Cardiac Resynchronization in the Elderly: Piloting Pacemaker vs. Defibrillator Therapy (Randomized Trial)
Phase: NA
Conditions: Heart Failure
Sponsor: Samir Saba

 
Cardiac Resynchronization in the Elderly: 
Piloting Pacemaker vs. Defibrillator Therapy 
(Randomized Trial and Observational) 
 
 
 
 
 
 
 
 
 
CRT-P vs. CRT - D 
Principal Investigator: Samir Saba, MD, FACC, FHRS.  
Funded by: National Heart, Lung, and Blood Institute (NHLBI) 
  
 
 
 
 
 
 
Protocol A Version 6 
24 May 2018 
NCT # 03031847 

i 
 
Table of Contents 
LIST OF ABBREVIATIONS ........................................................................................................................................ii 
STATEMENT OF COMPLIANCE...............................................................................................................................1 
SCHEMATIC OF STUDY DESIGN ............................................................................................................................ 2 
1 
KEY ROLES ................................................................................................................................................... 3 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE .......................... 3 
2.1 
Background Information ........................................................................................................................ 3 
2.2 
Rationale ................................................................................................................................................. 5 
2.3 
Potential Risks and Benefits ................................................................................................................... 6 
2.3.1 
Known Potential Risks........................................................................................................ 6 
2.3.2 
Known Potential Benefits ................................................................................................... 6 
3 
OBJECTIVES AND PURPOSE ..................................................................................................................... 6 
4 
STUDY DESIGN AND ENDPOINTS ........................................................................................................... 7 
4.1 
Description of the Study Design ............................................................................................................. 7 
4.2 
Study Endpoints...................................................................................................................................... 8 
4.2.1 
Primary Endpoint ................................................................................................................ 8 
4.2.2 
Secondary Endpoints .......................................................................................................... 8 
5 
STUDY ENROLLMENT AND WITHDRAWAL ......................................................................................... 8 
5.1 
Participant Inclusion Criteria .................................................................................................................. 8 
5.2 
Participant Exclusion Criteria ................................................................................................................. 8 
5.3 
Observational Subject Enrollment .......................................................................................................... 9 
5.4 
Strategies for Recruitment and Retention ............................................................................................... 9 
5.5 
Participant Withdrawal or Termination  ................................................................................................. 9 
5.6 
Premature Termination or Suspension of Study  .................................................................................. 10 
6 
STUDY PROCEDURES AND SCHEDULE ............................................................................................... 10 
6.1 
Schedule of Events ............................................................................................................................... 12 
7 
ASSESSMENT OF SAFETY ....................................................................................................................... 12 
7.1 
Adverse Event and Serious Adverse Event Reporting ......................................................................... 12 
7.2 
Reporting Procedures ........................................................................................................................... 12 
7.3 
Safety Oversite ..................................................................................................................................... 12 
8 
CLINICAL MONITORING ......................................................................................................................... 13 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 13 
9.1 
Statistical and Analytical Plans ............................................................................................................ 13 
9.2 
Sample Size .......................................................................................................................................... 14 
9.3 
Study Pitfalls and Suggested Solutions ................................................................................................. 14 
10 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ....................................... 15 
11 
QUALITY ASSURANCE AND QUALITY CONTROL ............................................................................. 15 
12 
ETHICS/PROTECTION OF HUMAN SUBJECTS ...................................................................................... 15 
12.1 
Ethical Standard .................................................................................................................................... 15 
12.2 
Institutional Review Board ................................................................................................................... 15 
12.3 
Informed Consent Process..................................................................................................................... 16 
12.4 
Participant and Data Confidentiality ..................................................................................................... 16 
13 
DATA HANDLING AND RECORD KEEPING.......................................................................................... 16 
13.1 
Data Collection and Management Responsibilities ............................................................................... 16 
13.2 
Study Records Retention....................................................................................................................... 17 
13.3 
Protocol Deviations .............................................................................................................................. 17 
13.4 
Publication and Data Sharing Policy..................................................................................................... 17 
14 
LITERATURE REFERENCES..................................................................................................................... 19 
APPENDIX.............................................................................................................................................................................................. 22 

CRT-P vs. CRT-D 
Protocol A 
         Version v.0.6 
         24 MAY 2018 
LIST OF ABBREVIATIONS 
 
ii 
 
 
AE 
Adverse Event 
BioLINCC 
Biologic Specimen and Data Repository Information Coordinating Center 
BMI 
Body Mass Index 
BNP 
Brain Natriuretic Peptide  
CFR 
Code of Federal Regulations 
CMS 
Centers for Medicare and Medicaid Services 
CRF 
Case Report Form 
CRT 
Cardiac Resynchronization therapy 
CRT-D 
Cardiac Resynchronization therapy-Defibrillator 
CRT-P 
Cardiac Resynchronization therapy- Pacemaker 
DCC 
Data Coordinating Center 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Forms 
EKG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HF 
Heart Failure 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
ICH E6 
International Conference on Harmonisation Guidance for Industry, Good Clinical Practice: 
Consolidated Guidance 
ICMJE 
International Committee of Medical Journal Editors 
IRB 
Investigational Review Board 
LVEF 
Left Ventricular Ejection Fraction  
NIH 
National Institutes of Health 
NHLBI 
National Heart, Lung, and Blood Institute  
NYHA 
New York Heart Association 
OSUMC 
Ohio State University Medical Center 
PI 
Principal Investigator 
QC 
Quality Control 
QOL 
Quality of Life 
RCT 
Randomized Clinical Trial  
REDCap 
Research Electronic Data Capture 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UPMC 
University of Pittsburgh Medical Center 
US 
United States 
VaPITT 
Veterans Hospital of Pittsburgh  

CRT-P vs. CRT-D 
Protocol A 
         Version v.0.6 
         24 MAY 2018 
STATEMENT OF COMPLIANCE 
 
1 
 
 
 
 
 
This trial will be conducted in accordance with all applicable US Federal regulations regarding 
the protection of hum subjects and the Declaration of Helsinki. All sites will maintain compliance to this 
protocol as well as any additional regulations imposed by their IRB. All personal who participate in the 
study related activities must have undergone Human Subjects Protection Training. 
 
 
I agree to ensure that all staff members involved in the conduct of this study are informed about their 
obligations in meeting the above commitments. 
 
 
Principal Investigator:    
 
Print/Type Name 
 
 
Signature    
 Date:_______________  

CRT-P vs. CRT-D 
Protocol A 
Version v.0.6 
         24 MAY 2018 
PROTOCOL SUMMARY 
 
2 
 
 
 
PROTOCOL SUMMARY 
 
 
 
Title: 
Cardiac Resynchronization in the Elderly: Piloting Pacemaker vs. Defibrillator Therapy 
(Randomized Trial and Observational). CRT – P vs. CRT – D.  
 
Précis:  
Pilot trial designed with a two part aim at enrollment. Aim 1 is designed as a 
randomized, controlled trial for older patients (≥75 years) who are indicated for CRT 
device implantation to receive a CRT-P or CRT-D. Information collected will help to 
assess the ability to enroll and retain older patients is a randomized controlled trial of 
CRT-P versus CRT-D in preparation for a large pivotal trial. Aim 2 is a non-
randomized, observational study of patients who were offered inclusion into Aim 1 but 
refused to participate. Aim 2 subjects present an opportunity to understand the reasons 
why older patients may refuse enrollment into a randomized trial as well as still 
allowing for collection of data regarding their chosen CRT device.  
 
Objectives: 
Primary Objective: Feasibility of enrolling and maintaining elderly heart failure 
patient in CRT-P vs CRT-D randomized trial. 
Secondary Objectives: Examine predictors of refusing randomization and of 
choosing CRT-P vs. CRT-D device implantation in elderly patients.  
 
