Multicenter Automatic Defibrillator Implantation Trial - Chemotherapy-Induced Cardiomyopathy
Phase: NA
Conditions: Cardiomyopathy
Sponsor: University of Rochester

 
 
 
 
 
 
 
MULTICENTER AUTOMATIC DEFIBRILLATOR IMPLANTATION TRIAL –
CHEMOTHERAPY-INDUCED CARDIOMYOPATHY 
(MADIT-CHIC) 
 
NCT # 02164721
Protocol Version 3.0 (February 23, 2018) 

Confidential 
 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 1 of 54 
 
 
 
MULTICENTER AUTOMATIC DEFIBRILLATOR IMPLANTATION TRIAL –
CHEMOTHERAPY-INDUCED CARDIOMYOPATHY 
(MADIT-CHIC) 
 
CLINICAL PROTOCOL 
Version 3.0 (February 23, 2018) 
 
 
Funding Provided By: 
Boston Scientific  
4100 Hamline Avenue North 
St. Paul, MN 55112-5798 
Tel: (612) 638-4000    
Fax: (612) 638-4166 
 
Study Sponsor:  University of Rochester Medical Center 
 
Principal Investigator: Valentina Kutyifa, MD, PhD, Associate Professor of Medicine,  
Heart Research Follow-up Program, University of Rochester Medical Center, 
265 Crittenden Boulevard, CU 420653, Rochester, NY14620 
Tel: (585) 275-2676   Fax: (585) 273-5283 
 
Co-Principal Investigator: Jagmeet Singh, MD, PhD, Associate Professor of Medicine, 
Cardiology Division, Massachusetts General Hospital,  
55 Fruit St., GRB-109, Boston, MA 02114 
Tel: (617) 726-4662    
 
 
 
 
 
 
 
 
This protocol contains confidential information for use by the Investigators and their 
designated representatives participating in this clinical investigation. It must be held 
confidential and maintained in a secure location. 
Do not copy or distribute without written permission from University of Rochester. 
 
 
 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 2 of 54 
 
 
Contact Information 
Role 
Contact  
Principal Investigator Valentina Kutyifa, MD, PhD 
Associate Professor of Medicine  
Heart Research Follow-up Program 
University of Rochester Medical Center, CPU Box 420653 
265 Crittenden Blvd 
Rochester, NY 14620 
 
Tel: (585) 275-2676     
Fax: (585) 273-5283 
 
Email address:  Valentina.Kutyifa@heart.rochester.edu  
Co- Principal 
Investigator 
Jagmeet Singh, MD, PhD  
Associate Professor of Medicine 
Cardiology Division, Massachusetts General Hospital 
55 Fruit St., GRB-109  
Boston, MA 02114 
 
Tel: (617) 726-4662   
 
E-mail address:  jsingh@partners.org 
Investigational Sites 
A list of investigational sites is maintained and provided in the 
Manual Of Operations.
Other Institutions 
A list of other institutions involved in the trial is maintained and 
provided in the Manual Of Operations. 
 
 
 
 
 
 
 
 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 3 of 54 
 
 
Current Version 3.0: Revision History  
Revision Number  
Release Date  
Section  
Change 
Reason for Change 
3.0 
February 23, 2018 
Protocol cover 
page, Contact 
Information, 
Section 28.1 and 
Appendix A 
Remove Dr. Moss 
as PI 
Passing of PI 
3.0 
February 23, 2018 
Protocol cover 
page, Contact 
Information, 
Section 28.1 and 
Appendix A 
Add Dr. Valentina 
Kutyifa as new PI 
Passing of PI 
3.0 
February 23, 2018 
Section 17.5 and 
Appendix A 
Remove references 
to Dr. Sanjeev 
Francis 
Dr. Francis is no 
longer at MGH and 
not involved in the 
study 
  
Version 2.0 Revision History 
Revision Number 
Release Date 
Section 
Change 
Reason for Change 
2.0 
Jan 27, 2015 
 
Added exclusion criteria 
Increase number of 
eligible subjects and 
clarification 
2.0 
Jan 27, 2015 
 
Added inclusion criteria 
Clarification on etiology 
of chemotherapy-
induced heart disease 
and time frame for 
enrollment 
2.0 
Jan 27, 2015 
 
Added verbiage with 
time frame to include 
months 
Oversight page 15 
section 4, paragraph 1 
2.0 
Jan 27, 2015 
 
Revised power 
calculation 
Decrease number of 
required enrolled 
subjects 
2.0 
Jan 27, 2015 
 
Changed programming 
definition 
Clarification 
2.0 
Jan 27, 2015 
 
Changed to Boston 
Scientific generator 
versus device system and 
components  
 Allow more flexible 
FDA-approved lead 
component use by site 
2.0 
Jan 27, 2015 
 
Added Device 
Deficiency reporting 
requirements 
Oversight 
 
 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 4 of 54 
 
 
2. Protocol Synopsis 
MULTICENTER AUTOMATIC DEFIBRILLATOR IMPLANTATION TRIAL –
CHEMOTHERAPY-INDUCED CARDIOMYOPATHY (MADIT-CHIC) 
Objective(s) 
The primary objective of this trial is to determine if CRT-D in high-
risk patients with chemotherapy-induced cardiomyopathy will 
significantly improve the left ventricular ejection fraction (LVEF) by 
echocardiography within 6 months of initiating CRT without adversely 
affecting mortality.  
 
The secondary objectives are to: 1) determine the effects of CRT on 
all-cause mortality; 2) determine by echocardiographic evaluation at 6 
months if CRT therapy improves left ventricular volume at end systole 
(LVESV) and end diastole (LVEDV). 
 
 
The tertiary objectives are to evaluate CRT therapy at 6 months on: 1) 
NYHA functional class when compared to baseline; and 2) change in 
atrial size. In addition, during the 6-month clinical course, the effects 
of CRT on the frequency of heart failure with the end point as inpatient 
hospitalization for heart failure will be evaluated in the study 
population. 
 
Indication(s) 
for Use 
Boston Scientific CRT-D devices are intended to provide 
resynchronization therapy for patients with overt or subclinical heart 
failure and compromised LV function. 
Device 
Subjects registered in this trial must be implanted with a Boston 
Scientific commercially available CRT-D generator, with the device 
implant procedure performed by a qualified physician per standard of 
care and indication guidelines. All device components used in the 
MADIT-CHIC trial must be market-released products and be 
implanted using standard operating procedures. 
 
Study Design 
The study is a non-randomized, prospective observational study in 30 
subjects with chemotherapy-induced cardiomyopathy who meet 
guideline-based indications for CRT-D. Subjects will be followed for 6 
months post-implant, and clinical data related to their functional status 
and echocardiographic measures of reverse remodeling will be 
collected at the 6-month follow-up visit. Day zero is date of implant. 
After the 6-month visit, each registered subject will then have clinical 
CRT-D and cardiac follow-up per device standard of care guidelines, 
but will no longer be registered in the research study and require study 
data collection. 
 
 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 5 of 54 
 
 
MULTICENTER AUTOMATIC DEFIBRILLATOR IMPLANTATION TRIAL –
CHEMOTHERAPY-INDUCED CARDIOMYOPATHY (MADIT-CHIC) 
Planned 
Number of 
Subjects 
 
30 registered subjects 
Planned 
Number of 
Centers / 
Countries 
The study will be initially conducted at approximately 10-15 US 
centers. If necessary, more sites may be invited to participate to meet 
the 30 subject registration goal. 
Primary 
Endpoint 
Significant improvement in echo-determined LVEF between baseline 
and 6 months in high-risk cardiac patients with chemotherapy-induced 
cardiomyopathy. 
Method of 
Assigning 
Subjects to 
Treatment 
Study enrollment and registration using the electronic data capture 
system that is available 24/7 to all designated enrolling center 
personnel. 
Follow-up 
Schedule 
Following registration, subjects will have scheduled visit follow-ups at 
3 (phone) and 6-month (clinic) intervals following device implant. 
Relevant event history, cardiac medications, physical assessment, 
device event and programming status, and adverse events will be 
collected at each clinic follow-up visit. Events will be collected at the 
3-month phone follow-up. At the 6-month visit, a repeat 
echocardiogram will be obtained. Subjects will be followed through 
the 6 month visit. The study will end when the last registered subject 
reaches the 6 month visit.  Once the study is finished, subjects will 
continue to be followed per local CRT-D standard of care guidelines.  
Study Duration The estimated duration of the trial is 2.25 years, and that includes 6 
months for start-up to get the enrolling centers on board, 12 months for 
subject registration, 6 months for follow-up of last registered subject, 
and 3 months for close-out and data analyses. 
 
Required 
Medication 
Therapy 
All study subjects will need to be on guideline-directed stable optimal 
pharmacologic therapy for the cardiac condition, consisting of loop 
diuretics, aldosterone antagonists, beta blockers and/or ACE/ARB as 
tolerated, unless contraindicated, with stable doses for one month prior 
to study registration. Medications may be prescribed and adjusted as 
required for cardiac condition. 
 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 6 of 54 
 
 
MULTICENTER AUTOMATIC DEFIBRILLATOR IMPLANTATION TRIAL –
CHEMOTHERAPY-INDUCED CARDIOMYOPATHY (MADIT-CHIC) 
Key Inclusion 
Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject is age 18 (or of legal age to give informed consent specific 
to state and national law) up to 80 years of age 
 
Male or female  
 
Subject who was without clinical heart failure at initiation of 
chemotherapy/radiation-induced treatment for an underlying 
malignancy, but developed clinical heart failure (cardiomyopathy: 
reduced LVEF with a LBBB-type of conduction disturbance; see 
next inclusion item) 6 months or more after initiation of the 
chemotherapy without other evident cause of the cardiomyopathy.  
 
Subject eligible for implantation of a CRT-D device according to 
one of the following options in currently available guidelines: 
Class 1:  
o LVEF < 35% AND 
o Sinus rhythm AND 
o LBBB with a QRS duration >150 ms AND 
o NYHA class II, III or ambulatory IV symptoms 
on guideline-directed medical therapy 
Class 2a1:  
o LVEF < 35% AND 
o Sinus rhythm AND 
o LBBB with a QRS duration 120-149ms AND 
o NYHA class II, III or ambulatory IV symptoms 
on guideline-directed medical therapy 
Class 2a2:  
o LVEF < 35% AND 
o Sinus rhythm AND 
o Non- LBBB with a QRS duration >150 ms AND 
o NYHA III or ambulatory IV symptoms on 
guideline-directed medical therapy 
 
Subject on stable* optimal pharmacologic therapy for the cardiac 
condition that is guideline-based and may include one or more of 
the following medications: Loop diuretics (e.g., furosemide, 
bumetanide, torsemide) unless the subject is not indicated, is 
contraindicated, or is intolerant of loop diuretics; Angiotensin 
converting enzyme (ACE) inhibitors and/or  angiotensin receptor 
blocker (ARB) unless the subject failed, is not indicated, or is 
contraindicated for these therapies; Aldosterone antagonists unless 
the subject is not indicated, or is intolerant of aldosterone 
antagonists; Beta-blockers unless the subject is not indicated, 
contraindicated, or is intolerant of beta-blockers. The choice of 
selective or non-selective beta-blockers use is left to the 
Investigator’s discretion 
* For purposes of the study, “stable” is defined as subject prescribed 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 7 of 54 
 
 
MULTICENTER AUTOMATIC DEFIBRILLATOR IMPLANTATION TRIAL –
CHEMOTHERAPY-INDUCED CARDIOMYOPATHY (MADIT-CHIC) 
Key Inclusion 
Criteria 
(Continued) 
 
set medication doses for at least one month prior to study registration, 
unless contraindicated or not tolerated. Medications may be prescribed 
and adjusted as required for cardiac condition during the study. 
 
Key Exclusion 
Criteria at 
Time of  
Consent 
 
 
Subject with a currently implanted pacemaker or ICD device 
 
Previous implant with a CRT/CRT-D device 
 
Subject cardiac condition not presumed to be caused by 
chemotherapy   
 
Documented symptomatic or hemodynamically unstable 
ventricular tachyarrhythmia  
 
Subjects on active chemotherapy (must be at least 6 calendar 
months after last chemotherapy treatment)   
 
Subject with permanent or chronic AF, or cardioversion for AF 
within the past 3 calendar months before consent date 
 
Subject with structural heart disease such as congenital heart 
disease, valvular heart disease, e.g., rheumatic valvular heart 
disease, amyloid heart disease, etc. 
 
