 1 calendar month)
Collects: Any adverse events, medication, 
(HbA1c and NYHA, if available), and a review of 
the subject chart
Screening Visit
Step 1: Consent Process
Step 2: Reconfirm inclusion/exclusion criteria
Step 3: S-ICD Screening ECG
Subject S-ICD Screening ECG = PASS

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11.2. Data Collection 
Table 11.2-1 CMT Cohort Data Collection Schedule 
Procedure/Assessment 
Screening  
Enrollment 
/ 
Randomiza
tion  
One Month 
Follow-up 
(Phone 
contact) 
6 Month 
Follow-up  
(Phone 
contact) 
Annual 
Follow-up 
(Phone 
contact) 
End of Study 
(Phone contact or 
in-clinic) 
Consent Date 
X 
 
 
 
 
 
Screening ECG 
X 
 
 
 
 
 
Randomization 
Assignment 
 
X 
 
 
 
 
Demographics and 
Medical History  
 
X 
 
 
 
 
Diabetes and 
Cardiovascular 
Medications 
 
X 
 
 
X 
 
Adverse events 
 
 
Y 
Y 
Y 
Y 
Vital Status 
 
 
X 
X 
X 
X 
Note: The randomization date will be used as the starting point for determining the timing of all follow-up visits. 
X: Data Required 
Y: If Applicable 
 

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Table 11.2-2 S-ICD Cohort Data Collection Schedule 
Procedure/Assessment 
Screening  
Enrollment / 
Randomization  
Implant 
One Month  
Follow-up 
(In-clinic)  
6 Month 
Follow-up 
(Phone 
contact or 
in-clinic)  
Annual  
Follow-up 
(In-clinic) 
System 
Revision 
Additional 
implant 
End of 
Study 
(Phone or 
in-clinic) 
Consent Date 
X 
 
 
 
 
 
 
 
 
Screening ECG 
X 
 
 
 
 
 
 
 
 
Randomization 
Assignment 
 
X 
 
 
 
 
 
 
 
Demographics and 
Medical History  
 
X 
 
 
 
 
 
 
 
Diabetes and 
Cardiovascular 
Medications 
 
X 
 
 
 
X 
 
 
 
Implant Details 
 
 
X 
 
 
 
 
X 
 
S-ICD system 
Parameters 
 
 
X 
X 
 
X 
X 
X 
X 
Conversion Testing 
 
 
X 
S 
S 
 S 
S 
S 
 
Adverse events 
 
 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Spontaneous Episodes 
 
 
S 
S 
S 
S 
S 
S 
S 
 
 
 
 
 
 
 
 
 
 
Note: The randomization date will be used as the starting point for determining the timing of all follow-up visits. 
S: If applicable, S-ICD group only 
X: Data Required 
Y: If Applicable 

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11.3. 
Screening Process 
Due to the nature of the trial and the patient population, it will be necessary to involve 
several medical disciplines for screening and enrollment as an interdisciplinary team 
approach.  This approach may involve several of the following members: a 
research/study coordinator, an electrophysiologist, cardiologist, interventional 
cardiologist, internal medicine specialist, endocrinologist specializing in diabetes 
mellitus, and potentially other specialists. The role of the team is to jointly make efforts 
in screening and identifying potential candidates in the study who may not be otherwise 
routinely seen by a cardiac electrophysiologist. 
A screening log must be used to document potential subjects who are evaluated for the 
MADIT S-ICD study. The screening log will be kept at the enrolling center and will 
identify subjects with a consecutive numeric value.  
Each enrolling site will be responsible for a consenting process that ensures study 
candidates understand the risks and potential benefits of study participation.  Efforts 
should be made to enroll subjects of all genders and ethnic backgrounds.   
11.3.1. WIN-Her Initiative 
Prior MADIT studies have increasingly enrolled women and reported on gender-specific 
outcomes. In the MADIT S-ICD clinical trial, we will further enhance enrollment of 
women by first applying the WIN-Her Initiative.23, 24 The Women Opt In for Heart 
Research (WIN-Her) Initiative, will be conducted at sites in the United States. WIN-Her 
is designed to test the use of gender-specific enrollment and in-trial educational 
materials and training approaches. Additional methods will be employed during clinical 
trials to encourage enrollment of female subjects into clinical trials and to assess gender-
specific adherence to trial processes, cross over rates, attitudes toward participation in 
the trial and ultimately, response to the WIN-Her program. Details of the WIN-Her 
initiative are outlined in the WIN-Her program materials.  

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11.4. MADIT S-ICD Screening Data and Consent 
Those subjects who meet the criteria for the trial, with the exception of the S-ICD 
screening ECG and agree to participate will sign the study consent.  All study candidates 
who undergo the consent process will be entered into the database.  After the informed 
consent process is complete, the candidate will undergo an S-ICD screening ECG to 
determine if they are eligible for implantation with the S-ICD system.   If the S-ICD 
screening ECG passes, then the candidate may go on to be randomized for the trial, 
completing the enrollment process.    All S-ICD screening ECGs (in all leads and 
postures evaluated) are to be retained at the enrolling site.  For candidates who fail the S-
ICD screening ECG, no further data are to be collected and no randomization assignment 
obtained.   
Table 11.4-1: Screening Source Documentation 
Data Collection 
Retention of Original Source 
Documentation 
 
“MADIT S-ICD Consent” Form   
 
Screening log 
 
Enrolling site 
 
Pre-randomization S-ICD Screening ECG 
Enrolling site;  (if requested by CDC, 
this de-identified documentation 
would be provided) 
   
 
 

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11.5. Randomization and Baseline Data (Enrollment) 
Subjects, who are consented, meet all the eligibility criteria (including a successful S-ICD 
screening ECG) and are randomized, are considered enrolled. All enrolled subjects will 
have baseline data collected for the study.  Subjects who do not meet the definition of 
enrolled (see section 10.1) should not have baseline data collected. Subject 
demographics, medical history, current cardiovascular and diabetes medications and 
eligibility criteria will be collected for all enrolled subjects.  The subjects randomization 
assignment will be documented in the electronic data capture system at baseline. Table 
11.5-1 lists the data collected at baseline. Once the subject is enrolled (consented and 
randomized) adverse events must be collected. 
 
Table 11.5-1: Baseline Data Collection 
 
Data Collection 
Retention of Original Source 
Documentation 
 
Eligibility criteria 
 
Demographics, Physical and Medical History 
 
Cardiovascular and Diabetic Medications 
 
 
Enrolling site 
 
 
 12-Lead ECG used for QRS duration inclusion criteria 
 
Enrolling site; upload de-identified 
copy to EDC 
11.6. Implant Data/Visit 
11.6.1. Implant Procedure 
Subjects randomized to receive the S-ICD must be implanted within 14 calendar days of 
randomization.  Implantation and testing of the S-ICD system should be performed using 
the methods established by the enrolling site for S-ICD system implantation. Refer to the 
applicable S-ICD system User’s Manual for detailed instructions regarding the 
implantation and use of the S-ICD system.   

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11.6.2. Conversion Testing 
As part of the S-ICD system implant procedure, conversion testing must be performed 
using the process defined in Appendix 27.5. Only sustained ventricular arrhythmias that 
result in a shock require documentation by capturing and annotating an ECG strip.  After 
the initial implant procedure, additional conversion testing may be performed at other 
times during the course of the study at the discretion of the investigator.  These additional 
conversion tests should be documented. All documents related to conversion testing 
including ECG strips are to be kept at the enrolling sites unless requested by the 
coordination data center (CDC). Adverse events that occur during conversion testing 
must be reported in the electronic data capture system according to the study protocol. If 
the conversion testing is not able to be completed due to instability of the patient, no 
protocol deviation will be assessed (this must be documented in the subjects record).   
 
 

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11.6.3. Implant Visit 
The implant visit collects S-ICD system procedural data such as procedure time, peri-
operative medication management, product information, implant details, conversion 
testing outcomes, adverse events and information transcribed from a Final Summary 
Report obtained before discharge from the hospital.  The Final Summary Report must 
document that the device is programmed per protocol (see Section 0).  A post-implant 
chest x-ray is strongly recommended to document system placement. If performed, the x-
ray would be retained by the enrolling site, and may be requested as source 
documentation if necessary. Table 11.6.3-1 lists the data collected at the implant visit. 
Table 11.6.3-1: Implant Data Collection 
Data Collection 
Retention of Original Source 
Documentation 
Peri-operative medication listing (anticoagulation; antiplatelet; 
antibiotics; type of anesthesia) 
 
Implanted product and accessories utilized for S-ICD system 
(model/seria1) 
 
Medical notes/worksheets documenting implantation technique 
(e.g. Number and location of incisions, location of electrode and 
device etc…) 
 
Programmer Printouts: 
- Final Summary Report 
- Captured S-ECG in each sensing vector 
 
Conversion testing episodes (S-ICD Induced Episode Report or 
external ECG strips)  
 
Adverse events, device deficiencies, if applicable 
 
Enrolling site 
 
 
Programmer Printouts: 
- Device episodes, if applicable 
 
Enrolling site; upload de-identified 
copy to EDC  
 
 
 
 

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11.6.4. Protocol Required Programming 
All subjects who are randomized to the S-ICD arm of the trial will be required to have the 
S-ICD rate zones programmed as listed in Table 11.6.4-1 at the time of implantation.  
Post-shock pacing is recommended to be programmed ON. All other S-ICD 
programming is left to physician discretion. 
 
Table 11.6.4-1: Required S-ICD Programming 
Parameter 
Value Required 
Conditional Shock Zone 
200 bpm 
Shock Zone 
250 bpm 
 
11.7. One Month Follow-up Visit 
The one month follow-up visit will be conducted by either an in-clinic visit for subjects 
randomized to S-ICD or phone contact for subjects randomized to CMT only.   This visit 
will be conducted to ensure that any device, procedure or episode related events are 
collected as well as any other applicable patient related adverse events are reported per 
Section 20. The one month visit must be conducted at one calendar month +/- 3 calendar 
weeks post-randomization for the S-ICD arm and at one calendar month +/- 3 calendar 
weeks post-randomization for the CMT only arm.  
Table 11.7-1 lists all the data 
required at one month follow-up visits. 
 
Table 11.7-1: One Month Follow-Up Visit Data Collection 
Data Collection 
Retention of Original Source 
Documentation 
 
Adverse events, device deficiencies if applicable 
 
(S-ICD only) Programmer Printouts: 
- Final Summary Report 
 
Enrolling site 
 
 
(S-ICD only) Programmer Printouts: 
- Device episodes, if applicable 
 
Enrolling site; upload de-identified 
copy to the EDC system 
 
 

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11.8. Six Month Follow-up Visit (Phone contact)/ Medical Record Review 
Between the annual visits a phone follow-up will be conducted by the enrolling site staff 
to verify survival status and ensure all adverse events are reported per Section 20. (This 
visit can be done in-clinic, but the data requirements remain the same). This visit requires 
a review of the subject’s medical record to ensure accurate reporting of events.  The six 
month visit must be conducted at 6 calendar months (+/- 1 calendar month) from 
randomization for all subjects, and annually thereafter at months 18, 30, 42, etc.  If the 
subject is in-clinic during the visit window the visit may be completed in-clinic. Data 
collection and requirements would remain the same. 
Table 11.8-1 lists the data 
required to be collected for the 6 month follow-up visit. 
 
Table 11.8-1: Six Month Follow-Up Visit Data Collection 
Data Collection 
Retention of Original Source 
Documentation 
 
Medical Record Review  
 
Adverse events, device deficiencies, if applicable 
 
Enrolling site 
 
 
(S-ICD only) Programmer Printouts: 
- Device episodes, if applicable and available through chart 
review 
 
Enrolling site; upload de-identified 
copy to the EDC system 
 
 
11.9. Annual Follow-up Visit 
All subjects are required to have an annual follow-up visit.  The annual visit must be 
conducted at 12 calendar months (+/- 1 calendar month) from randomization for all 
subjects, and annually thereafter at months 24, 36, 48, etc. 
11.9.1. CMT (Control) Group Annual Follow-up Requirements 
For subjects randomized to CMT only, this visit may be in-clinic or via phone contact 
and must be conducted by a member of the enrolling site investigative team. This visit 
will also require a review of the subject’s medical record to ensure accurate reporting of 
events. Specifically this would include collection of: 

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• Physical history (blood pressure, heart rate, height, weight), if available 
documented from medical records 
• NYHA Class, if available 
• Record most recent hemoglobin A1c (HbA1c) test results, if available 
• Protocol required adverse events that have not been previously reported (Note: 
hospitalization information will be collected on the adverse event form) 
• Cardiac related procedures 
• Record all currently prescribed diabetes and cardiovascular related medication 
11.9.2.  S-ICD (Treatment) Group Annual Follow-up Requirements 
For subjects randomized to S-ICD the annual visit is required to be performed in-clinic 
by the enrolling site investigative team. As a part of the annual visit a review of the 
subject’s medical record must be completed. The in-clinic visit includes collection of the 
following: 
•  Physical history (blood pressure, heart rate, height, weight) 
• NYHA Class, if available 
• Record most recent hemoglobin A1c (HbA1c) test results, if available 
• Cardiac related procedures 
• Record all currently prescribed diabetes and cardiovascular related medication 
• Device interrogation (S-ICD Final Summary Report) 
• Spontaneous device episodes that have not been previously reported; 
• Protocol required adverse events that have not been previously reported (Note: 
hospitalization information will be collected on the adverse event form) 
• Current S-ICD programming and changes in S-ICD programming; 
• Protocol required device deficiencies that have not been previously reported. 