Endpoint 
Primary Endpoint: The ability to enroll in the randomized controlled trial of 
CRT-P versus CRT-D patients.  
Secondary Endpoints: Determinants of refusing participation in CRT-P versus CRT-D 
clinical trial.  
 
Population: 
Patients 75 years or older who are clinically indicated for CRT device 
implantation based on published guidelines6 will be considered for this trial. 
The racial, gender, and ethnic characteristics of the proposed subject 
population represent the populations cared for at the participating 
institutions. Subjects meeting all inclusion and none of the exclusion criteria 
for Aims 1 and 2 will be enrolled in this research. No exclusion criteria shall 
be based on race, gender, or HIV status. Patients younger than75 years of 
age are excluded based on study rationale and design. 
 
Study Type: 
Pilot trial with two clinical Aims. Aim 1 is a randomized clinical trial and 
Aim 2 is an Observational clinical trial.    
 
Number of Sites 
 
Enrolling Participants: Total of four participating sites 
 
Study Duration: 
Approximately 24 months 
 
Participant Duration: Up to 18 months from enrollment  

CRT-P vs. CRT-D 
Protocol A 
Version v.0.6 
         24 MAY 2018 
PROTOCOL SUMMARY 
 
3 
 
 
 
 
Principal Investigator   
Samir Saba, MD FACC, FHRS  
University of Pittsburgh Medical Center 
200 Lothrop Street 
Pittsburgh, PA 15213 
(412)647-6272 
 
Chief Biostatistician 
Andrew Althouse  
Presbyterian Hospital, Office C701 
200 Lothrop Street 
Pittsburgh, PA 15213 
 
Data Coordinating Center 
University of Pittsburgh Medical Center 
200 Lothrop Street 
Pittsburgh, PA 15213 
 
Study Manager  
Sarah Herbert RN BSN 
University of Pittsburgh Medical Center 
200 Lothrop Street 
Pittsburgh, PA 15213 
 
 
 
 
Heart failure (HF)1-5 is a disease of epidemic proportions in the United States affecting over 5 
million individuals. While the incidence of many diseases in the U.S. is decreasing, HF represents one 
of only two human diseases that are increasing in frequency. It is estimated that nearly 400,000 new 
cases of HF will be diagnosed in the next year, one million patients will be hospitalized, and 300,000 
patients will die from HF in the U.S. Although the development of new medications has substantially 
broadened the therapeutic armamentarium over the past decades, the long-term prognosis for patients 
with HF remains poor with less than 50% of patients surviving five years after the initial diagnosis. A 
characteristic feature of HF is that it is a progressive disease with patients having repeated and 
progressively more frequent hospitalizations for worsening symptoms. HF puts an overwhelming 
burden on patients as evidenced by dramatically diminished quality of life (QOL). It also has a 
marked impact on the economics of our health system accounting for over 50 billion dollars in annual 
national healthcare expenditure. 
Cardiac resynchronization therapy (CRT) is an established therapy in HF6. HF patients with 
severe cardiomyopathy and ventricular conduction abnormalities, as demonstrated by a wide QRS 
waveform on surface electrocardiogram (>120 ms), who continue to suffer from HF symptoms (New 
York Heart Association Classes II, III, and ambulatory IV) despite optimal pharmacological therapy 
1 
KEY ROLES 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1 
BACKGROUND INFORMATION 

CRT-P vs. CRT-D 
Protocol A 
Version v.0.6 
         24 MAY 2018 
PROTOCOL SUMMARY 
 
4 
 
including angiotensin converting enzyme inhibitors/angiotensin receptor blockers, -blockers, and 
potassium-sparing diuretics can benefit from CRT with improved maximum oxygen consumption, 
exercise tolerance, and improved QOL7,8. Results of large, multicenter, randomized controlled trials 
such as Companion9 and Care-HF10 demonstrate, in addition, a significant decrease in the composite 
endpoint of death or HF hospitalization with CRT over optimal pharmacological therapy. Studies also 
suggest a benefit of CRT on reducing the burden of ventricular arrhythmias11. It is estimated that 
about 40% of patients who have systolic HF are CRT candidates by current guideline criteria6.   
CRT-P versus CRT-D 
 
CRT can be delivered through a pacemaker (CRT-P) or a defibrillator (CRT-D). CRT-P 
devices are smaller (i.e. require a smaller surgical incision at implantation) and cost a fraction of the 
price of CRT-D devices. Both CRT-P and CRT-D provide resynchronization to the failing heart 
through low energy pacing impulses, but CRT-D can additionally deliver high-energy shock therapy 
to terminate life-threatening ventricular arrhythmias. Compared to optimal pharmacological 
treatment, both CRT-P and CRT-D have been shown in randomized controlled trials9,10 to reduce all-
cause mortality and improve patient symptoms and cardiac function. In one study comparing them to 
each other9, CRT-P and CRT-D had equivalent benefits in reducing the composite endpoint of death 
or HF hospitalization9. For the endpoint of all-cause mortality however, CRT-D exhibited a non-
significant trend towards lower mortality compared to CRT-P when considering HF patients of all 
ages9. Published guidelines do not distinguish between the clinical indications for CRT-P and CRT-
D6.  
High Energy Defibrillator Therapy is Non-Specific 
High energy defibrillator shocks are non-specific i.e. most defibrillator recipients never 
receive shock treatments. Of 100 patients implanted with a defibrillator for primary prevention, ~23% 
receive appropriate shocks in response to life-threatening ventricular arrhythmias over long term 
follow-up12. In addition, it is estimated that about 4 appropriate defibrillator shocks account for one 
life saved13, 14.  Moreover, defibrillators may deliver inappropriate therapy15 and may have significant 
short and long term complications16 thus negatively impacting QOL. Shocks are painful, drain device 
battery, and add significantly to the cost of care for patients because of a higher burden of visits to the 
emergency department or outpatient clinics as well as admissions to the hospital and surgical 
procedures for replacement of depleted device batteries. In addition, the number of defibrillators and 
defibrillator lead malfunctions resulting in advisories and recalls by the Food and Drug 
Administration have increased significantly over the past decade17 out of proportion to those seen 
with the simpler pacemaker devices, thus adding to the morbidity and mortality of defibrillator 
recipients and to the overall cost of health care.  
CRT in the Elderly 
The U.S. and Europe populations are getting older. For instance, in the United States, the 
population aged 80-84 years increased by 16.1%, and those aged 85-89 years increased by 29.8% 
from 2000 to 201018. Although not excluded from the large CRT randomized trials9, 10, older patients 
(≥75 years) have been largely underrepresented in these trials but still receive up to 40% of all CRT-
D’s in the United States19,38. Moreover, older patients have a higher risk of death than younger 
patients based on competing causes of death and comorbid conditions, thus stirring controversy 
regarding the role of defibrillator therapy in the elderly20-24. In addition, data from large CRT-D 
registries show that the odds of receiving appropriate defibrillator shocks decrease significantly with 
every decade of age25. 
 
 

CRT-P vs. CRT-D 
Protocol A 
Version v.0.6 
         24 MAY 2018 
PROTOCOL SUMMARY 
 
5 
 
Potential Impact 
  
A large, randomized, non-inferiority trial comparing mortality and QOL in older HF patients 
receiving CRT-P versus CRT-D therapy addresses a critical clinical practice area. Uncertainty about 
the comparative outcomes of older patients with these two therapies leads to suboptimal and costly 
management of HF: Older CRT recipients often receive the larger and more expensive CRT-D device 
that can deliver painful shocks, in the absence of any proof for incremental survival benefit with 
CRT-D over CRT-P. The pilot randomized trial of this proposal (Aim 1) will be essential to the 
design of a large pivotal trial. This project will also have significant scientific impact because it will 
evaluate the clinical and demographic predictors of choosing CRT-P or CRT-D therapy as well as 
patients’ change in their satisfaction with their decision 6 months after enrollment. The results of this 
research will ultimately effect clinical change in the management of elderly CRT recipients driven by 
changes to the CRT published guidelines. This research is likely to impact clinical practice and will 
be important to many stakeholders, including elderly patients and their families, physicians, hospitals, 
and third party payers, especially Medicare. 
 