Subject with coronary artery bypass graft surgery or percutaneous 
coronary intervention within the past 3 calendar months before 
consent date 
 
Subject with enzyme positive myocardial infarction within the past 
3 calendar months prior to consent date 
 
Unstable angina requiring hospitalization, with diagnostic work up 
and intervention within the past 3 months prior to consent date 
 
Subject with angiographic evidence of coronary disease who are 
candidates for coronary revascularization and are likely to undergo 
coronary artery bypass graft surgery or percutaneous coronary 
intervention in the foreseeable future 
 
Subject in Class IV and expected to undergo transplant within 
study duration 
 
Current or past history of drug addiction or abuse that caused 
cardiomyopathy 
 
Subject who is pregnant or plans to become pregnant during the 
course of the trial. Note: Women of childbearing potential must 
have a negative pregnancy test within 7 days prior to consent date 
 
Subject with recent CVA or TIA within the previous 3 months 
prior to consent date. 
 
 
 
 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 8 of 54 
 
 
 
MULTICENTER AUTOMATIC DEFIBRILLATOR IMPLANTATION TRIAL –
CHEMOTHERAPY-INDUCED CARDIOMYOPATHY (MADIT-CHIC) 
Key Exclusion 
Criteria at 
Time of  
Consent 
(Continued) 
 
 
Subject with presence of any disease, other than the subject’s 
cardiac or cancer disease, associated with a reduced likelihood of 
survival for the duration of the trial, e.g., uremia, liver failure, 
active malignant disease, etc. 
 
Subject participating in any other clinical trial  
 
Subject unwilling or unable to cooperate with the protocol 
 
Subject who lives at such a distance from the clinic that travel for 
follow-up visits would be unusually difficult 
 
Subject who does not anticipate being a resident of the area for the 
scheduled duration of the trial 
 
Subject unwilling to sign the consent for participation 
 
Subject whose physician does not allow participation 
 
 
 
Statistical Methods 
Primary 
Statistical 
Hypothesis 
CRT-D is associated with a mean improvement in LVEF from baseline 
to six months. 
Statistical Test 
Method and 
Sample Size 
Parameters 
Per description in Section 12.2 
 
 
 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 9 of 54 
 
 
 
3. Table of Contents 
1. 
TITLE PAGE  ........................................................................................................................ 1 
2. 
PROTOCOL SYNOPSIS .......................................................................................................... 4 
3. 
TABLE OF CONTENTS .......................................................................................................... 9 
3.1.  Table of Figures ...................................................................................................... 13 
3.2.  Table of Tables ....................................................................................................... 13 
4. 
INTRODUCTION ................................................................................................................. 14 
5. 
DEVICE DESCRIPTION ....................................................................................................... 14 
6. 
OBJECTIVES ...................................................................................................................... 14 
7. 
ENDPOINTS ........................................................................................................................ 15 
7.1. 
Echocardiography Endpoints .............................................................................. 15 
7.2 
Recurrent Heart Failure ....................................................................................... 15 
7.3 
Subject Death ........................................................................................................ 15 
8. 
DESIGN .............................................................................................................................. 16 
8.1.  Scale and Duration ................................................................................................. 16 
8.2.  Treatment Assignment .......................................................................................... 17 
8.2.1. 
Treatment and Control ............................................................................... 17 
8.3.  Justification for the Study Design ......................................................................... 17 
9. 
SUBJECT SELECTION ......................................................................................................... 17 
9.1.  Study Population and Eligibility ........................................................................... 17 
9.2.  Inclusion Criteria ................................................................................................... 17 
9.3.  Exclusion Criteria .................................................................................................. 19 
10.  SUBJECT ACCOUNTABILITY .............................................................................................. 21 
10.1.  Point of Enrollment ................................................................................................ 21 
10.2.  Withdrawal ............................................................................................................. 21 
10.3.  Subject Status and Classification .......................................................................... 21 
10.4.  Registration Controls ............................................................................................. 22 
11.  STUDY METHODS .............................................................................................................. 22 
11.1.  Screening ................................................................................................................. 22 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 10 of 54 
 
 
11.2.  Enrollment/Informed Consent .............................................................................. 22 
11.3.  Registration ............................................................................................................. 23 
11.4.  Implant .................................................................................................................... 23 
11.5.  Device Programming. ............................................................................................ 23 
11.6.  Baseline ................................................................................................................... 24 
11.6.1. 
Baseline (before implant ........................................................... 24 
11.6.1. 
Baseline (after implant) ............................................................. 24 
11.7.  Clinic Follow-up Visits ........................................................................................... 24 
11.8.  Data Collection ....................................................................................................... 25 
11.9.  Study Completion ................................................................................................... 27 
11.10. Source Documents ................................................................................................ 27 
12.  STATISTICAL CONSIDERATIONS ....................................................................................... 28 
12.1.  Endpoints ................................................................................................................ 28 
12.1.1.  Primary Endpoint ....................................................................................... 28 
12.1.1.1.  Hypotheses ................................................................................ 28 
12.1.1.2.  Sample Size ............................................................................... 28 
12.1.1.3.  Statistical Methods .................................................................... 28 
12.1.2.  Efficacy Endpoints ..................................................................................... 29 
12.1.2.1.  Hypotheses ................................................................................ 29 
12.1.2.2.  Sample Size ............................................................................... 30 
12.1.2.3.  Statistical Methods .................................................................... 30 
12.2.  General Statistical Methods .................................................................................. 30 
12.2.1.  Analysis Sets .............................................................................................. 30 
12.2.2.  Control of Systematic Error/Bias ............................................................... 30 
12.2.3.  Number of Subjects per Investigative Site ................................................ 30 
12.2.4.  Interim Analyses ........................................................................................ 30 
12.2.5.  Subgroup Analyses .................................................................................... 30 
12.2.6.  Justification of Pooling .............................................................................. 30 
12.2.7.  Multivariable Analyses .............................................................................. 31 
12.2.8.  Other Analyses ........................................................................................... 31 
12.2.9.  Changes to Planned Analyses .................................................................... 31 
13.  DATA MANAGEMENT ........................................................................................................ 31 
13.1.  Data Collection, Processing, and Review ............................................................. 31 
13.2.  Data Retention ........................................................................................................ 31 
13.3.  Core Laboratories .................................................................................................. 32 
13.3.1.  Echocardiogram Core Laboratory ............................................................. 32 
13.3.2.  ECG Core Laboratory ................................................................................ 33 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 11 of 54 
 
 
14.  AMENDMENTS ................................................................................................................... 33 
15.  DEVIATIONS ...................................................................................................................... 33 
16.  DEVICE/EQUIPMENT ACCOUNTABILITY .......................................................................... 34 
17.  COMPLIANCE ..................................................................................................................... 34 
17.1.  Statement of Compliance ....................................................................................... 34 
17.2.  Investigator Responsibilities ................................................................................. 34 
17.2.1.  Delegation of Responsibility ..................................................................... 36 
17.3.  Institutional Review Board/ Ethics Committee ................................................... 36 
17.4.  Coordination and Data Center Responsibilities .................................................. 36 
17.5.  Clinical Center Responsibilities ............................................................................ 37 
17.6.  Role of Boston Scientific Representatives ............................................................ 37 
17.7.  Confidentiality ........................................................................................................ 37 
18.  MONITORING ..................................................................................................................... 38 
19.  POTENTIAL RISKS AND BENEFITS .................................................................................... 38 
19.1.  Anticipated Adverse Device Effects and Anticipated Adverse Events .............. 38 
19.2.  Risks Associated with the Study Device(s) ........................................................... 40 
19.3.  Risks associated with Participation in the Clinical Study .................................. 40 
19.4.  Possible Interactions with Concomitant Medical Treatments ........................... 40 
19.5.  Risk Minimization Actions .................................................................................... 40 
19.6.  Anticipated Benefits ............................................................................................... 40 
19.7.  Risk to Benefit Rationale ....................................................................................... 41 
20.  SAFETY REPORTING .......................................................................................................... 41 
20.1.  Definitions and Classification ............................................................................... 41 
20.2.  Relationship to Study Device(s) ............................................................................ 42 
20.3.  Investigator Reporting Requirements .................................................................. 43 
20.4.  Reporting to Regulatory Authorities / IRBs / ECs / Investigators .................... 43 
21.  INFORMED CONSENT ......................................................................................................... 43 
22.  COMMITTEES .................................................................................................................... 45 
22.1.  Safety Monitoring Process ..................................................................................... 45 
22.2.  Executive Committee ............................................................................................. 45 
22.3.  Data Safety and Monitoring Board Committee .................................................. 45 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 12 of 54 
 
 
22.4.  Mortality Review Committee ................................................................................ 46 
23.  SUSPENSION OR TERMINATION ......................................................................................... 46 
23.1  Premature Termination of the Study ................................................................... 46 
23.1.1 
Criteria for Premature Termination of the Study ....................................... 46 
23.2  Termination of Study Participation by the Investigator or Withdrawal of 
IRB/ EC Approval .................................................................................................. 47 
23.3  Requirements for Documentation and Subject Follow-up ................................. 47 
23.4  Criteria for Suspending/Terminating a Study Center ........................................ 47 
24.  PUBLICATION POLICY ....................................................................................................... 47 
25.  REIMBURSEMENT AND COMPENSATION FOR SUBJECTS .................................................. 48 
25.1.  Subject Reimbursement ........................................................................................ 48 
26.  BIBLIOGRAPHY .................................................................................................................. 48 
27.  ABBREVIATIONS AND DEFINITIONS .................................................................................. 48 
27.1.  Abbreviations ......................................................................................................... 48 
27.2.  Definitions ............................................................................................................... 50 
28.  APPENDICES ...................................................................................................................... 50 
28.1.  Clinical Trial Organization ................................................................................... 50 
Appendix A Executive Committee ................................................................................. 50 
Appendix B Declaration of Helsinki .............................................................................. 51 
 
 
 
 
 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 13 of 54 
 
 
 
2.1. Table of Figures 
Figure 11.8-1:  Study Data Flow…………………………………………………………26 
2.2. Table of Tables 
Table 9.2-1: Inclusion Criteria ........................................................................................... 18 
Table 9.3-1: Exclusion Criteria .......................................................................................... 20 
Table 11.8-1: Data Collection Schedule ............................................................................ 27 
Table 19.1-1: Potential Adverse Events and Potential Adverse Device Effects for Pulse 
Generator and/ or Lead System Implants……………………………………39 
Table 20.1-1: Adverse Event Definitions .......................................................................... 41 
Table 20.2-1: Criteria for Assessing Relationship of Study Device to Adverse Event ..... 42 
Table 20.3-1: Investigator Reporting Requirements .......................................................... 43 
Table 27.1-1: Abbreviations .............................................................................................. 49 
Table 27.2-1: Definitions ................................................................................................... 50 
 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 14 of 54 
 
 
4. Introduction 
With the advent of new therapies and an increasing number of long-term cancer 
survivors, the incidence and consequently the interest in chemotherapy-induced 
cardiomyopathy (CHIC) have been increasing. CHIC is a dose-dependent 
cardiomyopathy and presents as congestive heart failure several months to years after the 
administration of chemotherapy.1 Among the several chemotherapeutic agents that cause 
cardiomyopathy, the most frequently incriminated in the pathogenesis of CHIC are 
anthracyclines.   
 