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Table 11.9.2-1 lists all the data required at annual follow-up visits. 
 
Table 11.9.2-1: Annual Follow-Up Visit Data Collection 
Data Collection 
Retention of Original Source 
Documentation 
 
Physical History 
 
Diabetes and Cardiovascular Medications 
 
 NYHA Assessment, if available 
 
Most recent HbA1c test results, if applicable 
 
Cardiac procedures, if applicable 
 
Adverse events,  device deficiencies, if applicable 
 
(S-ICD Only) Programmer Printouts: 
- Final Summary Reports 
 
(S-ICD only) Conversion testing episodes ( ECG strips), if 
performed 
 
(S-ICD only) Programming changes that have not been 
previously reported; 
 
 
Enrolling site 
 
 
(S-ICD only) Programmer Printouts: 
- Device episodes, if applicable 
 
 
Enrolling site; upload de-identified 
copy to EDC system  
 
 
11.9.3. Additional Non-Visit Related Data Collection 
Protocol required adverse events, treated episodes; suspected device deficiency or device 
programming change must be recorded on the appropriate case report form.   These items 
must be documented in the EDC system within the required timelines. 
 

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11.10. Device Status Change (S-ICD treatment group) 
11.10.1. 
System Revision 
In the event that the electrode or PG is surgically revised, but not explanted, the system 
revision form must be completed.   Table 11.10.1-1. System Revision Data Collection 
lists all the data required for system revisions. 
Table 11.10.1-1. System Revision Data Collection 
Data Collection 
Retention of Original Source 
Documentation 
 
 Programmer Printouts: 
- Final Summary Reports 
 
Conversion testing episodes (ECG strips), if performed 
 
Adverse events, device deficiencies, if applicable 
 
Enrolling site;  
Programmer Printouts: 
- Episode Report printout, if applicable 
 
Enrolling site; Upload de-identified 
copy to EDC system 
  
11.10.2. 
 PG/Electrode Replacement 
If the PG or electrode is replaced, the new device(s) will be recorded on an additional 
implant form, and the electrode or PG removed from service must have an out-of-service 
device(s) form completed (see section11.10.4). It is expected, that due to the duration of 
the study, that the subject may need to receive a replacement device for normal battery 
depletion. If this occurs the subject shall remain in the study and continue study follow-
up from the original enrollment time point.  
Table 11.10.2-1 lists all the data 
required for PG/Electrode Replacements.  
 
 

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Table 11.10.2-1 PG/Electrode Replacement Data Collection 
 
Data Collection 
Retention of Original Source 
Documentation 
Peri-operative medication listing (anticoagulation, antiplatelet,  
antibiotics,  type of anesthesia) 
 
Implanted product and accessories utilized for S-ICD system 
(model/serial) 
 
Medical notes/worksheets documenting implantation technique 
(e.g. Number and location of incisions, location of electrode and 
device etc.) 
 
Programmer Printouts (Newly implanted device): 
- Final Summary Reports 
 
Conversion testing  episodes (ECG strips), if performed  
 
Adverse events, device deficiencies if applicable 
 
Enrolling site  
Programmer Printouts: 
- Episode Report printout, if applicable 
 
Enrolling site: Upload de-identified 
copy to EDC system 
 
11.10.3. 
PG/Electrode Explant without Replacement 
If the PG or electrode is explanted without replacement, an out-of-service device(s) form 
must be completed documenting details and rationale for explant (see section 11.10.4). 
Due to the intention to treat nature of the study, these subjects should still be followed to 
study completion.   
11.10.4. 
Out of Service Device(s) 
For the S-ICD treatment group, if the PG or electrode is explanted for any reason or in 
the case of death, interred with the subject, an out-of-service device(s) form must be 
completed (see section 11.10.4).   Table 11.10.4-1 lists all the data required for out of 
service device(s).   
 
 

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Table 11.10.4-1 Out of Service Data Collection 
 
Data Collection 
Retention of Original Source 
Documentation 
 
 
Programmer Printouts, if available: 
- Final Summary Reports 
 
Adverse events, device deficiencies, if applicable 
 
Enrolling site  
 
Programmer Printouts: 
- Episode Report printout, if applicable 
 
Enrolling site; upload a de-identified 
copy to EDC system 
 
11.10.5. 
Cardiac Implantable Electronic Device Information (Non-study 
device implantation) 
If the subject receives a non-study device in the duration of the trial, this information will 
be collected on a non-study device implant form. If the subject experiences an adverse 
event related to the implantation of the non-study related device, the adverse event will 
be classified as subject condition.  This includes any device or procedure related events 
they may experience. 
11.11. Study Completion Visit 
The study completion visit will take place at the subjects’ participation completion.  This 
includes the conclusion or termination of the study for any rationale and documented on 
the study status form.   
11.11.1. 
Subject Withdrawal Prior to Study Completion or Study Termination 
Subjects may be withdrawn prior to the study completion visit or study termination for a 
variety of reasons including: 
• Subject withdraws consent for any reason; 
• Subject is lost to follow-up despite best efforts to locate the subject; 

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• Subject is withdrawn at study investigator discretion; 
• The subject expires. 
The study status form documents withdrawal of any subject from the study. As this study 
is intention to treat, subjects should remain in the study and continue to be followed per 
the protocol unless this is unavoidable.  Study data is collected per the assigned treatment 
arm schedule up until the date of withdrawal. 
If a subject must be withdrawn for reasons other than death, study completion or lost to 
follow-up, the following level of withdrawal should be assessed and documented on the 
study status form and in the subject record.  Written documentation with signature of the 
subject must be completed and kept on file at the enrolling site documenting any of the 
withdrawal levels described below. 
• Subject declines to have further in-person follow-up, but agrees to phone follow-
up per the schedule noted in the protocol, they should not be withdrawn. 
• Subject declines further follow-up visits, but agrees to a phone call at the 
conclusion of the study to verify vital status, or Subject declines further direct 
contact of any kind, but agrees to: 1) study staff contacting their primary care 
provider and/or 2) reviewing their medical record, at the conclusion of the study, 
the subject should be withdrawn.  
• Subject declines further direct contact of any kind, and does not provide 
permission to allow vital status verification. 
There are no additional follow-up requirements once a subject has been fully withdrawn 
from the study.  All applicable case report forms must be completed at study exit. 
Subjects who are “lost-to-follow-up” must have three documented contact attempts prior 
to completion of the study status form.  Data collected up to the point of subject 
withdrawal may be used for study analysis, unless local regulations prohibit its use. 
At the point of study completion and/or withdrawal, all open adverse events must be 
assessed by the investigator. These events must be closed or documented as chronic.   
Additionally, the sponsor may ask that withdrawn subjects be followed for information 

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related to the safety of the device if available. If such withdrawal is due to problems 
related to device safety or performance, the investigator shall ask for the subject’s 
permission to follow his/her status/condition outside of the clinical study.  
Table 11.11.1-1 lists all the data that are required for study completion.   
 
Table 11.11.1-1 Study Completion Data Collection 
 
Data Collection 
Retention of Original Source 
Documentation 
 
(S-ICD only) Programmer Printouts: 
- Final Summary Reports 
 
Adverse events, device deficiencies, if applicable 
 
Enrolling site  
 
(S-ICD only) Programmer Printouts: 
- Device episodes, if applicable  
 
For the withdrawal reason of death: 
• 
Death Narrative 
• 
All medical records/hospitalization records pertaining to 
death 
• 
Death certificate, if available 
• 
Autopsy report, if available 
• 
S-ICD device interrogation after terminal event, if 
available (S-ICD only) 
 
Enrolling site; upload a de-identified 
copy to EDC system  
 

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11.12. Source Documents 
Where copies of the original source document as well as printouts of original electronic 
source documents are retained, these shall be signed and dated by a member of the 
enrolling site team.  All source documentation that is provided to the CDC must have 
personal health identifiers redacted and labeled with the subjects study identifier. 
11.13. 
Overall Study Completion Requirements 
This study will continue to follow subjects until the sequential stopping boundary is 
crossed. This is estimated to include an average follow-up time of approximately 2.6 
years. Once the stopping boundary has been crossed the study will be assessed to ensure 
adequate data has been collected. If the data safety monitoring board determines that it is 
appropriate to stop the trial, sites will be notified. Each subject will have a final follow-up 
contact and a withdrawal form to conclude their participation. For subjects withdrawn 
during the study, if permitted the site will contact the subjects to obtain vital status.  

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12. Statistical Considerations 
12.1. Endpoints 
Primary Endpoint 
All-cause mortality 
12.1.1.1. Hypotheses 
This study is being conducted to test the hypothesis that post-MI diabetes patients with a 
relatively preserved ejection fraction will have a lifesaving benefit from an implanted 
defibrillator. 
12.1.1.2. Sample Size  
1800 men and women from the U.S., Europe, and Israel will be enrolled based on the 
following assumptions: 
- 
Wang-Tsiatis (∆=0.1) Design with K=18 Possible Analyses                                                
- 
2:1 randomization (S-ICD:CMT) 
- 
α = 5% (two-sided) 
- 
Power = 80% 
- 
Hazard ratio of 0.75 
- 
Attrition rate of 10% 
 
12.1.1.3. Statistical Methods 
A plot of the log-rank statistic versus its variance (‘information’) will be carried out 
periodically. At 18 pre-specified information times the log-rank statistic will be compared 
with pre-specified stopping boundaries, as indicated in Figure 12-1.  If the boundary of A 
or B is reached prior to the final (18th) analysis, the trial will be terminated at that time.  
Otherwise, it will be continued until either (1) the maximum information level is reached, 
or (2) continuing the trial is determined to be futile based on current estimates of 
conditional power and projected trial termination (as discussed below).  
 

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Figure 12-1: Stopping and Decision Boundaries for the Design 
 
 
    AAA: S-ICD more effective     BBB: Med Rx more effective 
  CCC: no difference 
 
 
Reaching the upper boundary (A) leads to a decision in favor of the S-ICD, reaching the 
lower boundary (B) in favor of the medical treatment, and reaching the central part (C) of 
the vertical boundary results in a ‘no difference’ conclusion.  Hence, a no-difference 
conclusion is only possible at the final analysis.   
Numerical values of the boundaries, derived using SAS version 9.4, are in Table 12.1-1, 
along with the schedule of cumulative α-spending and cumulative power for hazard ratios 
(HR’s) of 0.70 and 0.75.  The cumulative power reaches 80% at analysis 18 for a HR of 
0.75.  For a HR of 0.70, the cumulative power exceeds 80% by analysis 14 and reaches 
94% at the final analysis.  Although this design could require as many as 454 events to 

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get to the final (18th) analysis, the trial would be expected to terminate at the 13th 
analysis if the HR is 0.75 and at the 10th analysis if the HR is 0.70. 
 