Since the initial introduction of the defibrillator as a life-saving therapy almost 30 years ago, 
most large scale clinical trials9, 10, 12-16 have focused on expanding its clinical indications by 
identifying newer patient groups at increased risk of sudden cardiac death that may benefit from this 
therapy. From the original surgically-implanted single-chamber ‘shock box’ devices used in survivors 
of cardiac arrest, the field moved steadily in the direction of expanding the indications to larger 
patient groups. Today, defibrillators are implanted mainly for primary prevention of sudden cardiac 
death in patients with low left ventricular ejection fraction (≤35%) who have never experienced a life-
threatening arrhythmia13, 14. They are also implanted in HF patients, a significant proportion of whom 
requires CRT devices9, 10. Driven by industry sponsors, on-going trials are now investigating the role 
of the implantable defibrillator in patients with relatively preserved ventricular function (ejection 
fraction between 36% and 50%)26 who never had ventricular arrhythmias. Yet, despite the established 
benefits of defibrillator therapy on survival, few patients implanted with these devices receive 
electrical treatment from them19.  
The proposed research is innovative because it takes a perspective that goes in the opposite 
direction to most studies of the past 3 decades that have aimed to expand the indications for 
defibrillator therapy. Instead, our project investigates whether in a subset of patients (age ≥ 75 years) 
who are currently indicated for CRT device implantation, the smaller, simpler, and cheaper CRT-P is 
equivalent to the CRT-D in decreasing mortality and improving QOL. Of note, the proposed patient 
population overwhelmingly receives CRT-D therapy in the U.S. today (>80% of cases)27, presumably 
because of an overinflated estimate of the protective role of defibrillator therapy in these patients, 
which is based on results extrapolated from other non-CRT trials, which were performed in different 
patient populations13-15. As opposed to studying the eligibility of non-indicated patients to receive an 
available therapy with the goal of expanding its clinical indications, we propose to study a subgroup 
of patients that is currently indicated for CRT-D therapy according to the published national 
guidelines6 and CMS reimbursement policies28 but is poorly represented in large randomized trials14 
and is least likely to benefit from defibrillator therapy.  
Our proposal is also important because it focuses exclusively on elderly patients who 
although not excluded from randomized trials of cardiac implantable electronic devices, have been 
grossly underrepresented in these trials9, 10, 12-16. Elderly patients constitute a fast-growing stratum of 
the United Sates population and an important one given that the burden of cardiac disease and the 
cost of health care increase dramatically in the later years of life. To our knowledge, the proposed 
trial would be the first cardiac implantable electronic device trial to be performed exclusively in 
2.2 
RATIONALE 

CRT-P vs. CRT-D 
Protocol A 
Version v.0.6 
         24 MAY 2018 
PROTOCOL SUMMARY 
 
6 
 
patients 75years of age or older, thus focusing on this large stratum of the population that is 
neglected in clinical cardiac research.  
  
Finally, our research will create a cohort of patients who declined enrollment into the pilot 
randomized controlled trial. This observational cohort will provide an opportunity to examine the 
clinical and demographic determinants of choosing CRT-P versus CRT-D in older HF patients. 
These decisions are typically made by the patients with help from caregivers and other family 
members, after discussing the pros and cons with the treating physician. We will also assess the 
patients’ satisfaction with their decision to receive CRT-P versus CRT-D, at baseline and 6 months 
after enrollment. Examining the factors that predict patients’ choice of CRT-P versus CRT-D in HF 
management and the level of satisfaction of patients is novel in the field of cardiac implantable 
electronic device management.
 
 
For the Aim 1 randomized trial subjects, they will be screened for appropriateness of the trial 
before being randomized. If there is any indication that the patient should receive a CRT-D over a 
CRT-P then the patient will not be considered for the trial. Once the patient is enrolled in the Aim 1 
the choice to have a randomized decision will not increase any health risks to the patient.  Both the 
CRT-P and CRT-D device implantations are part of the standard medical care for HF patients. The 
risks involved with the implantation of either device are comparable to those of patients not enrolled 
in this research study. The risks include, but are not limited to, death, stroke, heart attack, damage to 
the heart or lungs or veins, infections, bleeding, arrhythmias, or the need for emergent open-heart 
surgery. These risks are the same in patients undergoing the CRT-P or CRT-D implantation 
procedures but who are not enrolled in this research study.  Defibrillator devices include additional 
risk of shocks that can occur when there is an abnormal heart rhythm detected by the device. 
Occasionally, the device may deliver a shock for unintended reasons (a benign heart rhythm or noise). 
For the observational Aim there is no additional health risk to the patients as only the patients’ 
health information will be collected. There is a risk that the patients personal or health information 
may become exposed outside of the observational trial. This risk will be minimized by using all 
possible safeguards to help reduce risk of exposure. This risk also applies to the Aim 1 subjects.  
 
There may be no direct benefits to the subjects as a result of their participation in this study. 
The possible benefits of this procedure, using the pacemaker or the defibrillator, would be to help the 
subjects heart function in a more synchronized manner. By participating in this study, subjects may 
contribute valuable information to medical science that may benefit future patients with their same 
condition. The sponsor cannot guarantee any benefit to the subjects for their participation in this 
study. 
 
The primary objective is to evaluate and determine the feasibility of enrolling and maintaining 
elderly heart failure patients in the CRT-P versus CRT-D randomized trial. Additionally, for Aim 2, 
the observational arm will also maintain the same objective. Secondary objective is to examine the 
predictors of undergoing Pacemaker versus Defibrillator device implantation in elderly patients 
(≥75b years).  
 
 
 
 
2.3 
POTENTIAL RISKS AND BENEFITS 
2.3.1 KNOWN POTENTIAL RISKS 
2.3.2 KNOWN POTENTIAL BENEFITS 
3 
OBJECTIVES AND PURPOSE 

CRT-P vs. CRT-D 
Protocol A 
Version v.0.6 
         24 MAY 2018 
PROTOCOL SUMMARY 
 
7 
 
 
 
The design of this pilot study is in two parts corresponding to Aims 1 and 2 (Figure 1). Aim 1 
is designed as a pilot randomized, controlled trial to be conducted at 4 institutions in the United 
States. It will randomize older patients (≥75 years) who are indicated for CRT device implantation to 
receive a CRT-P or a CRT-D. The choice of the design of Aim 1 was intended to mimic the design 
of a future large, multicenter, non-inferiority trial which would provide definitive answers regarding 
the relative impact of CRT-P versus CRT-D on total mortality and QOL in older patients. This 
specific design is necessary to allow the gathering of hard data on rates of screening of patients, 
acceptance of enrollment, randomization, device implantation, and patient retention during follow-
up. Any design variations are likely to introduce biases which would increase the chances of flawed 
design of the pivotal trial.  
Aim 2 is a non-randomized, observational study of patients who were offered inclusion into 
Aim 1 but refused to participate. We speculate that a majority of those patients who refuse 
participation in the randomized pilot trial do so because of a strong preference for CRT-P or CRT-D. 
This cohort complements Aim 1 and presents an opportunity to understand the reasons why older 
patients may refuse enrollment into a randomized trial of CRT-P versus CRT-D and to examine the 
demographic and clinical determinants associated with choosing a CRT-P versus a CRT-D device. It 
also provides the means to measure patients’ QOL and satisfaction32-34 with decision (CRT-P or 
CRT-D), at baseline and 6 months after enrollment into this observational cohort.  
 