Greater than one-half of the patients exposed to just this class of drugs will show 
evidence of cardiac dysfunction, with 5% presenting with overt symptomatic heart 
failure. The overall incidence of CHIC is significantly underestimated as within the US 
alone, greater than 60,000 patients receive just anthracyclines every year.2 Despite this, 
there is little data on their response to conventional heart failure therapy. There is some 
preliminary evidence from two small, retrospective case-series suggesting that patients 
with CHIC and evidence of conduction tissue disease (i.e. a wide QRS duration) may 
significantly benefit from cardiac resynchronization therapy (CRT).3,4 
 
Our hypothesis is based on the assumption that CHIC is pathophysiologically similar to 
other forms of non-ischemic cardiomyopathy and CRT may serve to positively alter the 
natural history and improve the clinical trajectory and outcome in this cohort of patients 
as it has done in other forms of cardiomyopathy.5 Our study aims to assess the impact of 
cardiac resynchronization therapy on clinical response and left ventricular reverse 
remodeling in patients with chemotherapy-induced cardiomyopathy. 
5. Device Description 
Subjects registered in this trial will be implanted with a Boston Scientific commercially 
available CRT-D generator within the specific countries where enrolling centers are 
located, with the device implant procedure performed by a qualified physician per local 
standard of care guidelines. All device components used in the MADIT-CHIC trial must 
be market-released products and must be implanted using standard operating procedures. 
6. Objectives 
The primary objective of this trial is to determine if CRT-D in high-risk patients with 
chemotherapy-induced cardiomyopathy will significantly improve the left ventricular 
ejection fraction (LVEF) by echocardiography within 6 months of initiating CRT without 
adversely affecting mortality. The study population will consist of patients with approved 
guideline-based indication for CRT-D. All subjects will receive CRT-D device with 
resynchronization therapy and potential for defibrillation as required. 
 
 
The secondary objectives are to: 1) determine the effects of CRT on all-cause mortality; 
2) determine by echocardiographic evaluation at 6 months if CRT therapy improves left 
ventricular volume at end systole (LVESV) and end diastole (LVEDV). 
 
 
The tertiary objectives are to evaluate CRT therapy at 6 months on: 1) NYHA functional 
class when compared to baseline; and 2) change in atrial size. In addition, during the 6-

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 15 of 54 
 
 
month clinical course, the effects of CRT on the frequency of heart failure with the end 
point an inpatient hospitalization with augmented treatment for heart failure will be 
evaluated in the study population. 
7. Endpoints 
 
7.1  Echocardiography Endpoints 
Echocardiograms will be performed by the enrolling sites at baseline before implant and 6 
months following device implant. All images will be analysed centrally by an 
echocardiography core lab. The core lab will measure the left ventricular ejection fraction 
(LVEF), which is the primary endpoint of the trial, as well as the atrial size and the left 
ventricular volumes (LVESV and LVEDV), which are part of the secondary objectives. 
For more detail on the core lab, please refer to section 13.3.1. 
7.2    Recurrent Heart Failure 
Heart failure events will be documented by clinical data from the investigative center 
record in English, the official language of the study. These events will be documented in 
the electronic case report form as adverse events.  A heart failure event will be defined as 
when the subject has an inpatient admission for congestive heart failure. 
7.3    Subject Death 
The mortality event case report form will be completed in the electronic data capture 
system when reporting a subject death. Mortality events will be documented by clinical 
data from the investigative center record in English, the official language of the study. 
Collected death information includes details about cause of death, device functioning, and 
other relevant details. The device must be interrogated (if possible) and the case report 
form listed above must be completed and transferred to the electronic data capture 
website as soon as possible after notification to the center.  Every attempt must be made 
to return all Boston Scientific CRM system components to sponsor.  
A subject death during the study must be reported to the CDC as soon as possible and in 
conjunction with adverse event reporting requirements. 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. 
Notification of death shall include a detailed narrative of the pertinent events in addition 
to the required device status forms.  The death narrative must be submitted to the CDC as 
soon as possible and must include all of the following, if available: 
 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 
 
 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 16 of 54 
 
 
 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 
 
If any of the above information is not available, this must be stated in the death narrative.  
A copy of the death records and an autopsy report (if performed) must also be sent to the 
CDC as soon as possible with English translation provided as required by a certified 
language translator. The pulse generator must be interrogated, all data saved to the subject 
data disk, and the device returned to BSC if possible. An Out-of-Service data form must 
be submitted for all out-of-service devices. If spontaneous events have occurred and been 
recorded by the device since the last follow-up, an additional follow-up form must be 
completed with this additional data. In the event that the device is not explanted, the same 
procedure must be followed to retrieve the data and turn off the device.   
8. Design 
This is a prospective, non-randomized, multicenter investigation conducted at US centers. 
8.1. Scale and Duration 
The plan is to register approximately 30 subjects in approximately 10-15 enrolling centers 
in one year. We anticipate a registration rate averaging 0.21 subjects/center/month 
achieving 30 registered subjects in 12 months (0.21 x 12cntrs x 12mo = 30). Device 
implantation will be carried out within 14 days of registration. The ongoing recruitment 
rate will be closely monitored. If the monthly recruitment rate is meaningfully less than 
the projected average of 0.21 subjects/center/month, then new centers may be added to 
enhance registration upon MADIT-CHIC Executive Committee approval. 
The estimated duration of the trial is 2.25 years, and that includes 6 months for start-up to 
get the enrolling centers on board, 12 months for subject registration, 6 months for 
follow-up of last registered subject, and 3 months for close-out and data analyses. 
 
Consented (enrolled) subjects will be registered formally in the study using an electronic 
system and undergo CRT-D device implant. Following device implant, registered subjects 
will have scheduled clinical follow-ups at 3 (phone) and 6 (in-clinic) months. After the 6-
month visit, each registered subject will then have clinical CRT-D and cardiac follow-up 
per device standard of care guidelines, but will no longer participate in the research study 
and require study data collection. The subject must not be withdrawn after 
reprogramming or device explant or device inactivation and must be followed per 
protocol through the 6 month protocol-required clinic visit unless withdrawal requested 
by the physician or subject. 
8.2. Treatment Assignment 
There is no treatment assignment since all registered subjects will be implanted with a 
CRT-D device. 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 17 of 54 
 
 
8.2.1. Treatment and Control 
All registered subjects will be implanted with a Boston Scientific CRT-D generator that is  
commercially available (current or future generations) within the US. 
8.3. Justification for the Study Design 
The study design is a classical, non-randomized trial that minimizes bias, and this design 
is optimal for this trial. 
9. Subject Selection 
9.1. Study Population and Eligibility 
Enrollment 
Prior to formal registration into the trial as a study participant, the subject’s most recent 
ejection fraction, and the current 12-lead ECG will be examined if possible to determine 
if the subject initially meets the study inclusion/exclusion criteria. Subjects who meet all 
available entry criteria and agree to participate in the study will be asked to sign a written 
informed consent that has been approved by the investigational center’s Institutional 
Review Board (IRB) /Ethics Review Committee (ERC). All subjects who give written 
informed consent are considered enrolled in the study.  
 
9.2. Inclusion Criteria 
Subjects who meet all of the following criteria (see Table 9.2-1) will be given 
consideration for inclusion in this clinical investigation, provided no exclusion criterion 
(see Table 9.3-1) is met. 
 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 18 of 54 
 
 
Table 9.2-1: Inclusion Criteria 
Clinical 
Inclusion 
Criteria 
 
Subject is age 18 (or of legal age to give informed consent specific to 
state and national law) up to 80 years of age 
 
Male or female  
 
Subject who was without clinical heart failure at initiation of 
chemotherapy/radiation-induced treatment for an underlying 
malignancy, but developed clinical heart failure (cardiomyopathy: 
reduced LVEF with a LBBB-type of conduction disturbance; see next 
inclusion item) 6 months or more after initiation of the chemotherapy 
without other evident cause of the cardiomyopathy.  
 
Subject eligible for implantation of a CRT-D device according to one 
of the following options in currently available guidelines: 
Class 1:  
o LVEF < 35% AND 
o Sinus rhythm AND 
o LBBB with a QRS duration >150 ms AND 
o NYHA class II, III or ambulatory IV symptoms on 
guideline-directed medical therapy 
Class 2a1:  
o LVEF < 35% AND 
o Sinus rhythm AND 
o LBBB with a QRS duration 120-149ms AND 
o NYHA class II, III or ambulatory IV symptoms on 
guideline-directed medical therapy 
Class 2a2:  
o LVEF < 35% AND 
o Sinus rhythm AND 
o Non- LBBB with a QRS duration >150 ms AND 
o NYHA III or ambulatory IV symptoms on guideline-
directed medical therapy 
 
 
Subject on stable* optimal pharmacologic therapy for the cardiac 
condition that is guideline-based and may include one or more of the 
following medications: Loop diuretics (e.g., furosemide, bumetanide, 
torsemide) unless the subject is not indicated, is contraindicated, or is 
intolerant of loop diuretics; Angiotensin converting enzyme (ACE) 
inhibitors and/or  angiotensin receptor blocker (ARB) unless the 
subject failed, is not indicated, or is contraindicated for these therapies; 
Aldosterone antagonists unless the subject is not indicated, or is 
intolerant of aldosterone antagonists; Beta-blockers unless the subject 
is not indicated, contraindicated, or is intolerant of beta-blockers. The 
choice of selective or non-selective beta-blockers use is left to the 
Investigator’s discretion 
* For purposes of the study, “stable” is defined as subject prescribed 
set medication doses for at least one month prior to study registration, 
unless contraindicated or not tolerated. Medications may be prescribed 
and adjusted as required for cardiac condition during the study. 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 19 of 54 
 
 
9.3. Exclusion Criteria 
Subjects who meet any one of the following criteria (Table 9-3.1) will be excluded from 
this clinical study. 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 20 of 54 
 
 
Table 9-3.1: Exclusion Criteria 
Clinical 
Exclusion 
Criteria 
 
Subject with a currently implanted pacemaker or ICD device 
 
Previous implant with a CRT/CRT-D device  
 
Subject cardiac condition not presumed to be caused by chemotherapy  
 
Documented symptomatic or hemodynamically unstable ventricular 
tachyarrhythmia  
 
Subjects on active chemotherapy (must be at least 6 calendar months 
after last chemotherapy treatment) .  
 
Subject with permanent or chronic AF, or cardioversion for AF within 
the past 3 calendar months before consent date 
 
Subject with structural heart disease such as congenital heart disease, 
valvular heart disease, e.g., rheumatic valvular heart disease, amyloid 
heart disease, etc. 
 
Subject with coronary artery bypass graft surgery or percutaneous 
coronary intervention within the past 3 calendar months before consent 
date 
 
Subject with enzyme positive myocardial infarction within the past 3 
calendar months prior to consent date 
 
Unstable angina requiring hospitalization, with diagnostic work up and 
intervention within the past 3 months prior to consent date 
 
Subject with angiographic evidence of coronary disease who are 
candidates for coronary revascularization and are likely to undergo 
coronary artery bypass graft surgery or percutaneous coronary 
intervention in the foreseeable future 
 
Subject in Class IV and expected to undergo transplant within study 
duration 
 
Current or past history of drug addiction or abuse that caused 
cardiomyopathy 
 
Subject who is pregnant or plans to become pregnant during the course 
of the trial. Note: Women of childbearing potential must have a 
negative pregnancy test within 7 days prior to consent date 
 
Subject with recent CVA or TIA within the previous 3 months prior to 
consent date. 
 
Subject with presence of any disease, other than the subject’s cardiac 
or cancer disease, associated with a reduced likelihood of survival for 
the duration of the trial, e.g., uremia, liver failure, active malignant 
disease, etc. 
 
Subject participating in any other clinical trial  
 
Subject unwilling or unable to cooperate with the protocol 
 
Subject who lives at such a distance from the clinic that travel for 
follow-up visits would be unusually difficult 
 
Subject who does not anticipate being a resident of the area for the 
scheduled duration of the trial 
 
Subject unwilling to sign the consent for participation 
 Subject whose physician does not allow participation 
Abbreviations: AF = atrial fibrillation;   

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 21 of 54 
 
 
 
10. Subject Accountability 
10.1. Point of Enrollment 
The subject is considered enrolled in the study at the time the consent form is signed. No 
study related testing, procedures, etc. can take place until the informed consent is signed. 
Study personnel must explain to the subject that even if the subject agrees to participate in 
the study and signed the study ICF, more detailed record review and test results required 
to determine study eligibility may demonstrate that the subject is not a suitable candidate 
for the study.  
Study eligibility will be confirmed prior to formal study registration when a unique 
subject registration ID will be assigned to the subject. 
10.2. Withdrawal 
All subjects who sign an informed consent in this clinical study (including those 
withdrawn from the clinical study or lost to follow-up) shall be accounted for and 
documented in the specified case report form. If a subject withdraws from the clinical 
investigation, the reason(s) shall be reported in the specified case report form. Reasons 
could include but not limited to subject did not meet inclusion/exclusion criteria, consent 
withdrawal, lost to follow-up or death.  Lost to follow-up subjects must have documented 
attempts to contact them prior to declaration of withdrawal. All open adverse events must 
be closed or documented as chronic as of the date of subject withdrawal.  Data collected 
up to the point of subject withdrawal may be used in the study analysis.  Withdrawn 
subjects will not be replaced. While study withdrawal is discouraged, subjects may 
withdraw from the study at any time, with or without reason, without prejudice to further 
treatment. Subjects will remain with the existing device components implanted at the time 
of withdrawal.   
10.3. Subject Status and Classification 
All subjects are required to read, sign and date an Informed Consent prior to any study 
test and implant procedures.  All subjects who sign an Informed Consent Document will 
be considered enrolled in the study. All subjects who are registered will be included in the 
primary endpoint analysis based on the intention-to-treat principle. A deviation form will 
be required for all statuses listed below if the subject has been registered except implant 
and withdrawal. Adverse events will be collected on all consented subjects regardless of 
registration status up to the time of study withdrawal.  
Consent-ineligible refers to a subject who is not registered but who has signed the consent 
and does not meet study eligibility criteria.  
Intent refers to a subject who has signed the consent, is registered, but then does not 
undergo an implant. The original Informed Consent Document and screening 
documentation for intent subjects must be maintained in the Center’s administrative files.  
For example, if a subject signs the informed consent form, completes all baseline testing, 
is registered and then refuses implant, they would be handled as intent.   