Table 12.1-1: Coordinates of the Upper and Lower Stopping Boundaries 
and the Associated α-Spending and Cumulative Power 
 
The standardized (Normal) log-rank statistic will be plotted against information at each 
analysis until a boundary is reached.  The vertical boundary is at analysis 18, extending 
from –2.16 to +2.16.  Alternative boundary scales are presented in Table 12.1-2.  The 
Score statistic boundaries are based on the cumulative (non-standardized) log-rank 
statistic (and thus are simply the standardized boundaries multiplied by the square root of 
variance in Table 12.1-1).  The boundaries based on the Maximum Likelihood Estimator 
(MLE) of the HR show how extreme the treatment effect would have to be in order to 
reach a stopping boundary early in the trial.  In particular, the HR would have to be 
smaller than 0.31 or larger than 3.28 to stop on the first analysis.  These bounds narrow 
considerably as the interim analyses progress, but they still represent clinically 
 
Analysis 
(Info %) 
 
Varia
nce 
 
 
Events 
Standardized 
Boundaries (±) 
 
Nominal  
α 
 
α-Spending 
Cumulative 
Power 
HR=0.75   
HR=0.70 
1 (15) 
15.1 
68.0 
4.62 
0.00000 
0.00000 
0.0002 
0.0006 
2 (20) 
20.1 
90.6 
4.12 
0.00004 
0.00004 
0.0024 
0.0060 
3 (25) 
25.2 
113.3 
3.77 
0.00017 
0.00018 
0.0106 
0.0250 
4 (30) 
30.2 
136.0 
3.50 
0.00046 
0.00054 
0.0292 
0.0649 
5 (35) 
35.3 
158.6 
3.29 
0.00100 
0.00122 
0.0611 
0.1273 
6 (40) 
40.3 
181.3 
3.12 
0.00181 
0.00230 
0.1062 
0.2081 
7 (45) 
45.3 
204.0 
2.98 
0.00292 
0.00386 
0.1626 
0.3001 
8 (50) 
50.4 
226.6 
2.85 
0.00433 
0.00590 
0.2272 
0.3960 
9 (55) 
55.4 
249.3 
2.75 
0.00602 
0.00846 
0.2966 
0.4893 
10 (60) 
60.4 
271.9 
2.65 
0.00799 
0.01150 
0.3677 
0.5759 
11 (65) 
65.5 
294.6 
2.57 
0.01020 
0.01502 
0.4377 
0.6532 
12 (70) 
70.5 
317.3 
2.49 
0.01263 
0.01898 
0.5047 
0.7201 
13 (75) 
75.5 
339.9 
2.43 
0.01526 
0.02334 
0.5675 
0.7766 
14 (80) 
80.6 
362.6 
2.36 
0.01806 
0.02806 
0.6250 
0.8235 
15 (85) 
85.6 
385.3 
2.31 
0.02102 
0.03314 
0.6770 
0.8617 
16 (90) 
90.6 
407.9 
2.26 
0.02410 
0.03850 
0.7234 
0.8924 
17 (95) 
95.7 
430.6 
2.21 
0.02729 
0.04414 
0.7643 
0.9169 
  18 (100) 
100.7 
453.2 
2.16 
0.03058 
0.05000 
0.8000 
0.9361 

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meaningful effects at the final (18th) analysis.  Specifically, the HR would have to be 
smaller than 0.81 or larger than 1.24 in order to be significant (p<0.05) at the final 
analysis; any HR estimate between 0.81 and 1.24 at the final analysis would result in 
reaching boundary C (the no-difference conclusion). 
Table 12.1-2 Alternative Scales for the Upper and Lower Stopping Boundaries: 
Score Statistic and MLE of HR 
 
Any sample size that can eventually yield 454 events could be chosen, and the two-sided 
significance level of 5% and power of 80% at a HR of 0.75 would be maintained.   
 
Making assumptions and choices about the recruitment period, the event rate in CMT-
only patients, drop-out rates, the randomization ratio, and the desired maximum duration 
of the trial, an appropriate sample size can be determined.   
 
Analysis 
(Info %) 
 
Var-
iance 
 
 
Events 
Score 
Statistic 
Boundaries 
(±) 
HR MLE Boundaries 
Upper (Stop 
on A if HR <) 
Lower (Stop 
on B if HR >) 
1 (15) 
15.1 
68.0 
17.95 
0.305 
3.281 
2 (20) 
20.1 
90.6 
18.48 
0.400 
2.502 
3 (25) 
25.2 
113.3 
18.89 
0.472 
2.118 
4 (30) 
30.2 
136.0 
19.24 
0.529 
1.890 
5 (35) 
35.3 
158.6 
19.54 
0.574 
1.741 
6 (40) 
40.3 
181.3 
19.80 
0.612 
1.635 
7 (45) 
45.3 
204.0 
20.04 
0.643 
1.556 
8 (50) 
50.4 
226.6 
20.25 
0.669 
1.495 
9 (55) 
55.4 
249.3 
20.44 
0.691 
1.446 
10 (60) 
60.4 
271.9 
20.62 
0.711 
1.407 
11 (65) 
65.5 
294.6 
20.79 
0.728 
1.374 
12 (70) 
70.5 
317.3 
20.94 
0.743 
1.346 
13 (75) 
75.5 
339.9 
21.09 
0.756 
1.322 
14 (80) 
80.6 
362.6 
21.22 
0.768 
1.301 
15 (85) 
85.6 
385.3 
21.35 
0.779 
1.283 
16 (90) 
90.6 
407.9 
21.47 
0.789 
1.267 
17 (95) 
95.7 
430.6 
21.59 
0.798 
1.253 
  18 (100) 
100.7 
453.2 
21.70 
0.806 
1.240 

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12.1.1.3.1 Computations for Total Sample Size of 1,800 subjects 
Computations show that a total sample size of n = 1,800 will meet requirements (1)-(5) 
below (see section 28.3 for details): 
(1) Recruitment rates of 25 patients per month (ppm) in year 1, 35 ppm in year 2, and 45 
ppm in years 3-4 (1800 total patients over 48 months). 
(2) A 3-year cumulative event rate of 20%, 25%, or 30% in CMT-only patients. 
(3) A 5-year cumulative drop-out rate of 10% in each arm. 
(4) A randomization ratio of 2:1, S-ICD to CMT only. 
(5) The trial should end within 6 years (2 years after recruitment ends). 
12.1.1.3.2 Computations for Sample Size Expected to Generate 454 Events 
Computation of a sample size that would be expected to generate 454 events depends on: 
(1) The number of patients recruited each month: P1 in month 1, P2 in month 2, …  
(2) The overall event rate.  If the 3-year cumulative event rate is 25% in CMT-only 
patients, and the HR is 0.75, then the overall rate is a weighted average (due to 2:1 
randomization) of 0.25 (weight = 1) and 1-(1-0.25)^0.75 = 0.194 (weight=2).  That 
works out to 21.3% over 3 years, or a monthly event rate (MER) of 0.59%. 
(3) The 5-year cumulative drop-out rate of 10% in each arm.  That is a monthly drop-out 
rate (MER) of 0.17%. 
In the first month, P1 patients are enrolled, and assuming uniformly distributed 
enrollment times, they are expected to contribute P1/2 months of follow-up.  The 
expected numbers of events and withdrawals at the end of the first month are then 
(P1/2)*MER and (P1/2)*MDR, respectively.  The expected number of patients remaining 
at risk entering month 2 is then P1*(1- MER/2 - MDR/2).  These monthly computations 
can be done sequentially, where at month j: 
• Rj-1 patients are still at-risk from month j-1 
• Pj patients are enrolled uniformly in month j 
• Expected follow-up time in month j: Rj-1 + Pj/2 
• Expected numbers of events in month j: (Rj-1 + Pj/2)*MER 
• Expected withdrawals in month j: (Rj-1 + Pj/2)*MDR 
• Expected number of patients remaining at risk entering month j+1: Rj-1*(1-
MER - MDR) + Pj*(1-MER/2 - MDR/2).  
Setting Pj = 25 for j = 1, ... , 12, Pj = 35 for j = 13, ... , 24, Pj = 45 for j = 25, ... , 48, and Pj 
= 0 for j > 48, the expected counts that appear in Table 27.3-1 are obtained. 

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Table 27.3-1 in the Appendix provides a monthly accounting of patients with projections 
of events (assuming a HR of 0.75 and a 25% rate in (2)), withdrawals, and timing of 
analyses for this design.  The 1st analysis should be performed at 15% information (69 
events) and is projected to occur at month 30 with 990 patients enrolled.  Further analyses 
would be performed at 5% increments of information (every 23 events), and these are 
expected to occur approximately every 3-4 months. 
The trial will likely end earlier if the S-ICD is effective (even though events will 
accumulate more slowly). In particular, if the true HR is 0.75 and assumptions (1)-(4) 
hold, the trial will require 56-71 months.  A HR of 0.70 would require 4-6 fewer months.  
The worst case scenario is a HR of 1.00 and a 20% event rate, which could require 83 
months (See Table 12.1-4). 
Adaptive trial design elements will be used to guard against the possibility of a negative 
or overly lengthy trial.  Stochastic curtailment based on conditional power (i.e. the chance 
of reaching boundary A or B under the alternative hypothesis, given the currently 
available data) will be used as a basis for terminating the study early due to futility.  If the 
chance of reaching boundary C becomes so large that the no-difference conclusion is 
practically inevitable, then it would be futile to continue the study.   
Simulations were used to determine an appropriate threshold for conditional power in 
declaring futility. This involved repeatedly (1 million times for each scenario) generating 
the sequence of 18 log-rank test statistics (according to a multivariate normal distribution 
that depends on the set of information levels in Table 12.1-1 and the true HR25), 
calculating the conditional power (a function of observed log-rank test statistics, the 
information levels in Table 12.1-1, the overall significance level, and the true HR25) 
under the alternative hypothesis (HR = 0.75) after interim analyses 1-17, and determining 
the outcome (reaching boundary A, B, or C, or declaring futility early).  Simulations were 
conducted under a variety of true HR’s in order to find a suitable conditional power 
threshold.  Choosing a value of 0.0001% appears appropriate because (1) there is 
virtually no effect on the significance level or power; (2) declaring futility is practically 
impossible until the 15th analysis; (3) there is a good chance (64%) of declaring futility 
early if the true HR is 1.0; and (4) there is little chance (2%) of declaring futility early if 

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the true HR is 0.75.  Complete results of the simulation study using a conditional power 
threshold of 0.0001% are shown in Table 12.1-3.  Note that the simulation size implies a 
standard error for percentages of at most 0.05%, and thus percentages can be assumed 
accurate to ±0.2% (with 99.99% confidence). 
Table 12.1-3 Simulation Results Using a Conditional Power Threshold of 0.0001% 
True 
HR 
Chance (%) 
of Hitting 
Boundary  
A or B 
 
Chance (%) of 
Hitting 
Boundary C (No 
Difference) 
Chance (%) of 
Declaring 
Futility Before 
Analysis 18 
Chance (%) of Declaring Futility 
at 
Analysis 
15 
Analysis 
16 
Analysis 
17 
1.54 
98.8 
1.1 
0.09 
0.02 
0.03 
0.04 
1.43 
93.6 
5.5 
0.8 
0.2 
0.3 
0.4 
1.33 
80.0 
15.7 
4.3 
0.9 
1.7 
1.7 
1.25 
58.2 
28.1 
13.7 
2.8 
5.7 
5.1 
1.11 
17.4 
33.8 
48.8 
8.8 
21.9 
18.1 
1.00 
  5.0 
30.9 
64.2 
9.0 
27.3 
27.9 
0.90 
17.4 
44.4 
38.2 
3.5 
13.5 
21.2 
0.80 
58.2 
34.0 
7.9 
0.4 
2.0 
5.4 
0.75 
80.0 
18.0 
2.1 
0.07 
0.4 
1.6 
0.70 
93.6 
6.1 
0.3 
0.009 
0.06 
0.3 
0.65 
98.8 
1.2 
0.03 
0.0003 
0.004 
0.02 
 
The timing of these futility analyses will coincide with the scheduled interim analyses for 
efficacy, starting with Analysis 14 (projected at month 67; see Computations for Sample 
Size Expected to Generate 454 Events). This was selected because in none of the one 
million simulations was futility declared before Analysis 15.   
Another adaptive design feature that will be used is sample size re-estimation.  
Deviations from our assumed enrollment, withdrawal, and event rates could result in an 
overly lengthy trial (in calendar time).  Current projections are to observe 454 events in 
79 months.  These projections will be updated as the trial nears full enrollment (1800 
patients), and enrollment may be extended if needed to complete the trial on-time.  
Because this is an event-driven trial, altering the total sample size is acceptable as long as 
454 events could still eventually be observed.  None of the other design features (total 
number of events, alpha-spending and power-accumulating functions) will be adaptively 
re-estimated or changed after the trial commences.  To prevent bias, the decision to 
extend enrollment will be based only on overall (without regard to treatment group) 

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enrollment, withdrawal, and event rates.  If this decision is required, it will essentially be 
a choice between enrolling additional patients to complete the study sooner or following 
1800 patients longer.  
All interim analyses (efficacy, futility, sample size re-estimation) will be performed by 
the unblinded statistician, who will serve as a liaison to the DSMB.  The decision to 
terminate the trial due to efficacy or futility rests with the DSMB.  It is the sponsor’s 
decision whether to increase total enrollment.        
If recruitment is faster than in (1), it should be ended before 48 months with a smaller 
total n, for otherwise the average follow-up may be too short.  Also, a greater or lesser 
event rate will prolong or shorten the duration, as illustrated in Table 12.1-4. 
Table 12.1-4: Characteristics of the Study Design 
True HR 
Power 
(in %) 
Expected Trial Duration (Months) 
20% Event 
Rate 
25% Event 
Rate 
30% Event 
Rate 
1.00 
5 
83 
71 
64 
0.80 
58 
80 
69 
62 
0.75 
80 
71 
62 
56 
0.70 
94 
65 
57 
52 
0.65 
99 
60 
53 
49 
 
Any slower rate of recruitment or lesser total recruitment will prolong the duration of the 
trial, about one month additionally for each two months delay in reaching target 
enrollment. Alternative scenarios for the estimate of the duration of the trial are 
demonstrated below: 1) assuming a uniform, faster enrollment rate of 45 ppm for the 
duration of the trial (1800 pts in 40 months), shortening the trial by 7 months (Table 
12.1-5); 2) assuming a steady, slower enrollment rate of 30 ppm for the duration of the 
trial (1800 pts in 60 months), lengthening the trial by 3 months (Table 12.1-6).  
 