 
 
 
4 
STUDY DESIGN AND ENDPOINTS 
4.1 
DESCRIPTION OF THE STUDY DESIGN 

CRT-P vs. CRT-D 
Protocol A 
Version v.0.6 
         24 MAY 2018 
PROTOCOL SUMMARY 
 
8 
 
 
 
 
With the Aim 1 randomized subjects the primary endpoint is the ability to enroll in the 
randomized controlled trial of CRT-P versus CRT-D patients. The subjects enrolled with aid in 
determining and assessing feasibility of screening, enrolling, randomizing, and retaining participants 
in this pilot trial. 
 
 
The subjects enrolled in Aim 2 will help to determine the clinical and demographic 
characteristics of subjects who refused participation in the pilot randomized trial and to compare 
them to those in Aim 1.  Therefore the secondary endpoint is the determination of predictors of 
refusing participation in CRT-P versus CRT-D clinical trial. 
 
 
1. Age  75 years 
2. LVEF≤ 35% by cardiac imaging including echocardiogram, nuclear imaging, cardiac 
catheterization, or cardiac magnetic resonance imaging 
3. QRS width >120 ms on surface electrocardiogram 
4. New York Heart Association class II, III, or ambulatory IV for HF 
5. Patient undergoing de novo CRT device implantation or CRT-D device change-out for battery 
depletion 
 
1. Patient within 40 days of acute myocardial infarction 
2. Patient within 3 months of cardiac revascularization (percutaneous coronary intervention or 
bypass surgery) 
3. Patient with prior history of cardiac arrest or documented sustained ventricular arrhythmia 
4. Patient with expected longevity < 1 year 
5. Patient not on optimal medical therapy for HF management including when tolerated β-blockers, 
angiotensin converting enzyme inhibitors or angiotensin receptor blockers 
6. Patient unable or unwilling to sign a written informed consent 
7. Patient’s with dementia that are unable to consent for themselves  
 
8. Participating in any other clinical trials (observational/registries allowed) 
 
 
 
4.2 
STUDY ENDPOINTS 
4.2.1 PRIMARY ENDPOINT 
4.2.2 SECONDARY ENDPOINTS 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
5.1 
PARTICIPANT INCLUSION CRITERIA 
5.2 
PARTICIPANT EXCLUSION CRITERIA 
5.3 
OBSERVATIONAL SUBJECT ENROLLMENT 

CRT-P vs. CRT-D 
Protocol A 
Version v.0.6 
         24 MAY 2018 
PROTOCOL SUMMARY 
 
9 
 
Patients identified in Aim 1 who refuse to participate will be offered to enroll in the 
observational cohort of Aim 2. Patients are eligible to enroll in the observational cohort at the time 
of implant through fourteen days’ post procedure. There is a separate written, informed consent 
designed specifically for the prospective observational study. Sites are to collect, from all patients 
enrolled in Aim 2, their reason(s) why they refused enrollment in Aim 1. It is anticipated that a 
majority of these patients will accept participating in the observational study of Aim 2 that allows 
them to retain control over their decision.  
The research coordinator at each site will maintain a detailed log of all patients who were 
offered participation in the non-randomized observational cohort, whether they signed a consent 
form or not. Reasons for declining participation in the research protocol of Aim 2 will be recorded. 
The inclusion and exclusion criteria for Aim 2 are identical to Aim 1.  
 
Patients presenting to the outpatient cardiology clinics or inpatient services of the 4 
participating institutions and who are prescribed CRT device implantation or CRT-D device change-
out for battery depletion will be considered for participation in this pilot randomized trial. The main 
investigator at each site will identify prospective patients who may require CRT device implantation. 
This will be achieved by screening the inpatient services and outpatient clinics of the cardiac 
electrophysiology services at each site. Research coordinators will verify that the prospective subjects 
meet all the inclusion and none of the exclusion criteria for the study. Once this information is 
ascertained, the investigator, research coordinator, or both will approach the patient to explain the 
rationale of the study and its requirements. After signing written informed consent, patients will be 
randomized to receive a CRT-P or a CRT-D device. Block randomization by enrolling site will be 
adopted. The randomization status of the patient will be communicated to the treating cardiologist. Of 
note, the surgical procedure for CRT-P or CRT-D implantation is similar with respect to duration and 
risk of the procedure, with the exception that CRT-D implantations require a larger skin incision 
(~1.5 inches versus 0.75 inches). 
The research coordinator at each site will maintain a log of all patients who were screened for 
this pilot trial. The log should include reasons for why the patient did not meet either the inclusion or 
the exclusion criteria. Additionally, the log would also include the patient’s reason for not wanting to 
enroll in the Aim 1 clinical trial. This log will be maintained at each individual site and redacted of 
identifiable information in order to send to the sponsor upon request. Use of patient initials and age 
will be used in place of patient’s full name and date of birth. 
 
During the consenting process subjects will be informed of their rights to withdraw from the 
study at any time without prejudice. Subjects who no longer attend their required in-office follow-up 
or are unable to be reached by telephone after 2 documented attempts by investigator, will be 
considered lost to follow-up. These subjects will not undergo any additional study activities once 
they have been withdrawn. The Social Security Death Index37 will only be used as an adjunctive 
method of confirming death if no contact at all could be established with the patient or family during 
follow-up. Any identifiable research or medical record information recorded for, or resulting from, 
the subject’s participation in this research study prior to the date that they formally withdraw 
consent may continue to be used and disclosed by the investigators for research purposes. 
A patient may be discontinued from participating in this research if their device implantation 
procedure is not successful or is complicated by death or if they fail to follow-up after device 
implantation according to the research protocol requirements. 
 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION 
5.5 
PARTICIPANT WITHDRAWAL OR TERMINATION 

CRT-P vs. CRT-D 
Protocol A 
Version v.0.6 
         24 MAY 2018 
PROTOCOL SUMMARY 
 
10 
 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to each of the individual sites. 
It is the responsibility of each individual site to then notify their respective IRB.  If the study is 
prematurely terminated or suspended, the PI will promptly inform the sponsors IRB and will 
provide the reason(s) for the termination or suspension to each site. The study may resume once 
concerns about safety, protocol compliance, data quality are addressed and satisfy the sponsor and 
IRB. Before resuming any study enrollments each individual site must first receive notification 
from the sponsor.  
 
Randomization Aim 
 Table 1 details the baseline data collected for every enrolled patient. Baseline demographics 
(e.g. age, gender, and race) and clinical information (e.g. cardiac condition, comorbid conditions, 
echocardiographic parameters, EKG parameters) will be abstracted from the electronic medical 
records of each participating institution. QOL questionnaires will be obtained at enrollment and at 
the 6-month follow-up visit using both the RAND-36 health Status Inventory35 and the Minnesota 
Living with Heart Failure Questionnaire36. A paper and pencil option will be provided unless the 
patient is unable to read or write in which case the questionnaires will be administered verbally by a 
research coordinator.  
  Patients will be followed in the pilot randomized trial from the date of enrollment until study 
closure. During follow-up, information will be collected on procedural details and complications, as 
well as clinical events including death, hospitalizations, and emergency room visits. The events will 
be ascertained by asking the patient or their caregiver. Data pertaining to hospitalizations and 
emergency room visits will be readily available if they occurred at the enrolling institution. If at 
another institution, these data will be collected by asking the patient to sign a release of medical 
records form and by obtaining relevant clinical information from the other institution. The cause of 
death and primary reason for hospitalization will be adjudicated as cardiac (arrhythmic or non-
arrhythmic) or non-cardiac by an adjudication committee that is independent from the research 
team. For the CRT-D arm of the study, information about appropriate and inappropriate device 
shocks and anti-tachycardia pacing therapies will be collected. Importantly, rates of patient 
screening, enrollment, randomization, and retention in the study will also be collected.  
Table 1. Baseline Data 
Variables Collected 
Demographic variables 
Age, Gender, Ethnic background, type of insurance (primary and 
secondary), Zip code 
Clinical variables 
Type of heart disease (ischemic/non-ischemic), New York Heart 
Association class of heart failure, atrial fibrillation, BMI, tobacco 
and alcohol use, comorbidities that affect survival (19 conditions 
included in the modified Charlson comorbidity index, which 
include: myocardial infarction, congestive heart failure, peripheral 
vascular disease, cerebrovascular disease, dementia, chronic 
pulmonary disease, connective tissue disease, peptic ulcer disease, 
mild liver disease, Diabetes, hemiplegia, renal disease, end-organ 
damage from diabetes, any tumor, leukemia, lymphoma, metastatic 
solid tumor, moderate to severe liver disease, acquired immune 
deficiency syndrome) 
5.6 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
6 
STUDY PROCEDURES AND SCHEDULE 