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 22 of 54 
 
 
 
An attempt refers to a subject who has been registered and has had anesthesia 
administered in preparation for the surgical implant procedure, but does not receive a 
device.  These subjects are followed in accordance with the follow-up schedule. An 
example of an attempt subject is a subject in whom the physician is unable to place leads 
and stops the procedure before implanting a device. 
 
An implant refers to a subject who is registered and who is successfully implanted or 
tested with the system per the study protocol.  These subjects are followed in accordance 
with the follow-up schedule and included in all analyses of safety and performance. 
 
A withdrawal refers to a subject who has been consented and is determined to be inactive 
in the study due to physician discretion, subject choice, lost to follow-up, or subject death.  
Final status information will be included on all registered subjects as available per the 
Informed Consent document. If a subject is determined to be ineligible or refuses study 
participation after meeting eligibility criteria and signing consent without undergoing 
registration, the subject is formally withdrawn from the study. Subjects who have not 
signed consent do not need to be formally withdrawn.  
10.4. Registration Controls 
There is no pre-specified limit for number of subjects who can be enrolled (consented).  
The number of registered subjects will be strictly limited to 30 subjects.  Enrolling centers 
will be sent communication when the number of registered subjects reaches 25.  When 
the number of subjects reaches 25, registration will only be carried out manually with 
direct contact with center and the Coordination and Data Center at the University of 
Rochester.  All processes related to registration control will be communicated clearly to 
the enrolling centers.  There are no pre-specified ratios of male and female registered 
subjects.   
11. Study Methods 
11.1. Screening 
Prior to study registration, the subject’s medical record, laboratory results, the ejection 
fraction, and 12-lead ECG obtained within 1 calendar year prior to screen date will be 
examined to determine if the subject meets the study inclusion/exclusion criteria.  
11.2. Enrollment/Informed Consent 
Subjects who initially meet all the entry criteria per available standard of care testing and 
record review and agree to participate in the study will be asked to sign a written 
informed consent that has been approved by the investigational center’s Institutional 
Review Board (IRB) /Ethics Review Committee (ERC). All subjects who give written 
informed consent are considered enrolled in the study. No study related testing, 
procedures, etc. can take place until the informed consent is signed.  
If full record review not permitted per local regulations prior to study consent signature, 
then study consent signature may be obtained from the subject with subsequent complete 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 23 of 54 
 
 
review of record and study testing to determine if study eligibility criteria are fully met. 
Study personnel must explain to the subject that even if the subject agrees to participate in 
the study and signed the study ICF, test results required to determine study eligibility may 
demonstrate that the subject is not a suitable candidate for the study.  
No post-consent follow-up is required for subjects who do not meet study eligibility 
criteria for registration. All subjects who sign consent must be withdrawn from the study 
if subject is not registered.  
After initial study eligibility is confirmed using an echo and 12-lead ECG obtained within 
the past calendar year prior to screening date, then a post-consent standard 12 lead ECG 
and echocardiogram obtained using the study instruction manual for echocardiogram 
acquisition must be done to respectively confirm that the QRS and EF value meet study 
eligibility criteria and eligibility for a CRT-D implant.  These tests are usually done per 
standard of care at the time of device implant.  If the subject meets eligibility criteria and 
is registered, then these test results must be sent to the appropriate core laboratory 
following registration.  
11.3. Registration 
Registration assignment will be made by using the electronic data capture system that is 
available 24/7 to all PI-designated enrolling center personnel. Subjects will be registered 
within 1 calendar month following consent. Study eligibility and eligibility for a CRT-D 
implant must be confirmed prior to registration. 
11.4. Implant 
Subjects must have a commercially-available or future generation Boston Scientific CRT-
D generator implanted by a qualified physician within 14 days of registration. All devices 
in MADIT-CHIC must be implanted per physician and/or center standard operating 
procedure. It is recommended that the left ventricular lead be placed in a lateral or 
posterolateral coronary vein, but ultimately the choice of left ventricular lead location is 
left to the discretion of the implanting physician.  Following implant, the device must be 
programmed as pre-specified in Section 11.5. Subjects will be followed in accordance 
with the follow-up schedule. 
11.5. Device Programming 
Standard atrial synchronized-ventricular paced resynchronization therapy will be utilized. 
Should the subject develop atrial fibrillation during the course of the study, 
pharmacologic therapy will be utilized to control the ventricular response rate to achieve 
>90% ventricular pacing. On the basis of the recent MADIT-Reduce Inappropriate 
Therapy (MADIT-RIT) trial findings6, the CRT-D device will be programmed to deliver 
ATP/shock therapy at >200 beats per minute. 
 
 
 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 24 of 54 
 
 
General programming features for implanted biventricular devices include: 
• 
ATP values at default (81% coupling interval and 81% cycle length) 
• 
DFT at implanting physician’s discretion 
• 
Backup pacing: DDI with 300ms for paced AV  
 
 
Programming Requirements 
Parameters 
Programming
Ventricular Tachy Therapy Zones
2
Zone 1 (VT) Rate Cutoff 
170 bpm
Zone 1 (VT) Zone Rate Therapy 
Monitor Only
 
Zone 2 (VF) Zone Rate Cutoff 
200 bpm
Zone 2 (VF) Zone Duration 
2.5 seconds
Zone 2 (VF) Zone Therapy  
Shock + Quick Convert ATP 
11.6. Baseline 
11.6.1 
Baseline (before implant) 
• Demographics  
• Cancer treatment medications 
• Cardiac medications  
• Physical assessment 
• Medical and cardiac event history 
• Functional Status (NYHA) 
• 12-lead ECG (send to core lab) 
• Echocardiogram per study protocol (send to core lab) 
• Adverse events 
• Deviations 
11.6.2 
Baseline (after implant) 
• Device data (implant, device events, programming) 
• Adverse events 
• Deviations 
11.7 Clinic Follow-up Visits 
All follow-up visits will use the device implant date as the starting point for determining 
the timing of all follow-up visits. An in-clinic visit is required at the 6 month interval for 
all registered subjects. A phone visit will be done at 3 months to capture any events.  
 
A follow-up schedule that identifies the date intervals during which a subject must be 
contacted will be provided to the enrolling center for each subject following study 
registration and initial device implant.  Every effort will be made to ensure compliance 
with this schedule. 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 25 of 54 
 
 
 
At the clinic visit, a clinical evaluation must be carried out. In addition, all devices will 
undergo device testing according to agreed-upon guidelines. During all office/clinic 
visits, the device will be interrogated and the information will be documented on the 
follow-up form. At each clinical center, the routine follow-up interval history and 
examination will be used to identify possible adverse reactions to the implanted device. If 
a visit is missed for any reason, all major events as defined below will be collected at the 
subsequent visit. 
 
The following data is required at the phone visit: 
• Functional Status (NYHA) 
• Adverse Events including heart failure events, emergency department visits, 
hospitalizations, and deaths 
• Device events 
• Deviations 
 
The following data is required at the office/clinic visit: 
• Physical as directed on the follow-up case report form 
• Functional Status (NYHA) 
• Adverse Events including heart failure events, emergency department visits, 
hospitalizations, and deaths 
• Echocardiogram  
• Cardiac medications 
• Device programming 
• Changes in any device components such as explant, implant or revisions 
• Device events 
• Deviations 
11.8 Data Collection 
The figure indicating study data flow is shown in Figure 11.8-1. 
The figure indicating data collection is shown in Figure 11.8-2. 
 
 
 
 
 
 
 
 
 
 
 
 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 26 of 54 
 
 
Figure 11.8-1: Study Data Flow 
 
 
 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 27 of 54 
 
 
 
The data collection schedule is shown in Table 11.8-1.
Table 11.8-1: Data Collection Schedule 
Reportable  
Data Items 
Consent/ Before 
Registration 
Registration and 
Implant  
Phone Visit 
3 calendar 
months after 
implant date 
Clinic Visit 
6 calendar 
months after 
implant date 
Timeframe 
Consent obtained.  
Confirm study eligibility 
criteria are met before 
registration including all 
ECG and Echo eligibility 
required to confirm CRT-
D implant eligibility 
requirement.  
Registration to occur 
within 1 calendar 
month after date 
consent obtained.  
Implant to occur 
within 14 days after 
registration date.  
3 months  (+/- 
30 days)  
6 months  (+/- 30 
days)  
Inclusion/Exclusion 
√ 
√ (recheck prior to 
registration) 
 
 
Informed Consent 
including signature date 
√ 
 
 
 
ECG (Required) 
√  
 
 
 
Echo (Required) 
√ (after ECG and all 
inclusion and exclusion 
parameters met)
 
 
√ (6 month visit 
only) 
Cancer-Treatment 
Medications 
 
√ 
 
 
Cardiac Medications 
√ 
 
 
√ 
Demographics 
including gender, race 
and ethnicity 
 
√ 
 
 
Medical History 
 
√ 
 
 
Cardiac Events and 
Procedures 
 
√ 
√ 
√ 
Device Implant and 
Components 
 
√  
√ 
√ 
Device Programming   
 
√  
 
 
Device Interrogation/ 
Programming Status 
 
√  
 
√  
Physical Assessment 
including weight, 
height and NYHA class 
 
√ 
NYHA Class 
√ 
Adverse Events 
 
√ 
√ 
√  
Protocol Deviations 
 
√ 
√ 
√ 
 
11.9 Study Completion 
The DSMB may recommend termination of the study at any time should prospective 
ethical or safety guidelines not be met. The active trial will be completed after every 
subject has completed the 6 month visit. All 6 month follow-up data will be collected via 
an in-clinic visit. No follow-up data will be collected after the subject’s 6 month visit.  
11.10 Source Documents 
Data collection requirements are summarized in Table 11.8-1. Printed, optical or 
electronic document containing source data shall be used. Examples include hospital 
records, laboratory notes, device accountability records, radiographs, records kept at the 
investigation site, and at the laboratories involved in the clinical study. 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 28 of 54 
 
 
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 
investigation center team with a statement that it is a true reproduction of the original 
source document. 
12. Statistical Considerations 
12.1 
Endpoints 
12.1.1 Primary Endpoint 
The primary endpoint will be the change in left ventricular ejection fraction (LVEF) from 
baseline to six months.   
12.1.1.1 
Hypotheses 
The primary hypothesis is that CRT-D is associated with a mean improvement in LVEF 
from baseline to six months. 
12.1.1.2 
Sample Size 
In this clinical trial, 30 registered subjects will receive CRT-D.  This sample size should 
be sufficient for detecting clinically meaningful effects of CRT on LVEF over 6 months, 
allowing for an anticipated 20% dropout rate during this time period.   
 
12.1.1.3 
Statistical Methods 
The analysis will focus on the improvement in LVEF from baseline to six months for 
each patient. This primary outcome variable will be regressed on baseline LVEF, center, 
and disease etiology using an analysis of covariance (ANCOVA) model.  If the baseline 
LVEF term in the model has a p-value > 0.2, it will be omitted from the model, thereby 
concluding that the change from baseline is unaffected by the corresponding baseline 
value.   
 