 

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Alternative Scenarios: 
Table 12.1-5: Assuming 45 ppm throughout (1800 pts in 40 months) 
True HR 
Power 
(in %) 
Expected Trial Duration (Months) 
20% Event 
Rate 
25% Event 
Rate 
30% Event 
Rate 
1.00 
5 
76 
64 
57 
0.80 
58 
73 
62 
55 
0.75 
80 
64 
55 
49 
0.70 
94 
58 
50 
45 
0.65 
99 
53 
46 
42 
 
Table 12.1-6: Assuming 30 ppm throughout (1800 pts in 60 months) 
True HR 
Power 
(in %) 
Expected Trial Duration (Months) 
20% Event 
Rate 
25% Event 
Rate 
30% Event 
Rate 
1.00 
5 
86 
75 
68 
0.80 
58 
83 
72 
65 
0.75 
80 
74 
65 
60 
0.70 
94 
69 
61 
56 
0.65 
99 
63 
56 
52 
 
12.2. General Statistical Methods 
12.2.1. Analysis Sets 
All analyses will be carried out according to the intention-to-treat principle.  All subjects 
randomized in the study will be included in the analysis. 
12.2.2. Control of Systematic Error/Bias 
Selection of subjects will be made from the Investigators’ usual patient load.  All patients 
meeting the eligibility criteria and having signed the ICF will be eligible for randomization in 
the study. 
12.2.3. Number of Subjects per Investigative Site 
A maximum of 10% of the total number of subjects per investigative site has been 
established for this trial. Any one site may not enroll more than 180 subjects without written 
permission from the CDC. 

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12.3. Data Analyses 
Statistical tests of the difference in the primary endpoint (rate of all-cause mortality) between 
the randomized S-ICD and CMT groups will be computed by the unblinded statistician at 
periodic intervals during the trial and submitted to the Data Safety Monitoring Board 
(DSMB) as part of the group sequential design, and at the conclusion of the study (see 
section 12.1.1.3).  The primary analysis will be based on statistical evaluation comparing the 
life-table time-to-event curves for S-ICD and CMT arms of the trial, the graphs being 
constructed by the method of Kaplan and Meier.26  The stratified log-rank test27, 28 (stratified 
by enrolling site) will be used to evaluate statistical significance, adjusted for the group-
sequential stopping rule of the trial with maximum-likelihood ordering;25 late-reported data 
will be appropriately incorporated.29  The hazard ratio for S-ICD relative to CMT, based on 
Cox proportional hazards modeling,27-29 will likewise be estimated.   Also, 95% confidence 
limits for this hazard ratio will be determined, likewise adjusted for the sequential  design.29, 
30 
12.3.1. Other Objectives/Measurements  
The secondary objective of the study will evaluate the effects of the S-ICD on all-cause 
mortality in various subgroups and on sudden cardiac death.  Sudden cardiac death will be 
analyzed using methods similar to those for all-cause mortality, except that they will be 
performed without adjustment for the sequential design. Sudden cardiac death events in the 
study will be independently adjudicated by the Mortality Events Committee using the 
Hinkle-Thaler criteria (see Appendix 28.4). 
The pre-specified subgroups include but are not limited to: gender, race, age continuous and 
dichotomized at 75 years, duration of diabetes, presence versus absence of insulin therapy, 
HbA1c< 8% or ≥ 8%, LVEF continuous and dichotomized at 40%, MADIT II risk score 
subgroups.  For each subgroup analysis, the Cox proportional-hazards regression analysis 
will be used to evaluate differences between subgroups in the hazard ratios (S-ICD vs. 
CMT).  The baseline covariate or stratum and its interaction with treatment group will be 
added to the regression model and a test for significant interaction carried out.  Each analysis 
will be stratified by enrolling site, where appropriate. These analyses will be done without 

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adjustment for the sequential design.  Subgroup analyses are further described in section 
12.3.3. 
Pre-specified tertiary analyses include the following: 
1. Frequency and outcomes of S-ICD treated episodes of ventricular tachycardia (VT) 
and ventricular fibrillation (VF). 
2. Frequency and outcomes of S-ICD inappropriate shocks. 
3. Frequency of S-ICD device complications, including but not limited to: infection, 
device malfunction and electrode movement. 
4. Healthcare utilization assessed through adverse event reporting.  
Tertiary analyses will be descriptive and exploratory.  Detailed statistical methods for these 
outcomes will be presented in a Statistical Analysis Plan (SAP) prior to study termination. 
12.3.2. Interim Analyses  
Interim analyses for efficacy, futility, and sample size re-estimation are described in sections 
12.1.1.3 and 12.3. 
12.3.3. Subgroup Analyses 
Interactions between treatment and important baseline variables will be investigated by 
including the appropriate interaction term in the statistical model and testing for its 
significance.  The list of potential baseline variables to evaluate is listed below.  Also 
included are dichotomous cut points if applicable (based on clinically meaningful cut point, 
historical use, or median value): 
• Duration of diabetes > 2 years, 
• Presence or absence on insulin therapy, 
• Age ≥ 75 years, 
• LVEF ≤ 45%, 
• QRS ≥ 120 msec, 
• Males vs. females, 
• Caucasian (Non-Hispanic) vs other racial and ethnic categories, 

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• Small centers (<10 patients enrolled) vs. large centers (≥ 10 patients enrolled) 
 
12.3.4. Justification of Pooling 
Tests for interactions will be used to evaluate treatment differences between subgroups as 
described in section 12.3.3.  Random effects for centers will be used to justify pooling data 
across investigational sites 
12.3.5. Multivariable Analyses 
Multivariate models will be constructed using the method of best subsets to select important 
covariates predicting the primary outcome of all-cause mortality.  However data reporting in 
the primary analyses will include unadjusted models as appropriate in a randomized clinical 
trial. 
12.3.6. Other Analyses 
A table comparing baseline variables between treatment arms will be prepared.  A list of 
potential baseline variables is categorized below.  Differences between treatment groups will 
be evaluated by chi-square tests, Fisher’s exact tests, t-tests, or Wilcoxon rank sum tests, as 
appropriate. 
• Demographic: age (numeric and/or % ≥ 75 yrs), gender (%), Caucasian (non-
Hispanic) (%). 
• Clinical:  NYHA, paroxysmal atrial fibrillation (%), permanent atrial fibrillation 
(%),QRS (numeric and/or % ≥ 120 msec), LVEF (numeric and/or % ≤ 45), SBP, 
DBP, BMI, heart rate, prior atrial arrhythmias. 
• Medical History:  single/multiple MI, hypertension, CABG, angioplasty, smoking. 
• Medications:  amiodarone, ACE/ARB, beta blockers, calcium-channel blockers, class 
I antiarrhythmic, digitalis, diuretics, lipid-lowering statins, oral hypoglycemic agents, 
non-insulin injectable, insulin, valsartan / sacubitril. 
 

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12.3.7. Changes to Planned Analyses 
Any changes to the planned statistical analyses made prior to study completion will be 
documented in an amended Statistical Analysis Plan approved prior to implementation. 
Changes from the planned statistical methods after the study crossed the stopping 
boundary 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 clinical database will reside on a production server hosted by the University of 
Rochester. All changes made to the clinical data will be captured in an electronic audit 
trail and available for review by Boston Scientific Corporation (BSC) or its 
representative. The associated Trial Master 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 enrolling site principal investigator (PI) 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 PI 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. Enrolling site staff will be responsible 
for resolving all queries in the database, in a timely manner. 
 

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13.2. Data Retention 
The Investigator or enrolling site will maintain, at the site, in original format all essential 
study documents and source documentation that support the data collected on the study 
subjects in compliance with ICH/GCP guidelines.  Documents must be retained for at 
least 2 years after the last approval of a marketing application or until at least 2 years 
have elapsed since the formal discontinuation of the clinical investigation of the 
product/indication. These documents will be retained for a longer period of time by 
agreement with BSC or in compliance with other local regulations. The Investigator will 
take measures to ensure that these essential documents are not accidentally damaged or 
destroyed. If for any reason the Investigator withdraws responsibility for maintaining 
these essential documents, custody must be transferred to an individual who will assume 
responsibility and BSC must receive written notification of this custodial change. 
14. Study Organization 
The MADIT S-ICD study organization is visualized in Figure 14-1. 

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Figure 14-1:  Study Organization 
Events 
Committee 
Mortality /
Device Episode
Sponsor
Boston 
Scientific 
(Monitor)
DSMB
Data Safety 
Monitoring 
Board 
Executive Committee
Enrolling 
Centers
University of
 Rochester -
Coordination and
Data Center (CDC)  
External 
Consultants
FDA
 
14.1. University of Rochester 
Serving as the Coordination and Data Center (CDC) for the Sponsor (Boston Scientific), 
the University of Rochester will be responsible for overall study management, data 
management, data reporting and center communications for the study.  The University of 
Rochester will also be responsible for other project management tasks. 
14.2. Data Safety and Monitoring Board 
An Independent Data Safety and Monitoring Board (DSMB) will meet periodically (as 
pre-specified in the DSMB charter), or as needed, to review the results of the study and to 
evaluate any safety or efficacy issues that may arise during the course of the study. The 
results will be submitted to the DSMB on a monthly basis who will then inform Boston 
Scientific when the sequential monitoring has reached a stopping boundary.  The DSMB 
may recommend termination of the study at any time should prospective ethical or safety 

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guidelines not be met. The DSMB may also recommend increasing the sample size or 
lengthening the follow-up period based on the adaptive study design elements.  Such 
recommendations will not be possible until nearing the completion of enrollment.  The 
DSMB will also review the results of futility analyses and provide recommendations on 
terminating the trial early if the probability of no-difference conclusion is so large that it 
is practically inevitable. The DSMB consists of individuals who are not directly involved 
in the MADIT S-ICD study. 
 
14.3. Mortality Events Committee 
The Mortality Events Committee is an independent physician committee that will 
adjudicate all primary endpoint events that occur in the duration of the trial.  Their 
decisions will be based on independent review of the data.  Data will be provided to the 
Mortality Events Committee by the CDC throughout the duration of the trial. 
All-Cause Mortality Events: Efforts will be made to classify cardiac deaths in terms of 
suddenness and arrhythmic mechanism by pre-specified Hinkle-Thaler criteria (See 
Appendix 27.4). Operative deaths associated with implantation of the S-ICD devices will 
be counted as cardiac deaths. For review of terminal events source documentation will be 
provided including clinical data from the hospital or out-patient record in English. 
15. Amendments  
If a protocol revision is necessary which affects the rights, safety or welfare of the subject 
or scientific integrity of the data, an amendment is required. Appropriate approvals (e.g., 
IRB/EC/FDA/CA) of the revised protocol must be obtained prior to implementation. 
16. Deviations 
An Investigator must not make any changes or deviate from this protocol, except to 
protect the life and physical well-being of a subject in an emergency. An investigator 
shall notify the CDC and the reviewing IRB/EC of any deviation from the investigational 
plan to protect the life or physical well-being of a subject in an emergency, and those 

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deviations which affect the scientific integrity of the clinical investigation. Such notice 
shall be given as soon as possible, but no later than 5 working days after the emergency 
occurred, or per prevailing local requirements, if sooner than 5 working days.  
All deviations from the investigational plan, with the reason for the deviation and the date 
of occurrence, must be documented and reported to the CDC using the EDC system. Sites 
may also be required to report deviations to the IRB/EC, per local guidelines and 
government regulations.  
Deviations will be reviewed and evaluated on an ongoing basis and, as necessary, 
appropriate corrective and preventive actions (including notification, center re-training, 
or discontinuation) will be put into place by the CDC/sponsor. 
 
17. Compliance 
17.1. Statement of Compliance 
This study will be conducted in accordance with relevant parts of ISO14155:2011, 
MEDDEV 2.12/2 rev2 January 2012 (post market clinical follow-up studies), and 
MEDDEV 2.7/3 revision 3 May 2015 Clinical Investigations: serious adverse event 
reporting under directives 90/385/EEC AND 93/42/EEC. In addition, the study will be 
conducted in accordance with relevant parts of the ICH Guidelines for GCP, relevant 
parts of the Code of Federal Regulations (CFR), ethical principles that have their origins 
in the Declaration of Helsinki, and pertinent individual country laws and regulations. The 
study shall not begin until the required approval/favorable opinion from the IRB/EC 
and/or regulatory authority has been obtained, if appropriate. Any additional 
requirements imposed by the IRB/EC or regulatory authority shall be followed, where 
appropriate. 
17.2. Investigator Responsibilities 
The Principal Investigator of an Enrolling site is responsible for ensuring that the study is 
conducted in accordance with the Clinical Study Agreement, the investigational 

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plan/protocol, ISO 14155, ethical principles that have their origins in the Declaration of 
Helsinki, any conditions of approval imposed by the reviewing IRB/EC, and prevailing 
local and/or country laws and/or regulations, whichever affords the greater protection to 
the subject. 
The Principal Investigator’s responsibilities include, but are not limited to, the following:  
• Prior to beginning the study, sign the Clinical Study Agreement and Protocol 
Signature page documenting his/her agreement to conduct the study in accordance 
with the protocol. 
• Provide his/her qualifications and experience to assume responsibility for the 
proper conduct of the study and that of key members of the center team through 
up-to-date curriculum vitae or other relevant documentation and disclose potential 
conflicts of interest, including financial, that may interfere with the conduct of the 
clinical study or interpretation of results. 
• Make no changes in or deviate from this protocol, except to protect the life and 
physical well-being of a subject in an emergency; document and explain any 
deviation from the approved protocol that occurred during the course of the 
clinical investigation. 
• Create and maintain source documents throughout the clinical study and ensure 
their availability with direct access during monitoring visits or audits; ensure that 
all clinical-investigation-related records are retained per requirements. 
• Ensure the accuracy, completeness, legibility, and timeliness of the data reported 
to the CDC in the CRFs and in all required reports. At completion of the study the 
Principal Investigator will be responsible for approval of the data collected via 
electronic signature of all CRFs. 
• Record, report, and assess (seriousness and relationship to the device/procedure) 
every adverse event and observed device deficiency. 
• Report to BSC, per the protocol requirements (Table 20.4-1), all SAEs and device 
deficiencies that could have led to a SADE and potential/USADE or UADE. 