CRT-P vs. CRT-D 
Protocol A 
Version v.0.6 
         24 MAY 2018 
PROTOCOL SUMMARY 
 
11 
 
Laboratory variables 
Serum sodium, creatinine, calculated glomerular filtration rates, 
BNP 
EKG variables 
HR, PR, QRS, QT, QTc, Rhythm, QRS axis, QRS morphology 
Medications 
Β-adrenergic blocking agents, Angiotensin converting enzyme 
inhibitors, Angiotensin receptor blockers, aldosterone, Class I and 
class III antiarrhythmic medications, statins, nitrates 
Imaging variables 
LVEF assessment with imaging modality used. Left ventricular 
systolic and diastolic dimensions, any other abnormality 
Quality of Life 
RAND-36 Health Status Inventory34 (Appendix 1) 
Minnesota Living with heart Failure Questionnaire35 (Appendix 2) 
 
The milestones of data collection are detailed in Table 2. Patients enrolled in the randomized 
pilot trial will have baseline demographic, clinical, and pharmacological information collected after 
they sign written informed consent. QOL questionnaires and patient satisfaction will also be obtained 
at baseline. At the scheduled date of device implantation, which will be within 30 days of enrollment, 
procedural details will be collected including total and fluoroscopic durations of the procedure, device 
and lead models, and any acute major or minor procedural complications. Patients whose device 
implantation procedure is scheduled > 30 days from the date of enrollment have to be re-consented 
for participation in this trial. In follow-up, each patient will be contacted by phone at 30 days, 3 
months, and 6 months post enrollment and every 6 months thereafter until the end of the study. The 
phone calls will be used to collect interim information from patients or next of kin regarding non-
acute procedural complications or clinical events (e.g. death, hospitalization). Original medical 
records will be obtained for all clinical events and will be reviewed by an independent adjudication 
committee. Each scheduled phone visit will also be associated with a remote device interrogation to 
assess device function and obtain information about stored arrhythmic events.  
Observational Aim 
Patients enrolled in the observational cohort of Aim 2 will have demographic and clinical data 
collected at baseline similarly to patients enrolled in the randomized trial of Aim 1. Table 1 details 
the clinical variables collected at enrollment. Table 2 details the follow-up milestones. Also, 
patients enrolled in Aim 2 of this proposal will undergo QOL assessment using the RAND-36 
Health Status Inventory35 and the Minnesota Living with heart Failure Questionnaire36 (Appendices 
1 and 2) at baseline and at the 6-month follow-up visit which could be conducted by phone. 
Procedural information and complications as well as clinical events will be collected on patients 
enrolled in the non-randomized observational cohort, similarly to patients enrolled in Aim 1. Data 
on cost of care will also be collected for all patients enrolled in Aim 2.  
In addition, patients enrolled in the observational cohort will be asked about their decision  to 
receive a CRT-P or CRT-D device and will be probed for the reason (s) behind their decision and 
their answers will be recorded. The actual type of device implanted (CRT-P versus CRT-D) will be 
ascertained at the time of the implantation procedure. At baseline and at the 6-month research call, 
they will be assessed for their level of satisfaction with their decision about device therapy (CRT-P 
or CRT-D) using the Satisfaction with Decision Scale32-34 (Appendix 3), which assigns a score of 1 
to 5 to the answer of each of 6 questions pertaining to the patient’s level of satisfaction with their 
medical decision (lowest satisfaction score is 6 and highest is 30).  
 
 
6.1 
Schedule of Events 

CRT-P vs. CRT-D 
Protocol A 
Version v.0.6 
         24 MAY 2018 
PROTOCOL SUMMARY 
 
12 
 
 
Table 2. Schedule of Events 
Enrollment 
visit 
Device 
implant 
30-day 
phone 
call 
3-month 
phone 
call 
6-month 
visit or 
phone call 
Every 6 
months 
phone call 
End of 
Study 
Demographic Information 
X 
 
 
 
 
 
 
Baseline Clinical Characteristics 
X 
 
 
 
 
 
 
Medications 
X 
 
 
 
X 
X 
X 
Procedural Complications 
 
X 
X 
 
 
 
 
Clinical Events (survival, 
hospitalizations, arrhythmias) 
 
X 
X 
X 
X 
X 
X 
The Satisfaction with Decision 
Scale 
X 
 
 
 
X 
 
 
Quality of Life Questionnaires 
X 
 
 
 
X 
 
 
Device complications  
 
X 
 
X 
X 
X 
X 
Device Interrogation 
 
X 
 
 
X 
X 
X 
Economic Data 
 
 
 
 
 
 
X 
 
 
 
The main investigator at each of the participating institutions will be responsible daily for the 
appropriate implementation of study protocols and for patient safety. All adverse events will be 
reported to the DSMB, to the local IRB of the participating institution where the adverse event 
occurred per their respective reporting guidelines, and if required, to the NHLBI. Each adverse event 
will be classified by the site investigator as ‘study-related’ or ‘not study related’ and reviewed by the 
DSMB for adjudication. Serious adverse events (death, procedural complications, or hospitalizations 
for any reason) will be reported to the coordinating center and the local IRB (per their reporting 
guidelines) within 48 hours of adverse event awareness. 
 
  
The study clinician will have oversite of completed SAE Forms. Reporting of the forms should 
occur within the following timelines: 
 
• 
All deaths and immediately life-threatening events, whether related or unrelated to the 
clinical trial, will be recorded on the SAE Form and submitted to the study sponsor 
within 48 hours of site awareness.  
• 
Other SAEs regardless of relationship will be submitted to the study sponsor within 72 
hours of site awareness. 
 
All SAEs will be followed until resolution or until the site investigator deems the event to be 
chronic or stable. Other supporting documentation of the event may be requested by the study 
sponsor and should be provided as soon as possible.  
 
Safety oversight will be under the direction of a DSMB composed of individuals with the 
appropriate expertise, including cardiologists. The DSMB will meet at least quarterly to assess 
safety and efficacy data on each arm of the study. The DMSB will operate under the rules of 
an approved charter that will be written and reviewed at the organizational meeting of the 
DSMB. At this time, each data element that the DSMB needs to assess will be clearly defined. 
The DSMB will provide its input to the NHLBI. 
 
7 
ASSESSMENT OF SAFETY 
7.1 
ADVERSE EVENT (AE) AND SERIOUS ADVERSE EVENT (SAE) REPORTING 
7.2 
REPORTING PROCEDURES 
7.3 
SAFETY OVERSIGHT 

CRT-P vs. CRT-D 
Protocol A 
Version v.0.6 
         24 MAY 2018 
PROTOCOL SUMMARY 
 
13 
 
 
The primary responsibility of the DSMB, an independent group of experts that advises the 
study investigators, is to oversee the progress of the study and review adverse events. All adverse 
events in both arms of the clinical trial will be reviewed and adjudicated as ‘research-related’ or 
not. Stoppage rules of the clinical trial will be mandated by the DSMB if examination of the 
adverse events revealed that one treatment arm is clearly superior to the other treatment for the 
primary endpoint of all-cause mortality. The DSMB will also review the overall progress of the 
trial, the quality of data collection, the safety and confidentiality of data storage, and the overall 
management of the trial. A Data and Safety Monitoring report will be generated including 
information on study status and enrollment milestones, quality of data collected, and safety data. 
 