The underlying assumptions of the ANCOVA model will be thoroughly checked 
(normality, homogeneity of variances, etc.), and remedial measures (e.g. transformations) 
will be carried out if serious violations of these assumptions are detected. Data from the 
MADIT-CRT trial suggest that the model assumptions should be reasonable for the 
primary outcome variable. 
 
According to similar analyses in 749 MADIT-CRT patients, but comparing one-year 
LVEF with baseline, the standard deviation (SD) of the improvement in LVEF was 
approximately 5 percentage points.  Using this estimate of SD, the following total sample 
sizes (N) were obtained based on a 5% two-sided significance level and 80% power to 
detect various values of mean improvement from baseline to six months in LVEF for 
CRT using a t-test. 
 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 29 of 54 
 
 
 
This table shows that 80% power can be attained with 65-75 enrolled patients, assuming a 
dropout rate of 20-30% (i.e. complete LVEF data on 52 patients), to detect effects as 
small as 2 percentage points.  Effects of 5 or more points can be detected with 80% power 
using 15 or fewer patients.  
 
 
The primary analysis will be carried out according to the intention-to-treat principle.  All 
subjects registered in the study with complete data on the primary endpoint will be 
included in the primary analysis. 
12.1.2 Efficacy Endpoints 
The secondary and tertiary endpoints include: 
1. All-cause mortality. 
2. Recurrent heart failure  
3. Changes in LVESV and LVEDV between baseline and six months. 
4. Change in NYHA functional class between baseline and six months. 
5. Change in left atrial size between baseline and six months. 
12.1.2.1 
Hypotheses 
The hypotheses associated with the secondary and tertiary endpoints listed in section 
2.1.2 are as follows. 
1. CRT-D reduces the risk of all-cause mortality 
2. CRT-D reduces the risk of recurrent heart failure events 
3. CRT-D is associated with a mean improvement in LVESV and on LVEDV 
from baseline to six months  
4. CRT-D is associated with improvement in NYHA functional class from 
baseline to six months with change over time in NYHA functional class 
categorized as lower, same, or higher. 
5. CRT-D reduces left atrial size. 
 
Treatment Effect 
(mean improvement in LVEF) 
N with 
10% 
dropout 
N with 
20% 
dropout 
N with 
30% 
dropout 
1 
222 
249 
285 
2 
58 
65 
75 
3 
27
30
35 
5 
12
13
15 
8 
7
8
9 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 30 of 54 
 
 
12.1.2.2 
Sample Size 
The sample size for this clinical trial was determined based on the power to detect 
minimal clinically meaningful effects on LVEF over six months (see section 12.1.1.2). 
12.1.2.3 
Statistical Methods 
Detailed statistical methods for the secondary endpoints will be presented in a Statistical 
Analysis Plan (SAP) prior to the primary endpoint analysis. 
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 
registered 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 Investigator's usual patient load. All patients 
meeting the eligibility criteria and having signed the ICF will be eligible for registration 
in the study.  
12.2.3 Number of Subjects per Investigative Site 
No minimum or maximum number of subjects per Investigative Site has been established 
for this trial. 
12.2.4 Interim Analyses 
No formal interim analyses are planned for the purpose of stopping this study early for 
declaring effectiveness or for futility. Handling of drop-outs and missing data will depend 
on their frequency and the nature of the outcome measure. The distribution of prognostic 
factors between subjects with and without data may be examined.  Detailed statistical 
methods will be presented in the SAP prior to the primary endpoint analysis. 
12.2.5 Subgroup Analyses 
Interactions between disease etiology and important baseline variables such as sex and 
race/ethnicity will be investigated by including the appropriate interaction term in the 
statistical model and testing for its significance.  Detailed statistical methods, along with a 
list of potential subgroups, will be presented in the SAP prior to the primary endpoint 
analysis. 
12.2.6 Justification of Pooling 
Tests for interactions will be used to evaluate treatment differences between subgroups.  
Registration effects for centers will be used to justify pooling data across investigational 
sites.  Detailed statistical methods will be presented in the SAP prior to the primary 
endpoint analysis. 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 31 of 54 
 
 
12.2.7 Multivariable Analyses 
Multivariate models will be constructed using the method of best subsets to select 
important covariates. Specific details will be presented in the SAP prior to the primary 
endpoint analysis. 
12.2.8 Other Analyses 
Other analyses will be presented in the SAP prior to the primary endpoint analysis. 
12.2.9 Changes to Planned Analyses 
Any changes to the planned statistical analyses made prior to the primary endpoint 
analysis will be documented in an amended SAP approved prior to the primary endpoint 
analysis. Changes from the planned statistical methods after the primary endpoint analysis 
will be documented in the statistical files. 
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. Consistent terminology per the study protocol will be used in the study Case 
Report Forms to be completed in the EDC system.  
The clinical database will reside on a production server hosted by University of Rochester 
Coordination and Data Center using the Omnicomm TrialMaster system. 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 
TrialMaster software and database have been designed to meet regulatory compliance for 
deployment as part of a validated system compliant with laws and regulations applicable 
to the conduct of clinical studies pertaining to the use of electronic records and signatures. 
Database backups are performed regularly. 
The Investigator provides his/her electronic signature on the appropriate electronic case 
report forms (eCRFs) in compliance with local regulations. A written signature on 
printouts of the eCRFs must also be provided if required by local regulation.  
Visual and/or electronic data review will be performed to identify possible data 
discrepancies. Manual and/or automatic queries will be created in the EDC system and 
will be issued to the site for appropriate response. Site staff will be responsible for 
resolving all queries in the database. 
13.2. Data Retention 
The Investigator or Investigational site will maintain, at the investigative 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 2 years since the formal discontinuation of the clinical trial. These 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 32 of 54 
 
 
documents will be retained for a longer period of time by agreement with the University 
of Rochester 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 University of Rochester must receive written notification of this 
custodial change.  
13.3. Core Laboratories 
13.3.1 Echocardiogram Core Laboratory 
Echocardiograms will be analyzed from baseline and 6 months (6-month study visit) for 
all registered subjects.  A subset of a standard echocardiographic two-dimensional and 
Doppler examination will be performed at each time point.  A detailed echo analysis 
protocol will be finalized and available to centers prior to the start of the study.  
The echocardiograms for the baseline and 6 month evaluations will be sent to the core 
laboratory for analysis.  The site must retain a copy of the study for clinical and back-up 
purposes. Sites will not be making any measurements. The echo core laboratory will not 
be reporting any information to sites.   
 
The echo core laboratory (ECL) will prepare a site instruction manual (SIM) and pocket 
guide designed to provide study sites information regarding:   
1. The required echo views 
2. Instructions for how to optimize images for obtaining high quality views, to 
complement sonographer training with (ECL)  staff and serve as a real-time 
reference 
3. How to send echo images to the (ECL) for analysis.  This will serve as an onsite 
reference for study sonographers.   
Each site will be asked to designate specific sonographer(s) to perform all study 
echocardiograms per the SIM.  Following review of the SIM and any requested training, 
each site sonographer will be required to submit 1 sample study performed per the SIM.  
Studies will be scrutinized for adherence to protocol, acquisition of all required views, 
and image quality. Itemized direct written feedback and suggestions from the (ECL)  will 
be provided.  This is intended to address any individual equipment or operator dependent 
problems that may arise.  Sonographers will have the opportunity to re-submit a sample 
protocol study per the SIM. Following submission of an adequate sample study, site 
sonographer will be officially certified, with written documentation. Support will also be 
available to each enrolling site as needed during the study. Centers will be promptly 
notified if a study is not performed per the SIM.  
The following echocardiographic assessments will be performed: 
 
 Left ventricular volumes will be assessed using the modified Simpson’s method 
from the apical 4-chamber and 2-chamber views; LV ejection fraction will be 
calculated from LVEDV and LVESV 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 33 of 54 
 
 
 LV wall thickness, and end-systolic and end-diastolic chamber dimension will be 
measured from the parasternal long axis view 
 LA volumes at mitral valve opening will be measured from the apical four 
chamber and two-chamber views by means of the biplane area–length method, 
and corrected for body surface area.  
 LA size measured during systole along the parasternal long-axis view  
 Mitral inflow velocity profile: E velocity, A velocity, E/A ratio, deceleration time  
 Mitral annular tissue Doppler velocity (septal and lateral): E’, A’, calculated E/E’  
 Assessment and grading of mitral regurgitation by color flow Doppler  
 Right ventricular function will be assessed as fractional area change (FAC) from 
end-diastolic and end-systolic areas in the apical 4-chamber view 
 
All echocardiogram analysis data will be recorded at the Coordination and Data Center. 
13.3.2 Electrocardiogram Core Laboratory 
A copy of a standard 12-lead ECGs will be obtained and transmitted to the ECG core 
laboratory electronically at baseline.  The12-lead ECG will only be identified using the 
study-assigned subject ID number.  
The ECG will be analyzed centrally by the University of Rochester Noninvasive 
Electrocardiogram Core Lab and entered in the electronic database at the Coordination 
and Data Center. The 12-lead ECG will also be used to obtain information on the 
underlying rhythm (sinus, atrial fibrillation, paced rhythm, other), heart rate, QRS and QT 
duration, ventricular conduction disturbances, atrial and ventricular hypertrophy, and 
location of myocardial infarction. QRS duration automatic reading will be verified by 
manual/visual reading. The QT interval will be routinely measured in lead II. The JT 
interval will be computed by subtracting the QRS from the QT interval. Both QT and JT 
intervals will be corrected for heart rate using Bazett’s formula. The presence of left 
bundle branch block, right bundle branch block, or indeterminate ventricular conduction 
disturbances will be identified according to the WHO Task Force criteria. 
14. Amendments 
If a protocol revision is necessary which affects the rights, safety or welfare of the subject 
or scientific integrity of the data, an amendment is required. Appropriate approvals (e.g., 
IRB/EC/FDA/CA) of the revised protocol must be obtained prior to implementation. 
15. Deviations 
An Investigator must not make any changes or deviate from this protocol, except to 
protect the life and physical well-being of a subject in an emergency. An investigator 
shall notify the 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 
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.  

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 34 of 54 
 
 
All deviations from the investigational plan, with the reason for the deviation and the date 
of occurrence, must be documented and reported to the Coordination and Data Center at 
the University of Rochester using the EDC system. This data will be reported by the 
Coordination and Data Center to Boston Scientific, the sponsor of the study.  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 sponsor. 
16. Device/Equipment Accountability 
No investigational devices, device components or equipment will be used in this study.  
However, data regarding model and serial number of each device component as well as 
implant, explant, revision, and disposal action dates will be recorded in the EDE system 
for each study subject.  
17. Compliance 
17.1. Statement of Compliance 
This study will be conducted in accordance with ethical principles that have their origins 
in the Declaration of Helsinki (see Appendix B), 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, 
if appropriate. 
17.2.  Investigator Responsibilities 
The Principal Investigator of an investigational center is responsible for ensuring that the 
study is conducted in accordance with the Clinical Study Agreement, the investigational 
plan/protocol, Medical Device Reporting Regulations, ethical principles that have their 
origins in the Declaration of Helsinki, any conditions of approval imposed by the 
reviewing IRB/EC, and prevailing local 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 Investigator 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. 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 35 of 54 
 
 
 Make no changes in or deviate from this protocol, except to protect the life and 
physical well-being of a subject in an emergency; document and explain any deviation 
from the approved protocol that occurred during the course of the clinical 
investigation. 
 Create and maintain source documents throughout the clinical study and ensure their 
availability with direct access during monitoring visits or audits; ensure that all 
clinical-investigation-related records are retained per requirements. 
 Ensure the accuracy, completeness, legibility, and timeliness of the data reported to 
the sponsor in the CRFs and in all required reports. 
 Record, report, and assess (seriousness and relationship to the device/procedure) 
every adverse event and observed device deficiency. 
 Report all SAEs and device effects. 
 Maintain the device accountability records and control of the device, ensuring that the 
device is used in accordance with this protocol and instructions/directions for use. 
 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 this protocol and local 
IRB/EC requirements. 
 Provide adequate medical care to a subject during and after a subject’s participation in 
a clinical study in the case of adverse events, as described in the Informed Consent 
Form (ICF). 
 Inform the subject of the nature and possible cause of any adverse events experienced. 
 As applicable, provide the subject with necessary instructions on proper use, handling, 
storage, and return of the device when it is used/operated by the subject. 
 Inform the subject of any new significant findings occurring during the clinical 
investigation, including the need for additional medical care that may be required. 
 Provide the subject with well-defined procedures for possible emergency situations 
related to the clinical study, and make the necessary arrangements for emergency 
treatment, as needed. 
 Ensure that clinical medical records are clearly marked to indicate that the subject is 
registered in this clinical study. 
 Ensure that, if appropriate, subjects registered in the clinical investigation are 
provided with some means of showing their participation in the clinical investigation, 
together with identification and compliance information for concomitant treatment 
measures (contact address and telephone numbers shall be provided). 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 36 of 54 
 