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• Report to the IRB/EC and regulatory authorities any SAEs and device 
deficiencies that could have led to a SADE and potential/USADE or UADE, if 
required by the national regulations or this protocol or by the IRB/EC, and supply 
CDC/Sponsor 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 monitor and respond to questions during monitoring visits. 
• Allow and support regulatory authorities and the IRB/EC when performing 
auditing activities. 
• Ensure that informed consent is obtained in accordance with applicable laws, this 
protocol and local IRB/EC requirements. 
• Provide adequate medical care to a subject during and after a subject’s 
participation in a clinical study in the case of adverse events, as described in the 
Informed Consent Form (ICF). 
• Inform the subject of the nature and possible cause of any adverse events 
experienced. 
• Inform the subject of any new significant findings occurring during the clinical 
investigation, including the need for additional medical care that may be required. 
• Provide the subject with well-defined procedures for possible emergency 
situations related to the clinical study, and make the necessary arrangements for 
emergency treatment, including decoding procedures for blinded/masked clinical 
investigations, as needed. 
• Ensure that clinical medical records are clearly marked to indicate that the subject 
is enrolled in this clinical study. 
• Ensure that, if appropriate, subjects enrolled in the clinical investigation are 
provided with some means of showing their participation in the clinical 
investigation, together with identification and compliance information for 

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concomitant treatment measures (contact address and telephone numbers shall be 
provided). 
• Inform, with the subject’s approval or when required by national regulations, the 
subject’s personal physician about the subject’s participation in the clinical 
investigation. 
• Make all reasonable efforts to ascertain the reason(s) for a subject’s premature 
withdrawal from clinical investigation while fully respecting the subject’s rights. 
• Ensure that an adequate investigation site team and facilities exist and are 
maintained and documented during the clinical investigation. 
• Ensure that maintenance and calibration of the equipment relevant for the 
assessment of the clinical investigation is appropriately performed and 
documented, where applicable. 
17.2.1. Delegation of Responsibility 
When specific tasks are delegated by an investigator, including but not limited to 
conducting the informed consent process, the investigator is responsible for ensuring 
appropriate training requirements are met 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 enrolling site will provide to the CDC 
documentation verifying that their IRB/EC is registered or that registration has been 
submitted to the appropriate agency, as applicable according to national/regulatory 
requirements.   
A copy of the written IRB/EC and/or competent authority approval of the protocol (or 
permission to conduct the study) and Informed Consent Form, must be received by the 
CDC/Sponsor before recruitment of subjects into the study. Prior approval must also be 

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obtained for other materials related to subject recruitment or which will be provided to 
the subject. 
Annual IRB/EC approval and renewals will be obtained throughout the duration of the 
study as required by local/country or IRB/EC requirements. Copies of the Investigator’s 
reports and the IRB/EC continuance of approval must be provided to the CDC.  
17.4. Sponsor Responsibilities 
All information and data sent from University of Rochester or Boston Scientific (BSC) 
concerning subjects or their participation in this study will be considered confidential. 
Only authorized BSC personnel or a BSC representative including BSC’s designated 
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, for publication, and to support future research and/or other business 
purposes. All data used in the analysis and reporting of this study will be without 
identifiable reference to specific subject name. All information received from the 
enrolling site will be de-identified by the enrolling site and the University of Rochester 
for purposes of study use.  
CDC/Sponsor will keep subjects’ health information confidential in accordance with all 
applicable laws and regulations and will comply with all applicable personal data transfer 
requirements in the jurisdictions in which the study will take place.  CDC/Sponsor may 
use subjects’ health information to conduct this research, as well as for additional 
purposes, such as overseeing and improving the performance of its device, new medical 
research and proposals for developing new medical products or procedures, and other 
business purposes. Information received during the study will not be used to market to 
subjects; subject names will not be placed on any mailing lists or sold to anyone for 
marketing purposes.  

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17.4.1. Role of Boston Scientific Representatives 
Boston Scientific personnel can provide technical support to the investigator and other 
health care personnel (collectively HCP) as needed during implant, testing required by 
the protocol, and follow-ups. Support may include HCP training, addressing HCP 
questions, or providing clarifications to HCPs concerning the operation of BSC 
equipment/devices (including programmers, analyzers, and other support equipment). 
At the request of the investigator , BSC personnel may operate equipment during implant 
or follow-up, assist with the conduct of testing specified in the protocol, and interact with 
the subject to accomplish requested activities. Typical tasks may include the following. 
• Interrogating the device or programming device parameters to investigator-
requested settings 
• Performing diagnostic testing using a programmer to obtain system data (e.g. 
Impedance measurements) 
• Clarifying device behavior, operation or diagnostic output as requested by the 
investigator or other health care personnel 
• Assisting with the collection of study data from programmers and other 
equipment 
• Print out programming reports directly from the programmer and provide original 
to clinical site as source documentation 
• Provide technical expertise/support to subjects during office visits and/or during 
teleconference calls/electronic communications with the principal investigator or 
their delegated site staff and the subject 
Boston Scientific personnel may perform certain activities to ensure study quality. These 
activities may include the following: 
• Observing testing or medical procedures to provide information relevant to 
protocol compliance 
• Reviewing collected data and study documentation for completeness and accuracy 

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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 HCP 
• 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 
17.5. Insurance  
Where required by local/country regulation, proof and type of insurance coverage, for 
subjects in the study will be obtained by Boston Scientific. 
17.6    Medicare Study Criteria (pertains to US Enrolling Sites) 
The study protocol describes the method and timing of release of results on all pre-
specified outcomes, including release of negative outcomes and that the release should be 
hastened if the study is terminated early (see below). 
Access to clinical study data provides opportunities to conduct further research that may 
help advance medical science and improve patient care. This helps ensure the data 
provided by research participants are used in the creation of knowledge and 
understanding. To this end, the study results on all pre-specified outcomes, including 
negative outcomes, will be submitted to ClinicalTrials.gov not later than one year after 
the study completion date, where the completion date is defined as the date that the final 
subject was examined or received an intervention for purposes of data collection for the 
primary outcome measure. Results submission could be delayed if an extension is granted 
to the results submission deadline; however, the release of all results on pre-specified 
outcomes will be hastened if the study is terminated early.  
 

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The study protocol must describe how Medicare beneficiaries may be affected by the 
device under investigation, and how the study results are or are not expected to be 
generalizable to the Medicare beneficiary population. Generalizability to populations 
eligible for Medicare due to age, disability, or other eligibility status must be explicitly 
described (see below). 
Subjects in the MADIT S-ICD study include patients age > 65 years old with diagnosed 
diabetes mellitus, documented prior MI (> 3 calendar months) and an LVEF of 36-50%. 
Diabetes is currently one of the most prevalent, major health issues in the United States 
and throughout the world. It is estimated that DM affects nearly 29 million people in the 
United States alone and claims more than 250,000 lives annually, with higher mortality 
risk in those older than 60 years of age.14, 15 Diabetes has been shown to be associated 
with increased risk for SCD following a myocardial infarction, independent of the infarct 
size and LVEF, but is not currently used in the indication for ICD implantation8 Thus, the 
device under investigation will provide Medicare beneficiaries who are post-MI diabetic 
patients that have a relatively preserved ejection fractions with access to potentially life-
saving benefit from an implanted defibrillator. Further, the device under investigation is a 
market approved subcutaneous ICD (S-ICD) under investigation for a new indication for 
use. The S-ICD was chosen for this study design due to characteristics that could 
potentially provide advantages in diabetic patients who may otherwise be at a higher risk 
for device-related infections.16-18 It is anticipated the study's results will be highly 
representative of the Medicare-aged population, as the study’s key inclusion criteria 
includes post-infarction diabetic patients with a moderately impaired left ventricular 
ejection fraction (LVEF 36-50%) who are age 65 years or older. With the aging of the US 
population, expanding indications for ICD implantation, and growing evidence favoring 
device-based therapy over antiarrhythmic drugs, data on the utilization and efficacy of 
ICDs in older patients is becoming increasingly important.31 Therefore, the results of this 
study are expected to be generalizable to the Medicare eligible population primarily due 
to age (e.g., 65 years or older). 

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18. Monitoring 
Monitoring will be performed during the study to assess continued compliance with the 
protocol and applicable regulations. In addition, the 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 Investigator continues to have sufficient 
staff and facilities to conduct the study safely and effectively. The 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 
Investigator and relevant study personnel are available during on-site monitoring visits or 
audits and that sufficient time is devoted to the process. 
 
 

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19. Potential Risks and Benefits Associated with the S-ICD System 
19.1. Anticipated Adverse Events  
The following anticipated adverse events (AE) have been identified for this study related 
to the S-ICD system and /or implantation procedure (See Table 19.1-1).   
Table 19.1-1 Potential Adverse Events for Implantation of the S-ICD System 
 
Potential Adverse Events for Implantation of the S-ICD System* 
Acceleration/induction of atrial or ventricular 
arrhythmia 
Inability to defibrillate or pace 
Adverse reaction to induction testing 
Inappropriate post shock pacing 
Allergic/adverse reaction to system or medication 
Inappropriate shock delivery 
Bleeding 
Infection 
Conductor fracture 
Keloid formation 
Cyst formation 
Migration or dislodgement 
Death 
Muscle/nerve stimulation 
Delayed therapy delivery 
Nerve damage 
Discomfort or prolonged healing of incision 
Pneumothorax 
Electrode deformation and/or breakage 
Post-shock/post-pace discomfort 
Electrode insulation failure 
Premature battery depletion 
Erosion/extrusion 
Random component failures 
Failure to deliver therapy 
Stroke 
Fever 
Subcutaneous emphysema 
Hematoma/seroma 
Surgical revision or replacement of the 
system 
Hemothorax 
Syncope 
Improper electrode connection to the device 
Tissue redness, irritation, numbness or 
necrosis 
Inability to communicate with the device 
  
Note: If any adverse events occur, invasive corrective action and/or S-ICD system modification or 
removal may be required. 
 
Patients who receive an S-ICD system may develop psychological disorders that include, but are 
not limited to, the following: 
• Depression/anxiety 
• Fear of device malfunction 
• Fear of shocks 
• Phantom shocks 
 
* These events are documented within the physician manual for the EMBLEM S-ICD Pulse 
Generator User’s Manual. 

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19.2. Anticipated Adverse Device Effects  
All Adverse Events mentioned in the listing in Section 19.1 are to be considered 
Anticipated Adverse Device Effects Risks Associated with the Study Device.  
19.3. Risks associated with Participation in the Clinical Study 
All Adverse Events mentioned in the listing in Section 19.1 are to be considered risks 
associated with participation in the clinical study.   
19.4. Risk Minimization Actions 
Additional risks may exist. Risks can be minimized through compliance with this 
protocol, performing procedures in the appropriate hospital environment, adherence to 
subject selection criteria, close monitoring of the subject's physiologic status during 
research procedures and/or follow-ups and by promptly supplying the CDC with all 
pertinent information required by this protocol. 
19.5. Anticipated Benefits 
Implantation of an implantable cardioverter defibrillator (ICD) has been previously 
demonstrated to decrease sudden cardiac death (SCD) and improve survival in post-
infarction patients, both diabetic and non-diabetic who have severely reduced left 
ventricular ejection fraction (<35%).  However, diabetic patients have been shown to 
exhibit a greater risk of SCD when compared to non-diabetic patients, even with a 
relatively preserved LVEF of 36-50%.  Therefore, these post-MI diabetic patients may 
potentially derive survival benefit from an ICD.  This hypothesis is supported by results 
from the VALIANT study indicating that the incidence of SCD in post-MI diabetic 
patients and an LVEF >35% was equal to that of non-diabetic patients with an LVEF 
≤35%.32  The MADIT S-ICD study will prospectively test the hypothesis that post-
infarction diabetic patients with a relatively preserved LVEF (35-50%) will have greater 
survival with an S-ICD, which is indicated for the treatment of life-threatening 
ventricular arrhythmias, than those who do not receive an S-ICD.   