 
Randomized Aim  
 
Descriptive patient characteristics will be presented as mean (SD) for continuous variables and 
n (%) for categorical variables.  Baseline comparisons of patients assigned to CRT-P vs. CRT-D will 
be performed using t-tests for continuous variables (Wilcoxon rank-sum test if non-normally 
distributed) and chi-squared tests for categorical variables (Fisher’s Exact Test in case of small 
sample sizes within cells) to confirm that the randomized treatment arms are balanced in key 
demographics and potential confounders.  The proportion of patients experiencing major/minor 
procedural complications within 30 days will be reported as n (%) within each treatment arm. These 
complication rates will be ascertained through review of pertinent medical records following the 
device implantation. Mortality [as n (%)] and the 6-month QOL outcomes [as mean (SD)] within each 
treatment arm will be reported as well.  Cost of care for the index hospitalization for CRT device 
implantation and for the follow-up period will be measured at the conclusion of the study and 
compared between the 2 cohorts using a 2-sample t-test (or Wilcoxon test if the data are non-normally 
distributed). Retention will be presented as n (%) completing at least 6-month of follow-up.  In 
addition to the retention, in order to document the recruitment success, we will report the number of 
patients approached in order to successfully enroll n=50 patients, which will be useful information in 
planning a large scale trial. 
 
Observational Aim 
 
All patients who do not enroll in the trial, but consent to be followed, will be enrolled in a 
parallel observational cohort.  Patients’ clinical and demographic characteristics will be examined and 
compared between CRT-P and CRT-D recipients using t-tests, Wilcoxon rank-sum tests, chi-squared 
tests, or Fisher’s Exact tests, as appropriate. Patient satisfaction among CRT-P vs. CRT-D recipients 
will be assessed at baseline and 6 months after enrollment using the Satisfaction with Decision Scale. 
The scores will be presented as mean (SD) and tested using a 2-sample t-test (or Wilcoxon test if the 
data are non-normally distributed). Deceased patients will be included in the analysis (assigned the 
lowest possible satisfaction score of 6) to avoid survival bias in the event of differential mortality in 
CRT-P vs. CRT-D. Cost of care will also be presented as mean (SD) and compared between the two 
cohorts using a 2-sample t-test (or Wilcoxon test if the data are non-normally distributed).  
Multivariate modeling with adjustment for selected patient factors will be considered if there are 
differences in CRT-P vs. CRT-D patients on key demographics, but the power to test this difference 
while accounting for multiple confounders may be limited. 
 
8 
CLINICAL MONITORING 
9 
STATISTICAL CONSIDERATIONS 
9.1 
STATISTICAL AND ANALYTICAL PLANS 

CRT-P vs. CRT-D 
Protocol A 
Version v.0.6 
         24 MAY 2018 
PROTOCOL SUMMARY 
 
14 
 
 
Randomized Aim 
 
It will be of interest to estimate the recruitment success rate and the retention rate in this 
population, as that will be useful knowledge for designing a pivotal non-inferiority trial.  The 
proposed sample size of 50 patients guarantees a maximum sample standard deviation = √(.5*(1-
.5)/50) = 7%, meaning that a 95% confidence interval will have a maximum margin of error ± 13% in 
estimating true retention rate.  However, this margin-of-error may be lower (the further the sample 
retention is from 50%).  For example, if 40/50=80% participants enrolled complete at least the 6-
month visit, a 95% CI estimating the true 6-month retention in this population would range from 
68.9-91.1%, information that can be used to guide recruitment estimates for the large scale trial.  The 
recruitment success rate can be estimated with even more precision, as there will be a larger N 
approached than N enrolled (and thus a smaller standard deviation of the sample proportion). 
 
Observational Aim 
 
It is anticipated based on the physician and patient surveys that approximately 40% of patients 
offered the opportunity to enroll in the pilot randomized controlled trial of Aim 1 will do so.  
Therefore, 125 patients will need to be screen to enroll 50 in the pilot randomized trial.  It is assumed 
that 80% of those who decline participation in Aim 1 will agree to be followed in the observational 
cohort, the cohort will consist of 60 non-randomized patients.  A comparison will be scored on the 
Satisfaction with Decision Scale using a t-test (or Wilcoxon rank-sum test, if non-normally 
distributed).  Assuming roughly equal numbers select CRT-D vs. CRT-P, enrollment of 60 cohort 
participants will have 80% power to detect a difference in Satisfaction with Decision scores if one 
treatment group’s average score is at least 0.75 standard deviations higher than the other group. 
 
Randomized Aim 
 
Based on the total volume of CRT recipients at the 4 enrolling institutions and the estimated 
percentage of acceptance of patients to enroll in a randomized CRT-P versus CRT-D trial provided by 
the physician (Appendix 1) and patient (Appendix 2) surveys, it is anticipated that the actual 
enrollment rate will exceed the rate needed to reach the target sample size of 50 patients in Aim 1 
over a 1.25-year enrollment period. The required threshold for the rate of enrollment is 0.83 patients 
per institution per month. If the actual enrollment rate turns out to be slower than expected, then more 
institutions may be added to the pilot trial. The data gathered from this pilot trial will be necessary to 
inform the design of a future large, non-inferiority, randomized trial of CRT-P versus CRT-D with 
respect to number of sites needed and duration of the enrollment phase. 
The present pilot randomized trial is by necessity un-blinded, i.e. patients and physicians 
know whether the implanted device is a CRT-P or CRT-D. In order to better understand if there are 
biases in the type of patients who accept randomization, the research is to be conducted as described 
in Aim 2 by doing so this will provide insight into the determinants of accepting participation in the 
randomized trial (compare patients in Aim 1 versus Aim 2) as well as insights into the determinants 
of choosing a CRT-P versus CRT-D device (compare patients in Aim 2 who received CRT-P versus 
CRT-D).   
 
 
 
9.2 
SAMPLE SIZE 
9.3 
STUDY PITFALLS AND SUGGESTED SOLUTIONS 

CRT-P vs. CRT-D 
Protocol A 
Version v.0.6 
         24 MAY 2018 
PROTOCOL SUMMARY 
 
15 
 
Observational Aim 
 
The sample size needed for Aim 2 is likely to be easily achieved as we will offer enrollment to 
all patients screened but not enrolled into Aim 1. We expect the patient acceptance to enroll in an 
observational study where no clinical decisions are imposed by the research protocol to be very 
high. If our estimates of enrollment turn out to be too optimistic however, we would consider 
adding another institution to the research protocol to mitigate this issue.  
The main purpose of Aim 2 is to provide insight into which patients refuse to enroll in the 
large RCT and why in order to inform the design of the pivotal RCT. Since all investigators on this 
proposal are electrophysiologists, if the pilot proposal were to reveal that a major reason for 
patients’ refusal to participate in a randomized study of CRT-P vs. CRT-D is because of the opinion 
of their referring cardiologist about the relative merits of these devices, then the pivotal RCT could 
be designed to include referring cardiologists as primary site investigators, which would likely 
mitigate this problem. This is one example for how the results of Aim 2 may inform the design of 
the large scale trial. 
 
The individual study sites will maintain a patient binder to include all source documents that 
correlate with the information that is obtained with this trial. The sponsor has the right to request 
redacted source documents to aid in verification of information provided for the sole purpose of the 
trial. With each adverse event that is reported, the sites will submit all source documents pertaining 
to that event. These records will also be redacted of any patient identifiable information and marked 
with the corresponding patient identification number and correlating case report form. Each site is 
responsible for maintaining a patient log that indicates the patient that corresponds with their study 
identification number.  
 