 
 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 providing 
appropriate training and adequate supervision of those to whom tasks are delegated. The 
investigator is accountable for regulatory violations resulting from failure to adequately 
supervise the conduct of the clinical study.  
17.3. Institutional Review Board/ Ethics Committee 
Prior to gaining Approval-to-Register status, the investigational center will provide to the 
sponsor documentation verifying that their IRB/EC is registered or that registration has 
been submitted to the appropriate agency, as applicable according to national/regulatory 
requirements.   
A copy of the written IRB/EC and/or competent authority approval of the protocol (or 
permission to conduct the study) and Informed Consent Form, must be received by the 
Coordination and Data Center in Rochester before recruitment of subjects into the study. 
Prior approval must also be obtained for other materials related to subject recruitment or 
which will be provided to the subject by the Coordination and Data Center. 
Annual IRB/EC approval and renewals will be obtained throughout the duration of the 
study as required by local/country or IRB/EC requirements. Copies of the Investigator’s 
reports and the IRB/EC continuance of approval must be provided to the sponsor.  
17.4. Coordination and Data Center Responsibilities 
Study data will be monitored closely by the CDC. Monthly reports will be generated on 
data completion and error rates for each clinical site. An automatic forms accounting and 
monitoring system will be initiated for each participant at the time of enrollment. The 
system provides the capability to monitor the status, volume, and disposition of data as 
well as to identify data due, overdue, and backlogged. In addition, all study data will 
undergo an extensive computer edit which provides information to the clinical centers to 
help improve and maintain data quality control procedures designed to detect inaccuracies 
and inconsistencies. This information will be used in making decisions about adjustment 
procedures, re-reading of electrocardiograms, and functional evaluation of the devices. 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 37 of 54 
 
 
All end-point data will be managed by the CDC, and will be maintained at the CDC 
throughout the course of the trial. End-point data will be excluded from progress reports 
sent to Boston Scientific CRM and the Investigational Sites.  
17.5. Clinical Center Responsibilities 
Dr. Jagmeet Singh, the Co-Principal Investigator of the Clinical Core, will be overseeing 
and integrating all scientific and clinical aspects of this clinical trial. He will review all 
study protocols, operations and CRFs as well as be in charge of developing and 
implementing subject recruitment including regular contact with enrolling sites, and 
subsequently overseeing patient enrollment and activities of core labs. .  
17.6. Role of Boston Scientific Representative 
Boston Scientific (BSC) personnel can provide technical support to the investigator and 
other health care personnel (collectively HCP) as needed during implant, device testing, 
and follow-ups at the request of the site investigators. Support may include HCP training, 
addressing HCP questions, or providing clarifications to HCPs concerning the operation 
of BSC equipment/devices (including programmers, analyzers, and other support 
equipment) as part of standard BSC device support. 
Typical tasks may include the following. 
 Interrogating the device or programming device parameters to investigator-requested 
settings as well as operating investigational equipment 
 Performing lead diagnostic testing using a Pacing System Analyzer or programmer to 
obtain pacing and sensing thresholds and impedance measurements 
 Clarifying device behavior, operation or diagnostic output as requested by the 
investigator or other health care personnel 
 Assisting with the collection of study data from Pacing System Analyzers, 
programmers, and other equipment 
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 study data (defined as primary or secondary endpoint data) 
 Enter data in electronic data capture systems or on paper case report forms 
17.7. Confidentiality 
All information and data collected for MADIT-CHIC concerning subjects or their 
participation in this investigation will be considered confidential by Boston Scientific and 
the CDC. All data will be handled in accordance with applicable local laws. Authorized 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 38 of 54 
 
 
regulatory personnel have the right to inspect and copy all records pertinent to this 
investigation.  Study Data collected during this investigation may be used by the CDC for 
the purposes of this investigation, publication, to support future research and/or other 
business purposes. All data used in the analysis and reporting of this investigation will be 
without identifiable reference to specific subject name. 
The CDC and Boston Scientific will keep subjects’ health information confidential in 
accordance with all applicable laws and regulations.  Boston Scientific and the CDC 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. 
18. Monitoring 
Monitoring will not be performed routinely during the study to assess continued 
compliance with the protocol and applicable regulations. If it is determined that the site 
requires study monitoring the Investigator/institution guarantees direct access to original 
source documents by BSC or CDC personnel, their designees, and appropriate regulatory 
authorities. 
The study may also be subject to a quality assurance audit by BSC, the CDC, 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. 
19. Potential Risks and Benefits 
19.1. Anticipated Adverse Device Effects and Anticipated Adverse Events 
Subjects participating in this study are exposed to the same risks shared by all patients 
who undergo implantation of a conventional CRT-D system. Based on the literature and 
on pulse generator implant experience, Table 19.1-1 includes an alphabetical list of the 
possible adverse events and possible adverse device effects associated with implantation 
of pulse generator and/or lead system. 
As the devices used in this study are all approved devices for the treatment of heart failure 
patients with moderate to severe systolic dysfunction, no new adverse events are 
anticipated in this subject population. 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 39 of 54 
 
 
 
Table 19.1-1: Potential Adverse Events and Potential Adverse Device Effects for 
Pulse Generator and/ or Lead System Implants 
 
List of potential adverse events for implantation of a pulse generator and/ or lead 
system 
Air embolism 
Hemothorax 
Allergic reaction 
Inability to pace 
Arterial damage with subsequent stenosis 
Inappropriate therapy (e.g., pacing) 
Bleeding 
Incisional pain 
Breakage/ failure of the implant instruments 
Infection including endocarditis 
Cardiac perforation 
Lead dislodgment 
Cardiac tamponade 
Lead fracture 
Chronic nerve damage 
Lead insulation breakage or abrasion 
Component failure 
Lead tip deformation and / or breakage 
Conductor coil fracture 
Malignancy or skin burn due to fluoroscopic radiation 
Death 
Myocardial trauma (e.g., tissue damage, valve damage) 
Electrolyte imbalance/ dehydration 
Myopotential sensing 
Elevated thresholds 
Oversensing / undersensing 
Erosion 
Pericardial rub, effusion 
Excessive fibrotic tissue growth  
Pneumothorax 
Extracardiac stimulation (muscle/ nerve 
stimulation) 
Pulse Generator and/or lead migration 
Fluid accumulation  
Tachyarrhythmias, which include acceleration of 
arrhythmias, pacemaker mediated tachycardia, and early, 
recurrent atrial fibrillation 
Foreign body rejection phenomena 
Thrombus, thromboemboli 
Formation of hematomas or seromas 
Valve damage 
Heart block 
Venous occlusion 
Hemorrhage 
Venous trauma (e.g. perforation, dissection, erosion) 
 
In addition to the implantation of a pulse generator system, potential adverse events 
associated with implantation of a coronary venous lead system include: 
 Allergic reaction to contrast media 
 Renal failure from contrast media used to visualize coronary veins 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 40 of 54 
 
 
19.2. Risks Associated with the Study Device(s) 
Subjects implanted in this study will be exposed to similar risks from a standard device 
procedure when compared to patients previously implanted with a CRT-D. For a detailed 
listing of the possible physical effects of a CRT-D system implantation, please see the 
Physician’s Manual. 
 
One potential risk is that in a situation where the disease worsens with time, the CRT-D 
may not be enough to provide adequate treatment. Additionally, it is possible that a 
situation may arise where the worsening heart function may make subjects’ pacemaker 
therapy dependent. In that case, if for some unforeseen reason the left ventricular lead 
gets dislodged or is not working there is a risk of considerably reduced heart function and 
potentially asystole. 
19.3. Risks associated with Participation in the Clinical Study 
Participation in this study requires ECG and echocardiographic measurements.  Possible 
risks associated with these procedures include: 
 Allergic skin reaction or trauma to the skin associated with ECG electrode gel 
 If injection of contrast media is necessary to visualize the heart during an echo, 
discomfort, bleeding, and infection at the injection site or allergic reaction to the 
contrast media may occur  
19.4. Possible Interactions with Concomitant Medical Treatments 
Subjects may experience a reduction in volume overload upon initiation of CRT.  
Consequently, it may be necessary to reduce the dosage of diuretics post-implant.  Failure 
to reevaluate and adjust diuretic use may result in volume depletion and includes risks 
such as hypotension, fatigue, and lightheadedness.  There are no known interactions with 
other standard heart failure medications, including beta blockers, ACE/ARB, and 
aldosterone antagonists. 
19.5. Risk Minimization Actions 
Risks can be minimized through the use of strict aseptic technique, performing 
procedures in the appropriate hospital environment, compliance with this protocol and 
technical implant procedures, adherence to the guidelines for subject selection, close 
monitoring of the subject's physiologic status during implant and follow-up procedures, 
and by promptly supplying the CDC with all pertinent information required by this 
protocol. 
19.6. Anticipated Benefits 
In patients with severe and mild left ventricular dysfunction, randomized clinical studies 
on left ventricular pacing have demonstrated a reduction in all-cause mortality, alone or in 
combination with heart failure hospitalization, as well as a reduction in symptoms, an 
improvement of the exercise capacity, and quality of life.  Although it is likely that the 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 41 of 54 
 
 
subset of patients that are being studied will benefit from CRT, the extent of benefit in 
patients with chemotherapy-induced cardiomyopathy is unknown.   
19.7. Risk to Benefit Rationale 
The risks associated with CRT-D can typically be resolved non-invasively with 
reprogramming or with surgery to correct lead issues.  Given the potential for reduction in 
risk of mortality or hospitalization and symptomatic relief, the benefits generally 
outweigh the risks.   
20. Safety Reporting 
20.1. Definitions and Classification 
Adverse events will be reported in accordance with Medical Device Regulations.  An 
adverse event is defined as an event that affects device performance, cardiovascular 
function and/or study endpoints.  Information collected on the adverse event electronic 
case report form includes the classification of the adverse event and whether the event 
was patient- or pulse generator-/lead-related and the outcome of the event. All 
hospitalizations and emergency department visits will be recorded as adverse events; 
there is no separate case report form for hospitalizations in this investigation. 
 
Adverse event definitions are provided in Table 20.1-1. 
Table 20.1-1: Adverse Event Definitions 
Term 
Definition 
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 medical 
device.  
NOTE 1: This includes events related to the medical device or 
component. 
NOTE 2: This definition includes events related to any study-related 
procedures involved.  
NOTE 3: For users or other persons, this definition is restricted to events 
related to the medical device.  
Serious Adverse Event (SAE) 
 
 
 
Adverse event that: 
- Led to death, 
- Led to  serious deterioration in the health of the subject, that either 
resulted in: 
o a life-threatening illness or injury, or 
o a permanent impairment of a body structure or a body function, or 
o in-patient  or prolonged hospitalization of existing hospitalization, 
or 
o medical or surgical intervention to prevent life-threatening illness 
or injury or permanent impairment to a body structure or a body 
function 
- Led to fetal distress, fetal death, or a congenital abnormality or birth 
defect. 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 42 of 54 
 
 
Table 20.1-1: Adverse Event Definitions 
Term 
Definition 
NOTE 1: Planned hospitalization for a pre-existing condition, or a 
procedure required by the clinical investigational plan, without serious 
deterioration in health, is not considered a serious adverse event.  
Unanticipated Adverse Device 
Effect (UADE) 
 
 
 
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.  
Device Deficiency 
 
 
 
A device deficiency is any inadequacy of a medical device with respect to 
its identity, quality, durability, reliability, safety or performance. 
NOTE 1: Device deficiencies include malfunctions, misuse or use errors, 
and inadequate labeling. 
 