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19.6. Risk to Benefit Rationale 
There are risks of complications associated with implantation of a subcutaneous 
implantable cardioverter defibrillator however the projected benefit of S-ICD therapy to 
reduce sudden cardiac death is much greater.  
20. Safety Reporting 
20.1. Reportable Study Events  
Any reportable event(s), experienced by the study subject after enrollment (defined in 
section 10.1 as consented and randomized), must be recorded in the electronic data 
capture system.  It is the responsibility of the investigator to determine if the event meets 
the criteria and report the event to the sponsor per protocol requirements.       
For the purpose of this study, relevant reportable events are defined as:  
• Device and/or procedure related adverse events (serious and non-serious) 
• Unanticipated Adverse Device Effects/Unanticipated Serious Adverse Device 
Effects previously not defined in the User’s manual 
• Adverse events associated with cardiovascular conditions (serious and  non-
serious) 
• Serious adverse events, regardless of cause 
• Device Deficiencies 
Underlying diseases are not reported as AEs unless there is an increase in severity or 
frequency during the course of the investigation.  
Refer to Section 19 for the known risks associated with the study device(s). 
Note: Death should not be recorded as an adverse event. Death should be recorded as an 
outcome of only one (1) serious adverse event. 

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20.2. Definitions and Classification  
In order to provide clarity, the safety reporting definitions are provided in Table 20.2-1. 
Administrative edits were made to combine definitions from ISO 14155-2011 and 
MEDDEV 2.7/3 May 2015. Events Reportable for this study are listed in section 20.1 
 
Table 20.2-1: Safety Reporting Definitions 
Term 
Definition 
Adverse Event (AE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 revision 3 
May 2015 
 
 
Adverse Event (AE) 
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 definition includes events related to the investigational device 
or the 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 investigational medical devices. 
Adverse Device Effect (ADE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 revision 3 
May 2015 
Adverse event related to the use of an investigational medical device. 
NOTE 1- This includes any adverse event resulting from insufficiencies or 
inadequacies in the instructions for use, the deployment, the implantation, 
the installation, the operation, or any malfunction of the investigational 
medical device. 
NOTE 2- This includes any event that is a result of a use error or intentional 
abnormal use of the investigational medical device. 
Serious Adverse Event (SAE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 revision 3 
May 2015 
Serious Adverse Event (SAE) 
Adverse event that: 
a) led to a death, 
b) led to a serious deterioration in health of the subject, that either resulted 
in: - a life-threatening illness or injury, or - a permanent impairment of a 
body structure or a body function, or - in-patient hospitalization or 
prolongation of existing hospitalization, or - in medical or surgical 
intervention to prevent life threatening illness or- injury or permanent 
impairment to a body structure or a body function.  
c) led to fetal distress, fetal death or a congenital abnormality or birth defect. 
NOTE 1: Planned hospitalization for pre-existing condition, or a procedure 
required by the Clinical Investigation Plan, without a serious deterioration in 
health, is not considered a serious adverse event. 
  
Serious Adverse Device Effect 
(SADE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 revision 3 
May 2015 
 
Adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event. 

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Table 20.2-1: Safety Reporting Definitions 
Term 
Definition 
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 14155-2011 
 
Ref: MEDDEV 2.7/3 revision 3 
May 2015 
 
 
Unanticipated Serious Adverse Device Effect (USADE) 
Serious adverse device effect which by its nature, incidence, severity or 
outcome has not been identified in the current version of the risk analysis 
report. 
NOTE: Anticipated SADE (ASADE): an effect which by its nature, 
incidence, severity or outcome has been previously identified in the risk 
analysis report 
 
Device Deficiency 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 revision 3 
May 2015 
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. 
For Purposes of FDA reporting, the following definitions and classifications are used: 
Ref: FDA Guidance for the Submission of Research and Marketing Applications for Permanent Pacemaker 
Leads and for Pacemaker Lead Adaptor 510(k) Submissions 
Clinical Observation 
 
An adverse event that was transient or reversible and corrected with non-
invasive interventions, such as reprogramming or oral medications, or else 
resolved with no intervention or monitoring. 
Clinical Complication 
 
An adverse event that resulted in: death, serious injury a, correction using 
invasive intervention, or permanent loss of device functions. 
a) Per 21 CFR 803.3: Serious injury means an injury or illness that: 
• 
Is life-threatening 
• 
Results in permanent impairment of a body function or permanent 
damage to a body structure, or 
• 
Necessitates medical or surgical intervention to preclude permanent 
impairment of a body function or permanent damage to a body 
structure 
Permanent means irreversible impairment or damage to a body structure 
or function, excluding trivial impairment or damage 
b) Invasive interventions are those in which treatment necessary to 
correct the adverse event is delivered by cutting or piercing of the skin 
or placing an instrument in a body cavity to provide therapy. Examples 
of invasive interventions (complication) include, but are not limited to: 
• 
Surgical revision of a lead 

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Table 20.2-1: Safety Reporting Definitions 
Term 
Definition 
• 
Electrophysiology study in which an ablation is performed 
• 
Angiogram in which angioplasty or stent placement is performed 
• 
Intravenous medications 
• 
Blood transfusions 
• 
Intubation to provide respiratory support 
• 
Chemical (pharmacologic) cardioversion with IV sedation (This is a 
complication due to the IV antiarrhythmic medication used for the 
cardioversion.) 
Invasive procedures that are purely diagnostic in nature should not be 
considered as a complication. Some examples of procedures that are 
invasive, but not considered to be an intervention include: 
• 
Blood draw for laboratory analysis  
• 
Cardiac catheterization in which pressures are recorded, but 
without therapeutic intervention 
• 
Electrophysiology study to map arrhythmias, but without 
therapeutic intervention  
• 
Transesophageal echo (TEE) 
• 
Electrical (external) cardioversion with IV sedation (the IV 
sedation used is for subject comfort and not part of the treatment) 
Type I 
 
Related to the study device, device therapy or procedure related to the 
implant of the study device. 
Type II 
 
Related to protocol or procedures.  Specifically related to protocol testing 
that is not patient standard of care.     
Type III 
 
Not related to the investigational device(s), system component(s), or 
labeling, but would not have occurred in the absence of the investigational 
device(s) and/or system component(s).  This includes clinical events related 
to commercially released devices that are used in conjunction with 
investigational device(s) or protocol procedures. 
Type IV 
 
Related to a change in patient’s condition or to therapies other than 
delivered by the study device. 
Abbreviations: EC=Ethics Committee; IRB=Institutional Review Board 
 
20.3. Relationship to Study Device(s) 
The Investigator must assess the relationship of the AE to the study device as related or 
unrelated. See criteria in Table 20.3-1:  
 

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Table 20.3-1: Criteria for Assessing Relationship of Study Device/Study procedure to 
Adverse Event 
Classification 
Description 
Not Related 
Relationship to the device or procedures can be excluded when: 
o the event is not a known side effect of the product category the device belongs to 
or of similar devices and procedures; 
o the event has no temporal relationship with the use of the investigational device 
or the procedures; 
o 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; 
o 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; 
o 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); 
o the event does not depend on a false result given by the investigational device 
used for diagnosis, when applicable; harms to the subject are not clearly due to 
use error; 
In order to establish the non-relatedness, not all the criteria listed above might be met 
at the same time, depending on the type of device/procedures and the serious event. 
Unlikely Related 
The relationship with the use of the device seems not relevant and/or the event can be 
reasonably explained by another cause, but additional information may be obtained. 
Possibly Related 
The relationship with the use of the investigational device is weak but cannot be ruled 
out completely. Alternative causes are also possible (e.g. an underlying or concurrent 
illness/ clinical condition or/and an effect of another device, drug or treatment). Cases 
were relatedness cannot be assessed or no information has been obtained should also 
be classified as possible.  
Probably Related 
The relationship with the use of the investigational device seems relevant and/or the 
event cannot reasonably explained by another cause, but additional information may 
be obtained. 
Causal Relationship 
(Related) 
The serious event is associated with the investigational device or with procedures 
beyond reasonable doubt when: 
o the event is a known side effect of the product category the device belongs to or 
of similar devices and procedures; 
o the event has a temporal relationship with investigational device use/application 
or procedures; 

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Table 20.3-1: Criteria for Assessing Relationship of Study Device/Study procedure to 
Adverse Event 
Classification 
Description 
o the event involves a body-site or organ that: 
- 
the investigational device or procedures are applied to; 
- 
the investigational device or procedures have an effect on; 
o the serious event follows a known response pattern to the medical device (if the 
response pattern is previously known); 
o 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); 
o 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; 
o harm to the subject is due to error in use; 
o - 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 CDC/BSC are as shown in Table 
20.4-1. 
 
Table 20.4-1: Investigator Reporting Requirements 
Event Classification 
Communication Method  
Communication Timeline  
(MEDDEV 2.7/3 (2015) 
Unanticipated Adverse Device 
Effect / Unanticipated Serious 
Adverse Device Effect  
Note: UADE is for US IDE studies 
only, otherwise remove UADE from 
the table 
Complete AE eCRF page with all 
available new and updated 
information.  
 
• Within 1 business day of first 
becoming aware of the event. 
• Terminating at the end of the 
study 
Serious Adverse Event including 
Serious Adverse Device Effects 
Complete AE eCRF page with all 
available new and updated 
information.  
• Within 3 calendar 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 
requested by the CDC 

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Table 20.4-1: Investigator Reporting Requirements 
Event Classification 
Communication Method  
Communication Timeline  
(MEDDEV 2.7/3 (2015) 
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 a device deficiency 
with all available new and 
updated information.  
• Within 3 calendar days of first 
becoming aware of the event and 
as per local/regional regulations. 
• Reporting required through the 
end of the study 
Adverse Event 
Complete AE eCRF page, which 
contains such information as date 
of AE, treatment of AE 
resolution, assessment of 
seriousness and relationship to the 
device.  
• In a timely manner  (e.g. 
Recommend within 10 calendar 
days) after becoming aware of 
the information 
• Reporting required through EDC  
Abbreviations: AE=adverse event; eCRF=electronic case report form; EDC= electronic data capture; 
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 labeling errors) will be documented and reported to 
CDC/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 not to be reported as adverse events. However, if there is an adverse 
event that results from a device failure or malfunction, that specific event would be 
recorded on the appropriate eCRF. 
And, any Device Deficiency that could 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. 

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20.6. Reporting to Regulatory Authorities / IRBs / ECs / Investigators 
BSC is responsible for reporting adverse event information to all participating 
investigators and regulatory authorities, as applicable.  
The Principal Investigator is responsible for informing the IRB/EC, and regulatory 
authorities of UADE and SAE as required by local/regional regulations. 
 
20.7. Subject Death Reporting 
Subject death during the investigation shall be reported to the CDC as soon as possible 
and in any event within three calendar days of notification to center.  The center’s 
IRB/ERC must be notified of any deaths in accordance with that center’s IRB/ERC 
policies and procedures, even if supporting documents are not yet available. 
Documentation of endpoints will utilize appropriate sources of information.  All death 
related source documentation will be provided to the Mortality Events Committee for 
adjudication by the CDC. 
Notification of death must include a detailed narrative (death letter) of the pertinent 
events and be signed by the investigator or co-investigator, in addition to the required 
device status forms.  The death narrative summary should be submitted to the CDC as 
soon as possible and must include the items listed in Table 20.7-1, if available. 
Table 20.7-1 Death Narrative Summary Required Components 
Date and time of death 
Whether or not the death was witnessed 
Rhythm at the time of death, if known 
(include any available documentation) 
Any other circumstances surrounding the 
death 
Whether the death was device or procedure 
related 
Approximate time interval from the initiating 
event to death 
Place death occurred 
Device status/activity at the time of death 
Immediate cause of death 
 
 

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If any of the above information is not available, please state this in the death narrative 
summary.  A copy of the death records and an autopsy report (if performed) must also be 
uploaded to the database as soon as possible.  An Out-of-Service data form must be 
submitted for all implanted S-ICD system components.  If device episodes have occurred 
and been recorded by the device since the last follow-up, this should be reported on an 
episode form.  An attempt should be made to recover the device system post mortem. If 
the device is explanted it should be returned to Boston Scientific. If it is not explanted the 
device should be interrogated and the information reported on a final summary form. 
21. Informed Consent 
Subject participation in this clinical study is voluntary.  Informed Consent is required 
from all subjects or their legally authorized representative. The Investigator is responsible 
for ensuring that Informed Consent is obtained prior to randomization, 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 approved by CDC or Sponsor, the center’s IRB/EC, or central IRB, if applicable. 
A study-specific template of the ICF will be provided to investigators participating in this 
study. The ICF template may be modified to meet the requirements of the enrolling site’s 
IRB/EC.  Any modification requires approval from CDC prior to use of the form.  The 
ICF must be in a language understandable to the subject and if needed, CDC will assist 
the center in obtaining a written consent translation. Translated consent forms must also 
have IRB/EC approval prior to their use.  Privacy language shall be included in the body 
of the form or as a separate form as applicable.   
The process of obtaining Informed Consent shall at a minimum include the following 
steps, as well as any other steps required by applicable laws, rules, regulations and 
guidelines: 