QC procedures will be implemented beginning with the data entry system and data QC checks 
will be run on the database for reports to be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. Each site is responsible for conducting the 
clinical trial and that the data is generated, documented (recorded), and reported in compliance with 
the protocol, GCP, and the applicable regulatory requirements. The investigational sites will 
provide access to all trial related information, source data/documents, and reports for the purpose of 
monitoring and auditing by the sponsor. 
 
 
The investigator at each site will ensure that this study is conducted in full conformity with 
Regulations for the Protection of Human Subjects of Research. All personal planning to be involved 
must ensure that the trial is performed and the data are generated, documented (recorded), and 
reported in compliance with GCP and the applicable regulatory requirement(s). 
 
The protocol, informed consent form(s), and all participant materials will be submitted to the 
IRB for review and approval. Approval of both the protocol and the consent form must be obtained 
before any participant is enrolled. Any amendment to the protocol will require review and approval 
by the IRB before the changes are implemented to the study. All changes to the consent form will 
also need IRB approval; a determination will be made regarding whether previously consented 
participants need to be re-consented. Any changes to the consent by the individual sites will first be 
required to obtain approval from the sponsor prior to submitting changes to the IRB.  
10 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
11 
QUALITY ASSURANCE AND QUALITY CONTROL 
12 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
12.1 
ETHICAL STANDARD 
12.2 
INSTITUTIONAL REVIEW BOARD 

CRT-P vs. CRT-D 
Protocol A 
Version v.0.6 
         24 MAY 2018 
PROTOCOL SUMMARY 
 
16 
 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate 
in the study and continues throughout the individual’s study participation. Participants and their 
families should be informed of risks and possible benefits of participation. Consent forms will be 
IRB-approved and the participant will be asked to read and review the document. The investigator 
will explain the research study to the participant and answer any questions that may arise. All 
participants will receive a verbal explanation in terms suited to their comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants.  
Participants will have the opportunity to carefully review the written consent form and ask 
questions prior to signing. 
The participants should have the opportunity to discuss the study with their family members 
or think about it prior to agreeing to participate. The participant will sign the informed consent 
document prior to any procedures being done specifically for the study. The participants may 
withdraw consent at any time throughout the course of the trial. A copy of the informed consent 
document will be given to the participants for their records. The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their medical care will not 
be adversely affected if they decline to participate in this study. Additionally, each informed 
consent process will be documented and maintained with the original copy of the consent at each 
study site according their institutional SOP.  
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
and the sponsor. This confidentiality is extended to cover clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will be 
released to any unauthorized third party without prior written approval of the sponsor. The study 
participant’s contact information will be securely stored at each clinical site for internal use during 
the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by local IRB and Institutional regulations. 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at UPMC. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management 
systems used by clinical sites and by UPMC research staff will be secured and password protected. 
At the end of the study, all study databases will be de-identified and archived at the UPMC. 
 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site PI. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. Black ink is required to ensure clarity of reproduced copies. When making 
changes or corrections, cross out the original entry with a single line, and initial and date the 
change.  DO NOT ERASE, OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON THE 
ORIGINAL. 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and 
maintained for recording data for each participant enrolled in the study. Data reported in the eCRF 
derived from source documents should be consistent with the source documents or the discrepancies 
12.3 
INFORMED CONSENT PROCESS 
12.4 
PARTICIPANT AND DATA CONFIDENTIALITY 
13 
DATA HANDLING AND RECORD KEEPING 
13.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 

CRT-P vs. CRT-D 
Protocol A 
Version v.0.6 
         24 MAY 2018 
PROTOCOL SUMMARY 
 
17 
 
should be explained and captured in a progress note and maintained in the participant’s official 
electronic study record. 
All clinical data will be entered into REDcap by the individual sites, the data system will be 
provided by UPMC. The data system includes password protection and internal quality checks, 
such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the source documents. 
 
Each individual site is required to maintain research records for a period of no less than seven 
years after the study ends. The sponsor may continue to use and disclose study records which may 
contain subject identifiable information related to this research study for a minimum of 10 years and 
for as long (indefinite) as it may take to complete this research study.  
 
A protocol deviation is any noncompliance with the clinical trial protocol or GCP 
requirements. The noncompliance may be either on the part of the participant, the investigator, or 
the study site staff. It is the responsibility of the site to use continuous vigilance to identify and 
report deviations within 7-14 working days of identification of the protocol deviation, or within 7-
14 working days of the scheduled protocol-required activity. All deviations must be addressed in 
study source documents and reported the sponsor. Protocol deviations must be sent to the local 
IRB per their guidelines. The site PI/study staff is responsible for knowing and adhering to their 
IRB requirements.  
 
 
The sponsor plans to make the dataset generated by this research available to other 
investigators in the field. To that end, the sponsor will make the data available through the NHLBI 
data repository managed by BioLINCC, within 2 years of the end of the clinical activities and the 
publication of the main findings. The sponsor will also provide full description of variable 
definitions, format, forms used in data collection as well as study procedures and protocols. A 
summary documentation file, providing a brief description of the study’s general orientation, its 
components, and its examination and follow-up timeline, will also be made available in appropriate 
format in order to facilitate the use of these data by other researchers and institutions.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13.2 
STUDY RECORDS RETENTION 
13.3 
PROTOCOL DEVIATIONS 
13.4 
PUBLICATION AND DATA SHARING POLICY 

CRT-P vs. CRT-D 
Protocol A 
Version v.0.6 
         24 MAY 2018 
PROTOCOL SUMMARY 
 
18 
 
 
1. 
McKee PA, Castelli WP, McNamara PM, Kannel WB: The natural history of congestive heart 
failure: The Framingham Study. N Engl J Med 1971;285:1441-1446. 
2. 
Bart BA, Shaw LK, McCants CB, Fortin DF, Lee KL, Califf RM, O'Connor CM: Clinical 
determinants of mortality in patients with angiographically diagnosed ischemic or nonischemic 
cardiomyopathy. J Am Coll Cardiol 1997;30:1002-1008. 
3. 
Ho KL, Pinsky JL, Kannel WB, Levy D: The epidemiology of heart failure: The Framingham 
Study. J Am Coll Cardiol 1993;22:6A-13A. 
4. 
Schocken DD, Arrieta MI, Leaverton PE, Ross EA: Prevalence and mortality rate of 
congestive heart failure in the United States. J Am Coll Cardiol 1992;20:301-306.  
5. 
Zannad F, Briancon S, Juiiliere Y, Mertes PM, Villemot JP, Alla F, Virion JM, and the 
EPICAL investigators: Incidence, clinical and etiologic features, and outcomes of advanced chronic 
heart failure: The EPICAL study. J Am Coll Cardiol 1999;33:734-742. 
6. 
Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA 3rd, Freedman RA, Gettes LS, Gillinov 
AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, 
Silka MJ, Stevenson LW, Sweeney MO, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Buller 
CE, Creager MA, Ettinger SM, Faxon DP, Halperin JL, Hiratzka LF, Hunt SA, Krumholz HM, 
Kushner FG, Lytle BW, Nishimura RA, Ornato JP, Page RL, Riegel B, Tarkington LG, Yancy CW; 
American College of Cardiology/American Heart Association Task Force on Practice Guidelines 
(Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of 
Cardiac Pacemakers and Antiarrhythmia Devices); American Association for Thoracic Surgery; 
Society of Thoracic Surgeons. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of 
Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart 
Association Task Force on Practice Guidelines (Writing Committee to Revise the 
ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and 
Antiarrhythmia Devices): developed in collaboration with the American Association for Thoracic 
Surgery and Society of Thoracic Surgeons. Circulation. 2008;117:e350-408.  
 