Abbreviations: IRB=Institutional Review Board 
 
Underlying diseases are not reported as AEs unless there is an increase in severity or 
frequency during the course of the investigation. Death must not be recorded as an AE, 
but must only be reflected as an outcome of a specific SAE (see Table 20.1-1for AE 
definitions) unless cause of death is truly unknown.  
Any AE experienced by the study subject after informed consent, whether during or 
subsequent to the procedure, must be recorded in the eCRF. 
Refer to Section 19 for the known risks associated with the study device(s). 
20.2. Relationship to Study Device(s) 
The Investigator must assess the relationship of the AE to the study device and/or 
implantation procedure as related or unrelated. See criteria in Table 20.2-1. 
Table 20.2-1: Criteria for Assessing Relationship of Study Device to Adverse Event 
Classification 
Description 
Unrelated 
The adverse event is determined to be due to a concurrent illness or effect of 
another device/drug and is not related to a device component or implantation. 
Related 
 The adverse event is determined to be potentially related to a device component 
or implantation, and an alternative etiology is equally or less likely compared to 
the potential relationship to a device component or implantation, or 
 There is a strong relationship to a device component or implantation, or recurs 
on re-challenge, and another etiology is unlikely, or 
 There is no other reasonable medical explanation for the event. 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 43 of 54 
 
 
20.3. Investigator Reporting Requirements 
The communication requirements for reporting to BSC are as shown in Table 20.3-1. 
Table 20.3-1: Investigator Reporting Requirements 
Event Classification 
Communication Method  
Communication Timeline  
Unanticipated Adverse 
Device Effect 
Complete AE eCRF page with all 
available new and updated 
information. 
Provide all relevant source 
documentation (de-identified) for 
reported event on request. 
 Within 2 business days of first 
becoming aware of the event or 
as per local/regional 
regulations. 
 Reporting required through the 
end of the study 
Serious Adverse Event and 
Death 
Complete AE eCRF page with all 
available new and updated 
information 
 Within 10 business days of 
first becoming aware of the 
event or as per local/regional 
regulations. 
 Reporting required through the 
end of the study 
Provide all relevant source 
documentation (de-identified) for  
reported event on request 
 When documentation is 
available 
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 
 No later than 10 working days 
after becoming aware of the 
information 
 Reporting required through end 
of study  
Device Deficiency 
Complete Device Deficiency eCRF 
with all available new and updated 
information 
 Within 1 business day of first 
becoming aware of the event 
and as per local/regional 
regulations 
 Reporting required through the 
end of the study 
Abbreviations: AE=adverse event; CRF=case report form 
20.4. Reporting to Regulatory Authorities / IRBs / ECs / Investigators 
The CDC is responsible for reporting adverse event information to all participating 
investigators and regulatory authorities, as applicable.  
The enrolling center Principal Investigator is responsible for informing the local IRB/EC, 
and regulatory authorities of SAE as required by local/regional regulations. 
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 the use of any devices, study-
required procedures and/or testing, or data collection. If a subject agrees to participate in 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 44 of 54 
 
 
the study and signs an Informed Consent form, the final medical review, ECG and/or 
echocardiogram may demonstrate that the subject is not a suitable candidate for the study. 
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 
University of Rochester Coordination Center IRB must approve the prototype ICF prior 
to distribution to the investigative center. The ICF must be approved by the center’s 
IRB/EC, or central IRB, if applicable. 
The CDC will provide a study-specific template of the ICF to investigators participating 
in this study following approval by the University of Rochester IRB. The ICF template 
may be modified to meet the requirements of the investigative center’s IRB/EC.  Any 
modification requires approval from the CDC prior to use of the form.  The ICF must be 
in a language understandable to the subject and if needed, the 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: 
 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 or legal representative 
and by the investigator or an authorized designee responsible for conducting the informed 
consent process. If a legal representative signs, the subject shall be asked to provide 
informed consent for continued participation as soon as his/her medical condition allows. 
The original signed ICF will be retained by the center 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 CDC to the applicable regulatory 
body according to their requirements (e.g., FDA requirement is within 5 working days of 
learning of such an event). Any violations of the informed consent process must be 
reported as deviations to the sponsor and local regulatory authorities (e.g. IRB/EC), as 
appropriate. 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 45 of 54 
 
 
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, registered subjects may be requested to sign 
and date an addendum to the ICF. In addition to new significant information during the 
course of a study, other situations may necessitate revision of the ICF, such as if there are 
amendments to the 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. CDC approval is required if changes to the revised ICF are requested by the 
center’s IRB/EC. The local IRB/EC will determine the subject population to be re-
consented. 
22. Committees 
22.1. Safety Monitoring Process 
The University of Rochester Coordination and Data Center will provide a report of safety 
events to BSC as requested. 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. 
22.2. Executive Committee 
The MADIT-CHIC Executive Committee is independent of Boston Scientific CRM and 
is responsible for the overall guidance of the study. The Executive Committee will review 
and finalize the protocol and any amendments. The Executive Committee has the 
authority to appoint an External Advisory Group as deemed necessary to optimize the 
conduct of the trial. 
 
The Executive Committee is composed of selected study Coordinating Principal 
Investigator(s) and key management members of the University of Rochester 
Coordination and Data Center. Responsibilities may include oversight of the overall 
conduct of the study with regard to protocol development, study progress, subject safety, 
overall data quality and integrity, as well as disseminating any study results through 
appropriate scientific sessions and publications. Executive Committee members may 
participate in the review and approval of all requests for data analysis, abstract and 
manuscript preparation, and submission. As appropriate, the Executive Committee may 
request participation of enrolling site Investigators on the Committee. Current Executive 
Committee members are listed in Appendix A.  
22.3. Data Safety and Monitoring Board Committee 
An Independent Data Safety and Monitoring Board (DSMB) Committee will meet 
biyearly, or as needed, to review the results of the trial and to evaluate any safety issues 
that may arise during the course of the study. The DSMB will consist of individuals who 
are not involved in this study and no affiliation with BSC and have expertise in 
biostatistics, electrophysiology, and preventive cardiology. The ongoing trial data will be 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 46 of 54 
 
 
transmitted to the DSMB on a weekly basis. The DSMB will carry out periodic data 
review and will inform the study Principal Investigator on any safety concerns. The 
DSMB may recommend termination of the study at any time should prospective ethical or 
safety guidelines not be met. The active trial will be completed after every subject has 
been followed for 6 months. Responsibilities, qualifications, membership, and committee 
procedures are outlined in the DSMB Charter. 
22.4. Mortality Review Committee 
The Mortality Review Committee will review all deaths that occur during the MADIT-
CHIC trial. Their decisions are based on independent physician review of the data from 
device interrogation, adverse event case report forms, and subject status case report 
forms. Classification of the cause of death will utilize the Hinkle-
Thalercriteria.8Responsibilities, qualifications, membership, and committee procedures 
are outlined in the Mortality Review Committee Charter. A quorum of three physicians is 
required for the committee to convene. 
 
All mortality analyses reflect the committee's death classifications. Submission of 
complete information to the committee is essential for accurate conclusions to be drawn 
and to reduce the need for additional information and multiple reviews. From the data 
submitted by the center as outlined in this protocol, the Coordination and Data Center at 
the University of Rochester compiles a summary of events including date of implant, date 
of death, age at death, immediate cause of death, subject classification (e.g., attempt, 
intent, implant), Investigator death classifications, implanted system with serial numbers, 
implanting center, narrative, observations/complications, deviations, device status, 
autopsy results, gender, and registration assignment (if applicable). 
23. Suspension or Termination 
23.1. Premature Termination of the Study 
The CDC and Data Safety Monitoring Board reserves the right to terminate the study at 
any stage but intends to exercise this right only for valid scientific or administrative 
reasons and reasons related to protection of subjects. Investigators, associated IRBs/ECs, 
and regulatory authorities, as applicable, will be notified in writing in the event of study 
termination. 
23.1.1 Criteria for Premature Termination of the Study 
Possible reasons for premature study termination include, but are not limited to, the 
following. 
 The occurrence of unanticipated adverse device effects that present a significant or 
unreasonable risk to subjects registered in the study. 
 A registration rate far below expectation that prejudices the conclusion of the study.  
 Suspension or discontinuance of the study device. 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 47 of 54 
 
 
23.2. Termination of Study Participation by the Investigator or Withdrawal of 
IRB/ EC Approval 
Any investigator, or IRB/ EC in the MADIT-CHIC Study may discontinue participation 
in the study or withdrawal approval of the study, respectively, with suitable written notice 
to the CDC. Investigators, associated IRBs/ECs, and regulatory authorities, as applicable, 
will be notified in writing in the event of these occurrences. 
23.2. Requirements for Documentation and Subject Follow-up 
In the event of premature study termination a written statement as to why the premature 
termination has occurred will be provided to all participating centers by the CDC. The 
IRB/EC and regulatory authorities, as applicable, will be notified. Detailed information 
on how registered subjects will be managed thereafter will be provided.  
In the event an IRB or EC terminates participation in the study, participating 
investigators, associated IRBs/ECs, and regulatory authorities, as applicable, will be 
notified in writing. Detailed information on how study subjects will be managed 
thereafter will be provided by the CDC. 
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 
transfer investigator responsibility; detailed information on how registered subjects will 
be managed thereafter will be provided by the CDC. 
23.4 Criteria for Suspending/Terminating a Study Center 
The CDC 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 registered for a period beyond 6 
months after center initiation, or if the center has multiple or severe protocol 
violations/noncompliance without justification and/or fails to follow remedial actions. 
In the event of termination of investigator participation, all study devices and testing 
equipment, as applicable, will be returned to the CDC unless this action would jeopardize 
the rights, safety or well-being of the subjects. The IRB/EC and regulatory authorities, as 
applicable, must be notified. All subjects in the study at the center will continue to be 
followed per standard of care guidelines. The Principal Investigator at the center must 
make provision for these follow-up visits unless the CDC notifies the enrolling center 
otherwise. 
24. Publication Policy 
The investigators will adhere to the Contributorship Criteria set forth in the Uniform 
Requirements of the International Committee of Medical Journal Editors (ICMJE; 
http://www.icmje.org).  

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 48 of 54 
 
 
25. Reimbursement for Subjects 
25.1. Subject Reimbursement 
Travel and other expenses incurred by subjects as a result of participation in the study 
will be reimbursed in accordance with pertinent local laws and regulations and per the 
study site’s policy as appropriate.  
26. Bibliography 
REFERENCES 
1. Cardinale D, Colombo A, Lamantia G, et al.  Anthracycline-Induced Cardiomyopathy 
Clinical Relevance and Response to Pharmacologic Therapy. J Am CollCardiol 2010; 
 
2. Steinherz LJ, Steinherz PG, Tan CT, Heller G, Murphy ML. Cardiac toxicity 4 to 20 
years after completing anthracyline therapy. JAMA 1991;266:1672–7. 
 
3. Rickard J, Kumbhani DK, Baranowski B et al. Usefulness of cardiac resynchronization 
therapy in patients with Adriamycin-induced cardiomyopathy. Am J Cardiol 2010; 
105:522–526. 
 
4. Ajijola OA, Nandigam KV, Chabner BA et al. Usefulness of cardiac resynchronization 
therapy in the management of Doxorubicin-induced cardiomyopathy. Am J Cardiol 
2008;101:1371–1372. 
 
5. Moss AJ, Hall WJ, Cannom D, et al. Cardiac resynchronization therapy for the 
prevention of heart failure. N Engl J Med 2009;361:1329-38. 
 
6. Moss AJ, Schuger C, Beck CA, et al. Reduction in inappropriate therapy and mortality 
through ICD programming. N Engl J Med 2012 (published on-line Nov. 6, 2012. 
 
7. Hinkle LE, Jr., Thaler HT. Clinical classification of cardiac deaths. Circulation 
1982;65:457-64. 
27. Abbreviations and Definitions 
27.1. Abbreviations 
Abbreviations are shown in Table 27.1-1. 
 