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• be conducted by the Principal Investigator or designee authorized to conduct the 
process,  
• include a description of all aspects of the clinical study that are relevant to the 
subject’s decision to participate throughout the clinical study, 
• avoid any coercion of or undue influence of subjects to participate, 
• not waive or appear to waive subject’s legal rights, 
• use native language that is non-technical and understandable to the subject 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 competent to sign the 
ICF under the applicable laws, rules, regulations and guidelines and by the investigator 
and/or an authorized designee responsible for conducting the informed consent process. 
The original signed ICF will be retained by the enrolling site and a copy of the signed and 
dated document and any other written information must be given to the person signing 
the form.  
Failure to obtain subject consent will be reported by the sponsor to the applicable 
regulatory authority according to their requirements (e.g., FDA requirement is within 5 
working days of learning of such an event). Any violations of the informed consent 
process must be reported as deviations to the CDC and local regulatory authorities (e.g. 
IRB/EC), as appropriate. 
If new information becomes available that can significantly affect a subject's future health 
and medical care, that information shall be provided to the affected subject(s) in written 
form via a revised ICF or, in some situations, enrolled subjects may be requested to sign 
and date an addendum to the ICF. In addition to new significant information during the 

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course of a study, other situations may necessitate revision of the ICF, such as if there are 
amendments to the applicable laws, protocol, a change in Principal Investigator, 
administrative changes, or following annual review by the IRB/EC. The new version of 
the ICF must be approved by the IRB/EC. Approval is required if changes to the revised 
ICF are requested by the center’s IRB/EC. The IRB/EC will determine the subject 
population to be re-consented. 
22. Additional Safety Monitoring 
22.1. Safety Monitoring Process 
To promote early detection of any potential device safety issues, Boston Scientific will 
evaluate safety events. Success of this program requires dynamic collection of 
unmonitored data as soon as the event is reported. During regularly scheduled monitoring 
visits, clinical research monitors will support the dynamic reporting process through their 
review of source document information. In addition to the DSMB, Boston Scientific will 
internally review on a periodic basis aggregate adverse event rates as well as specific 
events when necessary in order to provide additional safety oversight of the study device 
system. This may include obtaining subject data from internal Boston Scientific Systems 
(device tracking, technical services, and LATITUDE patient management systems). If 
required this information may be provided to MADIT S-ICD Event Committee members 
to ensure accurate adjudication. Any concerns found during the periodic reviews will be 
provided to the DSMB for evaluation. 
23. Suspension or Termination 
23.1 Premature Termination of the Study by the Sponsor 
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.  A determination to terminate prematurely will 
be evaluated and agreed upon by the CDC/Executive Committee/DSMB/Sponsor. 

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Investigators, associated IRBs/ECs, and regulatory authorities, as applicable, will be 
notified in writing in the event of study termination. 
In the event of premature study termination a written statement as to why the premature 
termination has occurred will be provided to all participating centers by the CDC. The 
IRB/EC and regulatory authorities, as applicable, will be notified. Detailed information 
on how enrolled subjects will be managed thereafter will be provided.  
The investigator must return all documents to the CDC/Sponsor, unless this action would 
jeopardize the rights, safety, or welfare of the subjects. 
23.1.1 
Criteria for Premature Termination of the Study by the Sponsor 
Possible reasons for premature study termination include, but are not limited to, the 
following. 
• The occurrence of unanticipated adverse device effects that present a significant 
or unreasonable risk to subjects enrolled in the study. 
• An enrollment rate far below expectation that prejudices the conclusion of the 
study.  
23.2 Termination of Study Participation by the Investigator or Withdrawal of IRB/ EC 
Approval 
Any investigator, or IRB/ EC in the MADIT S-ICD Study may discontinue participation 
in the study or withdrawal approval of the study, respectively, with suitable written notice 
to the CDC/sponsor. Investigators, associated IRBs/ECs, and regulatory authorities, as 
applicable, will be notified in writing in the event of these occurrences. 
In the event an IRB or EC terminates participation in the study, participating 
investigators, associated IRBs/ECs, and regulatory authorities, as applicable, will be 
notified in writing. Detailed information on how enrolled subjects will be managed 
thereafter will be provided.  
In the event an investigator terminates participation in the study, study responsibility will 
be transferred to a co-investigator, if possible. In the event there are no opportunities to 

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transfer investigator responsibility; detailed information on how enrolled subjects will be 
managed thereafter will be provided by the CDC/Sponsor. 
The investigator must return all documents to the CDC/Sponsor, unless this action would 
jeopardize the rights, safety, or welfare of the subjects. 
23.3 
Criteria for Suspending/Terminating an Individual Study Center by the 
CDC/Sponsor 
The CDC/Sponsor reserves the right to stop the inclusion of subjects at a study center at 
any time after the study initiation visit if no subjects have been enrolled  for a period 
beyond 12 months after center initiation, or if the center has multiple or severe protocol 
violations/noncompliance without justification and/or fails to follow remedial actions. 
The IRB/EC and regulatory authorities, as applicable, will be notified. All subjects 
enrolled in the study at the site will continue to be followed per standard of care for their 
device and/or condition.  
24. Publication Policy 
Oversight of the publication process for the MADIT S-ICD study will be performed by 
the University of Rochester Coordination Data Center (CDC) with the primary oversight 
by the MADIT S-ICD Principal Investigator. In accordance with the Conduct of Human 
Subject Research policy, the study results will be submitted for publication (regardless of 
study outcome) following the conclusion or termination of the study in a timely manner. 
The MADIT S-ICD study will follow the Contributorship Criteria set forth in the 
Uniform Requirements of the International Committee of Medical Journal Editors 
(ICMJE; http://www.icmje.org).  
 
 

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25. Reimbursement and Compensation for Subjects 
 
25.1. Subject Reimbursement 
An optional stipend may be provided to participants to cover travel and other expenses 
incurred by subjects and specific to in-clinic visits required as a result of participation in 
the study.  Enrolling sites will be responsible for distributing the stipend as applicable in 
accordance with pertinent country laws and regulations and per the site’s regulations.  
The implementation of the subject stipend will be determined by each enrolling site and 
is not a requirement of the study.  
25.2. Compensation for Subject’s Health Injury 
Boston Scientific Corporation will purchase an insurance policy to cover the cost of 
potential health injury for study subjects, as required by applicable law.  
26. Abbreviations and Definitions  
26.1. Abbreviations 
Abbreviations are shown in Table 26.1-1.  
Table 26.1-1: Abbreviations 
 
Abbreviation/Acronym 
Term 
bpm 
beats per minute 
BSC 
Boston Scientific Corporation 
CDC 
Coordination Data Center (University of Rochester) 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EIT 
Electrode Insertion Tool 
FCC 
Federal Communications Commission 
ERI 
Elective Replacement Indicator 
GCP 
Good Clinical Practice 
ICD 
Implantable Defibrillator 
ICF 
Informed Consent Form 
IDE 
Investigational device exemption 

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Abbreviation/Acronym 
Term 
IRB 
Institutional Review Board 
J 
Joules 
LVEF 
Left Ventricular Ejection Fraction 
ms 
Millisecond 
N/A 
Not Applicable 
NR 
Not Required 
NSR 
Normal Sinus Rhythm 
NYHA 
New York Heart Association 
OUS 
Outside the United States 
ppm 
pulses per minute 
RF 
Radio Frequency 
SAS 
Statistical Analysis System 
SVT 
Supraventricular Tachycardia 
EMBLEM S-ICD System 
The BSC subcutaneous defibrillator, including the EMBLEM Pulse Generator, 
Subcutaneous Electrode, Programmer, and Electrode Insertion Tool (EIT) 
TV-ICD 
Transvenous ICD 
US 
United States  
VF 
Ventricular Fibrillation 
VT 
Ventricular Tachycardia  
VT/VF Storm 
3 or more treated VT/VF episodes occurring within 24 hours 
26.2. Definitions 
Terms are defined in Table 26.2-1.  
Table 26.2-1: Definitions 
Term 
Definition 
Normal Battery Depletion 
A pulse generator that is not associated with a complaint and has reached its 
elective replacement indicator(s) with implant time that meets or exceeds the 
nominal (50th percentile) predicted longevity at default (labeled) programmable 
settings OR with implant time exceeding 75% of the expected longevity using 
the longevity calculation tool available at time of product introduction, 
calculated using the device’s actual use conditions and programmable settings 
Premature Battery 
Depletion 
A pulse generator that does not meet the expected battery longevity. 
Permanent Loss of Device 
Function 
Refers to: 1) the permanent loss of shock therapy and/or post shock pacing; 2) 
permanent loss of appropriate sensing in all available sensing configurations 
(oversensing that results in persistent inappropriate shocks or undersensing that 
could lead to undetected arrhythmias).  Loss of device function includes 
programming the PG permanently off or temporarily off in advance of an 
explant/revision. 
 
 
Abbreviations are defined in Table 26.1-1. 

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27. Appendices 
27.1. MADIT S-ICD Executive Committee Members 
Members of the MADIT S-ICD Executive Committee include the following: 
• Valentina Kutyifa, MD, PhD (Principal Investigator) - University of Rochester 
Heart Research Follow-up Program, Rochester, NY 
• Arthur J. Moss, MD, (Co-Principal Investigator) - University of Rochester Heart 
Research Follow-up Program, Rochester, NY 
• Christopher Beck, PhD - University of Rochester Department of Biostatistics and 
Computational Biology, Rochester, NY 
• Mary W. Brown, MS - University of Rochester Heart Research Follow-up 
Program Rochester, NY 
• David Cannom, MD – Good Samaritan Hospital, Los Angeles, CA 
• James Daubert, MD – Duke University Health System, Chapel Hill, NC 
• Mark Estes, MD - Tufts Medical Center, Boston, MA  
• Henry Greenberg, MD - New York, NY 
• Ilan Goldenberg, MD - Sheba Medical Center, Israel 
• Stephen Hammes, MD - Strong Memorial Hospital, Rochester, NY 
• David Huang, MD – University of Rochester Medical Center, Rochester, NY 
• Helmut Klein, MD - Munich, Germany 
• Reinoud Knops, MD - Academic Medical Center, Amsterdam, The Netherlands 
• Mikhail Kosiborod, MD - St. Luke’s Hospital of Kansas City, Kansas City, MO 
• Jeanne Poole, MD – University of Washington, Seattle, WA 
• Claudio Schuger, MD – Henry Ford Hospital, Detroit, MI 
• Jagmeet Singh, MD – Massachusetts General Hospital, Boston, MA 
• Scott Solomon, MD – Brigham and Women’s Hospital, Boston, MA  
• David Wilber, MD – Loyola University Medical Center, Maywood, IL  
• Wojciech Zareba, MD - University of Rochester Heart Research Follow-up 
Program, Rochester, NY 
 
 

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27.2. MADIT S-ICD Mortality Events Committee 
Composition and Duties 
The MADIT S-ICD Mortality Events Committee will be responsible for the independent 
adjudication of the occurrence of mortality.  The purpose of this process is to provide 
maximum uniformity and continuity in the review and categorization of terminal events, 
while still maintaining latitude for professional judgment by the investigators and 
committee members. 
The committee will receive information regarding all deaths from the enrolling sites. This 
information will be first sent to the Coordination and Data Center (CDC) where the 
supporting documentation will be reviewed for completeness and then forwarded to the 
committee.  The committee will review and adjudicate the events, provided that sufficient 
supporting documentation has been received from the enrolling site.  If the supporting 
documentation is not sufficient or non-existent within a reasonable period of time, the 
enrolling site is contacted and the required documents are requested.  As with all data, 
sometimes the enrolling site is unable to retrieve sufficient source documentation on the 
terminal event.  If there is sufficient evidence in the form of notes from the PI or 
enrolling site that the requested supporting documentation is not available despite 
numerous attempts and these requests have been made diligently, the case is sent to the 
Mortality Events Committee for adjudication. 
Voting Procedures 
The Committee meeting will proceed as long as two of three members of the committee 
are present.  No vote will be taken without the presence of three members, in person or 
by phone. All votes will be recorded, and a final classification document, indicating the 
committee’s decision, will be completed and signed and dated by the Chair.  
If there is initial agreement on the classification among the committee members, the 
endpoint will be classified accordingly and considered closed. However, if there is 
disagreement among the team members, the endpoint will go to full committee 
discussion. The three voting members will determine the classification of the event. In a 

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case where there is a split vote that cannot be resolved through discussion, the Chair 
reserves the right to make the final determination of the case classification.   
In events initially classified as needing additional information, the Chair will request 
additional information from the site investigator. The request will be forwarded via the 
CDC to the site investigator. That decision will be tabled and placed on the agenda for 
review at the next committee meeting, pending the provision of the additional 
information requested. If with all available additional information, the committee is still 
unable to classify the event, the event will be adjudicated as an uncertain mortality event.  
Reporting of Classification 
The committee will forward a completed Event Adjudication Data Form to the CDC that 
will be included in the database with a confirmation report document forwarded to the 
DSMB by the CDC following data entry.  A copy of each confirmation document will be 
archived by the committee and the event review will be considered closed. 
 
 
 

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27.3. Statistical Considerations 
Computation of a sample size that would be expected to generate 454 events depends on: 
(1) The number of patients recruited each month: P1 in month 1, P2 in month 2, ... 
(2) The overall event rate.  If the 3-year cumulative event rate is 25% in CMT-only 
patients, and the HR is 0.75, then the overall rate is a weighted average (due to 2:1 
randomization) of 0.25 (weight = 1) and 1-(1-0.25)^0.75 = 0.194 (weight=2).  That 
works out to 21.3% over 3 years, or a monthly event rate (MER) of 0.59%. 
(3) The 5-year cumulative drop-out rate of 10% in each arm.  That is a monthly drop-out 
rate (MDR) of 0.17%. 
In the first month, P1 patients are enrolled, and assuming uniformly distributed enrollment 
times, they are expected to contribute P1/2 months of follow-up.  The expected numbers of 
events and withdrawals at the end of the first month are then (P1/2)*MER and (P1/2)*MDR, 
respectively.  The expected number of patients remaining at risk entering month 2 is then 
P1*(1- MER/2 - MDR/2).  These monthly computations can be done sequentially, where at 
month j: 
• Rj-1 patients are still at-risk from month j-1 
• Pj patients are enrolled uniformly in month j 
• Expected follow-up time in month j: Rj-1 + Pj/2 
• Expected numbers of events in month j: (Rj-1 + Pj/2)*MER 
• Expected withdrawals in month j: (Rj-1 + Pj/2)*MDR 
• Expected number of patients remaining at risk entering month j+1: Rj-1*(1-MER - 
MDR) + Pj*(1-MER/2 - MDR/2).  
Setting Pj = 25 for j = 1, ... , 12, Pj = 35 for j = 13, ... , 24, Pj = 45 for j = 25, ... , 48, and Pj = 
0 for j > 48, the expected counts that appear in Table 28.3-1 are obtained. 
 
Table 27.3-1: Monthly Projections and Accounting for the Study Design 
Analysis 
Number 
 
Month 
Newly 
Enrolled 
Total 
Enrolled 
New 
Events 
Total 
Events 
New 
Withdrawals 
Total 
Withdrawals 
Remaining 
at Risk 
 
1 
25 
25 
0.07 
0.07 
0.02 
0.02 
24.91 
 
2 
25 
50 
0.22 
0.29 
0.06 
0.08 
49.62 
 
3 
25 
75 
0.37 
0.66 
0.10 
0.19 
74.15 
 
4 
25 
100 
0.51 
1.17 
0.14 
0.33 
98.49 
 
5 
25 
125 
0.66 
1.83 
0.18 
0.52 
122.65 
 
6 
25 
150 
0.80 
2.63 
0.23 
0.74 
146.63 
 
7 
25 
175 
0.94 
3.57 
0.27 
1.01 
170.42 
 
8 
25 
200 
1.08 
4.65 
0.30 
1.31 
194.04 
 
9 
25 
225 
1.22 
5.87 
0.34 
1.66 
217.47 
 
10 
25 
250 
1.36 
7.23 
0.38 
2.04 
240.73 

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11 
25 
275 
1.50 
8.73 
0.42 
2.46 
263.81 
 
12 
25 
300 
1.63 
10.36 
0.46 
2.92 
286.72 
 
13 
35 
335 
1.80 
12.16 
0.51 
3.43 
319.42 
 
14 
35 
370 
1.99 
14.15 
0.56 
3.99 
351.86 
 
15 
35 
405 
2.18 
16.33 
0.62 
4.61 
384.07 
 
16 
35 
440 
2.37 
18.70 
0.67 
5.28 
416.02 
 
17 
35 
475 
2.56 
21.26 
0.72 
6.00 
447.74 
 
18 
35 
510 
2.75 
24.01 
0.78 
6.77 
479.22 
 
19 
35 
545 
2.93 
26.95 
0.83 
7.60 
510.45 
 
20 
35 
580 
3.12 
30.07 
0.88 
8.48 
541.45 
 
21 
35 
615 
3.30 
33.37 
0.93 
9.41 
572.22 
 
22 
35 
650 
3.48 
36.85 
0.98 
10.40 
602.75 
 
23 
35 
685 
3.66 
40.52 
1.03 
11.43 
633.05 
 
24 
35 
720 
3.84 
44.36 
1.08 
12.51 
663.12 
 
25 
45 
765 
4.05 
48.41 
1.14 
13.66 
702.93 
 
26 
45 
810 
4.29 
52.70 
1.21 
14.86 
742.44 
 
27 
45 
855 
4.52 
57.22 
1.27 
16.14 
781.64 
 
28 
45 
900 
4.75 
61.97 
1.34 
17.48 
820.55 
 
29 
45 
945 
4.98 
66.95 
1.41 
18.89 
859.16 
1 
30 
45 
990 
5.21 
72.16 
1.47 
20.35 
897.48 
 
31 
45 
1035 
5.44 
77.60 
1.53 
21.89 
935.51 
 
32 
45 
1080 
5.66 
83.26 
1.60 
23.48 
973.26 
 
33 
45 
1125 
5.88 
89.14 
1.66 
25.14 
1010.71 
2 
34 
45 
1170 
6.11 
95.25 
1.72 
26.87 
1047.89 
 
35 
45 
1215 
6.32 
101.57 
1.78 
28.65 
1084.78 
 
36 
45 
1260 
6.54 
108.11 
1.85 
30.50 
1121.39 
3 
37 
45 
1305 
6.76 
114.87 
1.91 
32.40 
1157.72 
 
38 
45 
1350 
6.97 
121.85 
1.97 
34.37 
1193.78 
 
39 
45 
1395 
7.19 
129.03 
2.03 
36.40 
1229.57 
4 
40 
45 
1440 
7.40 
136.43 
2.09 
38.48 
1265.08 
 
41 
45 
1485 
7.61 
144.04 
2.15 
40.63 
1300.33 
 
42 
45 
1530 
7.82 
151.86 
2.20 
42.83 
1335.31 
5 
43 
45 
1575 
8.02 
159.88 
2.26 
45.10 
1370.02 
 
44 
45 
1620 
8.23 
168.11 
2.32 
47.42 
1404.47 
 
45 
45 
1665 
8.43 
176.54 
2.38 
49.80 
1438.66 
6 
46 
45 
1710 
8.63 
185.17 
2.44 
52.23 
1472.60 
 
47 
45 
1755 
8.83 
194.01 
2.49 
54.72 
1506.27 
 
48 
45 
1800 
9.03 
203.04 
2.55 
57.27 
1539.69 
7 
49 
0 
1800 
9.10 
212.14 
2.57 
59.84 
1527.86 
 
50 
0 
1800 
9.03 
221.16 
2.55 
62.38 
1516.28 
8 
51 
0 
1800 
8.96 
230.12 
2.53 
64.91 
1504.80 
 
52 
0 
1800 
8.89 
239.02 
2.51 
67.42 
1493.40 

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53 
0 
1800 
8.82 
247.84 
2.49 
69.91 
1482.08 
9 
54 
0 
1800 
8.76 
256.60 
2.47 
72.38 
1470.86 
 
55 
0 
1800 
8.69 
265.29 
2.45 
74.83 
1459.71 
10 
56 
0 
1800 
8.63 
273.91 
2.43 
77.26 
1448.66 
 
57 
0 
1800 
8.56 
282.47 
2.41 
79.68 
1437.68 
 
58 
0 
1800 
8.49 
290.97 
2.40 
82.07 
1426.79 
11 
59 
0 
1800 
8.43 
299.40 
2.38 
84.45 
1415.98 
 
60 
0 
1800 
8.37 
307.76 
2.36 
86.81 
1405.25 
 
61 
0 
1800 
8.30 
316.07 
2.34 
89.15 
1394.61 
12 
62 
0 
1800 
8.24 
324.31 
2.32 
91.48 
1384.04 
 
63 
0 
1800 
8.18 
332.49 
2.31 
93.78 
1373.56 
13 
64 
0 
1800 
8.12 
340.60 
2.29 
96.07 
1363.15 
 
65 
0 
1800 
8.05 
348.66 
2.27 
98.34 
1352.83 
 
66 
0 
1800 
7.99 
356.65 
2.25 
100.60 
1342.58 
14 
67 
0 
1800 
7.93 
364.58 
2.24 
102.84 
1332.41 
 
68 
0 
1800 
7.87 
372.46 
2.22 
105.06 
1322.32 
 
69 
0 
1800 
7.81 
380.27 
2.20 
107.26 
1312.30 
15 
70 
0 
1800 
7.75 
388.02 
2.19 
109.45 
1302.36 
 
71 
0 
1800 
7.70 
395.72 
2.17 
111.62 
1292.49 
 
72 
0 
1800 
7.64 
403.36 
2.15 
113.77 
1282.70 
16 
73 
0 
1800 
7.58 
410.93 
2.14 
115.91 
1272.98 
 
74 
0 
1800 
7.52 
418.46 
2.12 
118.03 
1263.34 
 
75 
0 
1800 
7.46 
425.92 
2.11 
120.14 
1253.77 
17 
76 
0 
1800 
7.41 
433.33 
2.09 
122.23 
1244.27 
 
77 
0 
1800 
7.35 
440.68 
2.07 
124.30 
1234.85 
 
78 
0 
1800 
7.30 
447.98 
2.06 
126.36 
1225.49 
18 
79 
0 
1800 
7.24 
455.22 
2.04 
128.40 
1216.21 
 
 
 

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27.4. Hinkle- Thaler Criteria 
Clinical classification of cardiac deaths 
LE Hinkle Jr. and HT Thaler 
 
One hundred forty-two deaths among 743 men ages 50 - 65 years who had been examined 
and followed 5 - 10 years were investigated and classified on the basis of clinical information 
from medical and non- medical observers, ECGs and autopsies. A classification based on the 
condition of the circulation immediately before death appears to be most relevant to studies 
of sudden death. In 58% of the cases, the subjects collapsed abruptly and his pulse ceased 
without prior circulatory collapse (arrhythmic death); in 42%, the pulse ceased only after the 
peripheral circulation had collapsed (deaths in circulatory failure). Thirty-three percent of 
arrhythmic deaths and 10% of deaths in circulatory failure occurred in a setting of clinical 
evidence of acute ischemic heart disease (p less than 0.005). Forty-five percent of arrhythmic 
deaths were preceded by chronic congestive heart failure without circulatory collapse. 
Ninety-three percent of final illnesses that lasted less than 1 hour ended in arrhythmic deaths; 
74% lasted more than 1 day ended in deaths in circulatory failure (p less than 0.001). Eighty-
eight percent of deaths that occurred outside of the hospital were arrhythmic; 71% of deaths 
that occurred in the hospital were deaths in circulatory failure (p less than 0.001). Ninety 
percent of deaths in which the primary cause of the final illness was heart disease were 
arrhythmic; 86% of deaths in which the primary cause was other than heart disease were 
deaths in circulatory failure (p less than 0.001). Ninety-one percent of deaths precipitated by 
an acute cardiac event were arrhythmic; 98% precipitated by acute respiratory obstruction, 
hemorrhage, infection, stroke or other non-cardiac events were deaths in circulatory failure (p 
less than 0.001).  
 
 
Circulation, Vol 65, 457-464, Copyright © 1982 by American Heart Association  
 
 

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27.5.   MADIT S-ICD Conversion Testing Protocol 
 
Conversion (defibrillation) testing is required at S-ICD implantation. 
1. Prepare for conversion testing.  Prior to S-ICD implantation, external defibrillation 
patches should be applied to the patient and connected to an external defibrillator.  
External rescue shocks should be ready if the S-ICD defibrillation shock fails.  
2. Implant the S-ICD (refer to the S-ICD pulse generator user’s manual for guidance).  
Prior to defibrillation testing, carefully close the deep layers of all incisions and 
express any excess air or fluid along the parasternal electrode tunnel.  
3. Induce VF* (refer to the S-ICD pulse generator user’s manual for guidance) and 
allow the S-ICD to deliver a 65 J shock. (15 J safety margin) 
4. If 65 J shock is successful, complete the S-ICD Implantation. 
 
5. If 65 J shock fails, allow the S-ICD to re-detect and deliver an 80J shock or provide 
an external defibrillation rescue shock to terminate the defibrillation test. This step is 
per physician discretion. 
6. For 65 J S-ICD shock failures, check the position of the S-ICD generator and position 
of the electrode relative to anatomy and revise if needed.  If the positions seem 
appropriate, consider reversing polarity. 
7. Induce VF* and allow the S-ICD to deliver a 65 J shock. If 65 J shock fails, either 
allow the S-ICD to re-detect and deliver an 80J shock or provide external 
defibrillation rescue shock to terminate the defibrillation test. 
8. Regardless of failure or success, complete the implantation procedure. 
 
*If VF cannot be induced despite 3 attempts, a dedicated shock can be delivered to identify 
the shock impedance.  
 
Note: If conversion testing has to be terminated due to the instability of the patient, additional 
conversion testing is recommended within 30 days of S-ICD implant.  Additional conversion 
testing can be done per the physician’s discretion. 
 
 

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