 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 49 of 54 
 
 
Table 27.1-1: Abbreviations 
Acronym/Abbreviation 
Term 
ACC 
American College of Cardiology  
ACE 
Angiotensin-Converting-Enzyme 
ADE 
Adverse Device Effect 
AE  
Adverse Event 
AHA  
American Heart Association 
ASADE 
Anticipated serious adverse device effect 
ARB 
Angiotensin receptor blocker 
bpm 
Beats per minute 
BSC 
Boston Scientific 
CDC 
Coordination and Data Center 
CA 
Competent Authority 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations  
CRT 
Cardiac Resynchronization Therapy 
CRV 
Cardiology, Rhythm and Vascular (a business division of Boston 
Scientific) 
DDD(R) 
Rate Adaptive Dual Chamber Mode (Tracking) 
EC/ IEC 
Ethics Committee/ Institutional Ethics Committee 
ECG 
Electrocardiogram 
CRF 
Case Report Form 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data capture 
FDA 
Food and Drug Administration 
FU 
Follow-up 
GCP 
Good Clinical Practice 
HF 
Heart Failure 
HCP 
Health Care Professional 
HRS 
Heart Rhythm Society 
ICD 
Implantable Cardioverter-Defibrillator 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IPG 
Implantable Pulse Generator 
IRB 
Institutional Review Board 
ISO 
International Standard Organization 
LRL 
Lower Rate Limit 
LBBB 
Left bundle branch block 
LVEF 
Left ventricular ejection fraction 
MV 
Minute Ventilation 
NM 
Neuro-mediated syndromes 
NYHA 
New York Heart Association 
PM 
Pacemaker 
PRM 
Programmer/ Recorder/ Monitor 
PSA 
Pacing System Analyzer 
RV 
Right ventricle/ ventricular 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
US 
United States of America 
USB 
Universal Serial Bus 
USADE 
Unanticipated Serious Adverse Device Effect 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 50 of 54 
 
 
 
27.2. Definitions 
 
Table 27.2-1: Definitions 
Term 
Definition 
Source Data 
All information in original records of clinical findings, observations, or other 
activities in a clinical investigation, necessary for the reconstruction and 
evaluation of the clinical study (original records or certified copies). 
Source Document 
Printed, optical or electronic document containing source data. Examples: 
Hospital records, laboratory notes, device accountability records, radiographs, 
records kept at the investigation site, and at the laboratories involved in the 
clinical study. 
 
 
Abbreviations are defined in Table 27.1-1. 
28. Appendices 
28.1. 
Clinical Trial Organization  
The study will be conducted with the University of Rochester Medical Center (URMC) 
serving as the Coordination and Data Center (CDC).  URMC is located at 265 Crittenden 
Boulevard, CPU Box 420653, Rochester NY 14620, USA.  Multiple individuals will be 
responsible for duties under the direction of Valentina Kutyifa, MD, PhD, the PI and 
Mary Brown, RN, MS who is the Program Manager.  Other responsibilities are identified 
in Sections 17. and 22. 
 
APPENDIX A: EXECUTIVE COMMITTEE 
 
Valentina Kutyifa, MD, PhD (PI) 
 
University of Rochester Medical Center 
 
 
 
 
 
 
Rochester, NY 
Jagmeet Singh, MD, PhD (Co-PI) 
 
Massachusetts General Hospital 
 
 
 
 
 
 
Boston, MA 
Christopher Beck, PhD 
 
 
University of Rochester Medical Center 
 
 
 
 
 
 
Rochester, NY 
Mary W. Brown, RN, MS 
 
 
University of Rochester Medical Center 
 
 
 
 
 
 
Rochester, NY 
Scott D. Solomon, MD 
 
 
Brigham and Women’s Hospital 
 
 
 
 
 
 
Boston, MA 
Wojciech Zareba, MD, PhD  
 
University of Rochester Medical Center 
 
 
 
 
 
 
Rochester, NY 
 
 
 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 51 of 54 
 
 
APPENDIX B:  DECLARATION OF HELSINKI 
 
The World Medical Association  
Declaration of Helsinki 
 
World Medical Association Declaration of Helsinki: Recommendations Guiding 
Medical Doctors in Biomedical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the 29th WMA 
General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, Venice, Italy, October 1983 41st 
WMA General Assembly, Hong Kong, September 1989 48th WMA General Assembly, Somerset West, Republic of 
South Africa, October 1996 and the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000  Note of 
Clarification on Paragraph 29 added by the WMA General Assembly, Washington 2002. 
 
 
A. INTRODUCTION  
1. 
The World Medical Association has developed the Declaration of Helsinki as a statement of ethical 
principles to provide guidance to physicians and other participants in medical research involving 
human subjects. Medical research involving human subjects includes research on identifiable 
human material or identifiable data. 
2. 
It is the duty of the physician to promote and safeguard the health of the people. The physician's 
knowledge and conscience are dedicated to the fulfillment of this duty. 
3. 
The Declaration of Geneva of the World Medical Association binds the physician with the words, 
"The health of my patient will be my first consideration," and the International Code of Medical 
Ethics declares that, "A physician shall act only in the patient's interest when providing medical 
care which might have the effect of weakening the physical and mental condition of the patient."  
4. 
Medical progress is based on research which ultimately must rest in part on experimentation 
involving human subjects. 
5. 
In medical research on human subjects, considerations related to the well-being of the human 
subject should take precedence over the interests of science and society. 
6. 
The primary purpose of medical research involving human subjects is to improve prophylactic, 
diagnostic and therapeutic procedures and the understanding of the etiology and pathogenesis of 
disease. Even the best proven prophylactic, diagnostic, and therapeutic methods must continuously 
be challenged through research for their effectiveness, efficiency, accessibility and quality.  
7. 
In current medical practice and in medical research, most prophylactic, diagnostic and therapeutic 
procedures involve risks and burdens.  
8. 
Medical research is subject to ethical standards that promote respect for all human beings and 
protect their health and rights. Some research populations are vulnerable and need special 
protection. The particular needs of the economically and medically disadvantaged must be 
recognized. Special attention is also required for those who cannot give or refuse consent for 
themselves, for those who may be subject to giving consent under duress, for those who will not 
benefit personally from the research and for those for whom the research is combined with care.  
9. 
Research Investigators should be aware of the ethical, legal and regulatory requirements for 
research on human subjects in their own countries as well as applicable international requirements. 
No national ethical, legal or regulatory requirement should be allowed to reduce or eliminate any of 
the protections for human subjects set forth in this Declaration. 
 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 52 of 54 
 
 
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH  
10. It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of 
the human subject.  
11. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
information, and on adequate laboratory and, where appropriate, animal experimentation. 
12. Appropriate caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected. 
13. The design and performance of each experimental procedure involving human subjects should be 
clearly formulated in an experimental protocol. This protocol should be submitted for consideration, 
comment, guidance, and where appropriate, approval to a specially appointed ethical review 
committee, which must be independent of the investigator, the sponsor or any other kind of undue 
influence. This independent committee should be in conformity with the laws and regulations of the 
country in which the research experiment is performed. The committee has the right to monitor 
ongoing trials. The researcher has the obligation to provide monitoring information to the 
committee, especially any serious adverse events. The researcher should also submit to the 
committee, for review, information regarding funding, sponsors, institutional affiliations, other 
potential conflicts of interest and incentives for subjects.  
14. The research protocol should always contain a statement of the ethical considerations involved and 
should indicate that there is compliance with the principles enunciated in this Declaration.  
15. Medical research involving human subjects should be conducted only by scientifically qualified 
persons and under the supervision of a clinically competent medical person. The responsibility for 
the human subject must always rest with a medically qualified person and never rest on the subject 
of the research, even though the subject has given consent.  
16. Every medical research project involving human subjects should be preceded by careful assessment 
of predictable risks and burdens in comparison with foreseeable benefits to the subject or to others. 
This does not preclude the participation of healthy volunteers in medical research. The design of all 
studies should be publicly available. 
17. Physicians should abstain from engaging in research projects involving human subjects unless they 
are confident that the risks involved have been adequately assessed and can be satisfactorily 
managed. Physicians should cease any investigation if the risks are found to outweigh the potential 
benefits or if there is conclusive proof of positive and beneficial results.  
18. Medical research involving human subjects should only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the subject. This is especially important when 
the human subjects are healthy volunteers.  
19. Medical research is only justified if there is a reasonable likelihood that the populations in which 
the research is carried out stand to benefit from the results of the research.  
20. The subjects must be volunteers and informed participants in the research project. 
21. The right of research subjects to safeguard their integrity must always be respected. Every 
precaution should be taken to respect the privacy of the subject, the confidentiality of the patient's 
information and to minimize the impact of the study on the subject's physical and mental integrity 
and on the personality of the subject. 
22. In any research on human beings, each potential subject must be adequately informed of the aims, 
methods, sources of funding, any possible conflicts of interest, institutional affiliations of the 
researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail. 
The subject should be informed of the right to abstain from participation in the study or to withdraw 
consent to participate at any time without reprisal. After ensuring that the subject has understood 
the information, the physician should then obtain the subject's freely-given informed consent, 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 53 of 54 
 
 
preferably in writing. If the consent cannot be obtained in writing, the non-written consent must be 
formally documented and witnessed.  
23. When obtaining informed consent for the research project the physician should be particularly 
cautious if the subject is in a dependent relationship with the physician or may consent under 
duress. In that case the informed consent should be obtained by a well-informed physician who is 
not engaged in the investigation and who is completely independent of this relationship.  
24. For a research subject who is legally incompetent, physically or mentally incapable of giving 
consent or is a legally incompetent minor, the investigator must obtain informed consent from the 
legally authorized representative in accordance with applicable law. These groups should not be 
included in research unless the research is necessary to promote the health of the population 
represented and this research cannot instead be performed on legally competent persons.  
25. When a subject deemed legally incompetent, such as a minor child, is able to give assent to 
decisions about participation in research, the investigator must obtain that assent in addition to the 
consent of the legally authorized representative.  
26. Research on individuals from whom it is not possible to obtain consent, including proxy or advance 
consent, should be done only if the physical/mental condition that prevents obtaining informed 
consent is a necessary characteristic of the research population. The specific reasons for involving 
research subjects with a condition that renders them unable to give informed consent should be 
stated in the experimental protocol for consideration and approval of the review committee. The 
protocol should state that consent to remain in the research should be obtained as soon as possible 
from the individual or a legally authorized surrogate. 
27. Both authors and publishers have ethical obligations. In publication of the results of research, the 
investigators are obliged to preserve the accuracy of the results. Negative as well as positive results 
should be published or otherwise publicly available. Sources of funding, institutional affiliations 
and any possible conflicts of interest should be declared in the publication. Reports of 
experimentation not in accordance with the principles laid down in this Declaration should not be 
accepted for publication.  
C. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE 
28. The physician may combine medical research with medical care, only to the extent that the research 
is justified by its potential prophylactic, diagnostic or therapeutic value. When medical research is 
combined with medical care, additional standards apply to protect the patients who are research 
subjects. 
29. The benefits, risks, burdens and effectiveness of a new method should be tested against those of the 
best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of 
placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method 
exists. See footnote 
30. At the conclusion of the study, every patient entered into the study should be assured of access to 
the best proven prophylactic, diagnostic and therapeutic methods identified by the study. 
31. The physician should fully inform the patient which aspects of the care are related to the research. 
The refusal of a patient to participate in a study must never interfere with the patient-physician 
relationship. 
32. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods do not 
exist or have been ineffective, the physician, with informed consent from the patient, must be free 
to use unproven or new prophylactic, diagnostic and therapeutic measures, if in the physician's 
judgment it offers hope of saving life, re-establishing health or alleviating suffering. Where 
possible, these measures should be made the object of research, designed to evaluate their safety 
and efficacy. In all cases, new information should be recorded and, where appropriate, published. 
The other relevant guidelines of this Declaration should be followed.  
 

Confidential 
 
University of Rochester 
 
MADIT-CHIC Protocol 
 
Version 3.0 
 
Page 54 of 54 
 
 
Footnote: Note of clarification on paragraph 29 of the WMA Declaration of Helsinki 
The WMA hereby reaffirms its position that extreme care must be taken in making use of 
a placebo-controlled trial and that in general this methodology should only be used in the 
absence of existing proven therapy. However, a placebo-controlled trial may be ethically 
acceptable, even if proven therapy is available, under the following circumstances: 
  - Where for compelling and scientifically sound methodological reasons its use is 
necessary to determine the efficacy or safety of a prophylactic, diagnostic or 
therapeutic method; or  
  - Where a prophylactic, diagnostic or therapeutic method is being investigated for a 
minor condition and the patients who receive placebo will not be subject to any 
additional risk of serious or irreversible harm.  
All other provisions of the Declaration of Helsinki must be adhered to, especially the 
need for appropriate ethical and scientific review.