7. 
Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, Garrigue S, Kappenberger 
L, Haywood GA, Santini M, Bailleul C, Mabo P, Lazarus A, Ritter P, Levy T, McKenna W, 
Daubert JC. Effects of Multisite Biventricular Pacing in Patients with Heart Failure and 
Intraventricular Conduction Delay. N Engl J Med 2001;344:873-880. 
8. 
Linde C, Leclercq C, Rex S, Garrigue S, Lavergne T, Cazeau S, McKenna W, Fitzgerald M, 
Deharo JC, Alonso C, Walker S, Braunschweig F, Bailleul C, Daubert JC. Long-terra benefits of 
biventricular pacing in congestive heart failure: results from the MUltisite STimulation in 
cardiomyopathy (MUSTIC) study. J Am Coll Cardiol 2002;40:111-118. 
9. 
Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, 
DeMets D, White BG, DeVries DW, Feldman AM. Cardiac resynchronization therapy with or 
without an Implantable defibrillator in advanced chronic heart failure. N Engl J Med 
2004;350:2140-2150. 
10. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L; 
Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators. The effect of cardiac 
resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352:1539-1549. 
11.  Higgins SL, Yong P, Sheck D, McDaniel M, Bollinger F, Vadecha M, Desai S, Meyer DB. 
Biventricular pacing diminishes the need for implantable cardioverter defibrillator therapy: Ventak 
CHF Investigators. J Am Coll Cardiol 2000;36:824-827. 
12. Goldenberg I, Gillespie J, Moss AJ, Hall WJ, Klein H, McNitt S, Brown MW, Cygankiewicz 
I, Zareba W; Executive Committee of the Multicenter Automatic Defibrillator Implantation Trial II. 
Long-term benefit of primary prevention with an implantable cardioverter-defibrillator: an extended 
14 
LITERATURE REFERENCES 

CRT-P vs. CRT-D 
Protocol A 
Version v.0.6 
         24 MAY 2018 
PROTOCOL SUMMARY 
 
19 
 
8-year follow-up study of the Multicenter Automatic Defibrillator Implantation Trial II. Circulation. 
2010 Sep 28;122:1265-1271.  
13. Moss, AJ, Zareba, W, Hall, WJ, et al. Prophylactic implantation of a defibrillator in patients 
with myocardial infarction and reduced ejection fraction. N Engl J Med 2002; 346:877.  
14. Bardy, GH, Lee, KL, Mark, DB, et al. Amiodarone or an implantable cardioverter-defibrillator 
for congestive heart failure. N Engl J Med 2005; 352:225.  
15. Daubert JP, Zareba W, Cannom DS, McNitt S, Rosero SZ, Wang P, Schuger C, Steinberg JS, 
Higgins SL, Wilber DJ, Klein H, Andrews ML, Hall WJ, Moss AJ; MADIT II Investigators. 
Inappropriate implantable cardioverter-defibrillator shocks in MADIT II: frequency, mechanisms, 
predictors, and survival impact. J Am Coll Cardiol. 2008;51:1357-1365.  
16. Poole JE, Gleva MJ, Mela T, Chung MK, Uslan DZ, Borge R, Gottipaty V, Shinn T, Dan D, 
Feldman LA, Seide H, Winston SA, Gallagher JJ, Langberg JJ, Mitchell K, Holcomb R; REPLACE 
Registry Investigators. Complication rates associated with pacemaker or implantable cardioverter-
defibrillator generator replacements and upgrade procedures: results from the REPLACE registry. 
Circulation. 2010;122:1553-1561. 
17. Liu J, Brumberg G, Rattan R, Jain S, Saba S. Class I recall of defibrillator leads: a comparison 
of the Sprint Fidelis and Riata families. Heart Rhythm. 2012;9:1251-1255. 
18. Bureau. USC. The older population: 2010. 2011 
19. Epstein AE, Kay GN, Plumb VJ, McElderry HT, Doppalapudi H, Yamada T, Shafiroff J, Syed 
ZA, Shkurovich S; ACT Investigators. Implantable cardioverter-defibrillator prescription in the 
elderly. Heart Rhythm. 2009;6:1136-43.  
20. Pellegrini CN, Lee K, Olgin JE, Turakhia MP, Tseng ZH, Lee R, Badhwar N, Lee B, Varosy 
PD. Impact of advanced age on survival in patients with implantable cardioverter defibrillators. 
Europace. 2008;10:1296-1301. 
21. Mezu U, Adelstein E, Jain S, Saba S. Effectiveness of implantable defibrillators in 
octogenarians and nonagenarians for primary prevention of sudden cardiac death. Am J Cardiol. 
2011;108:718-722. 
22. Yung D, Birnie D, Dorian P, Healey JS, Simpson CS, Crystal E, Krahn AD, Khaykin Y, 
Cameron D, Chen Z, Lee DS. Survival after implantable cardioverter-defibrillator implantation in 
the elderly. Circulation. 2013;127:2383-2392. 
23. Heidenreich PA, Tsai V. Is anyone too old for an implantable cardioverter-defibrillator? Circ 
Cardiovasc Qual Outcomes. 2009;2:6-8.  
24. Healey JS, Hallstrom AP, Kuck KH, Nair G, Schron EP, Roberts RS, Morillo CA, Connolly 
SJ. Role of the implantable defibrillator among elderly patients with a history of life-threatening 
ventricular arrhythmias. Eur Heart J. 2007;28:1746-1749. 
25. Saba S, Adelstein E, Wold N, Jones P. Differences in Mortality and Risk of Shocks from ICD 
and CRT-D Devices According to Patient Age at Implant. Heart Rhythm Society Scientific Sessions 
2015, Boston , MA [Abstract] 
26. Efficacy of Implantable Defibrillator Therapy After a Myocardial Infarction (REFINE-ICD). 
http://clinicaltrials.gov/ct2/show/NCT00673842. 
27. Lam SKH, Tse HF, Lau CP. CRT Begets CRT-D: Is One Better Than the Other? J Cardiovasc 
Electrophysiol. 2008;19:1266-1269.  
28. Decision Memo for Implantable Cardioverter Defibrillators (ICDs) (CAG-00157N). 
http://www.cms.gov/medicare-coverage-database/details/nca-decision-
memo.aspx?NCAId=39&fromdb=true 
29. M.E. Charlson, P. Pompei, K.L. Ales, C.R. MacKenzie. A new method of classifying 
prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 
1987;40:373–383. 

CRT-P vs. CRT-D 
Protocol A 
Version v.0.6 
         24 MAY 2018 
PROTOCOL SUMMARY 
 
20 
 
30. Munir MB, Althouse AD, Rijal S, Shah MB, Daya HA, Adelstein E, Saba S. Clinical 
Characteristics and Outcomes of Older Cardiac Resynchronization Therapy Recipients Using a 
Pacemaker Versus a Defibrillator. J Cardiovasc Electrophysiol. 2016 [Epub ahead of print] 
31. Adelstein E, Althouse A, Jain S, Schwartzman D, Saba S. Clinical Outcomes in Cardiac 
Resynchronization Therapy-Defibrillator Recipients 80 Years of Age and Older. Europace 2015 (in 
press) 
32. O’Connor AM. Validation of a decisional conflict scale. Med Decis Making. 1995;15:25-30. 
33. https://decisionaid.ohri.ca/eval_dcs.html 
34. Holmes-Rovner M, Kroll J, Schmitt N, Rovner DR, Breer L, Rothert ML, Padonu G, 
Talarczyk G. Patient satisfaction with health care decisions: the satisfaction with decision scale. 
Med Dec Making. 1996;16:56-64. 
35. Hays, R.D., Prince-Embury, S., & Chen, H. (1998). RAND-36 Health Status Inventory. San 
Antonio, TX: The Psychological Corporation.  
36. Rector TS, Cohn JN. Assessment of Patient Outcome with the Minnesota Living with Heart 
failure Questionnaire: Reliability and validity during a randomized, double-blind, placebo-
controlled trial of pimobendan. Am Heart J. 1992;124:1017-1025. 
37. http://www.deathindexes.com/ssdi.html 
38. Heidenreich PA, Tsai V, Bao H, Curtis J, Goldstein M, Curtis L, Hernandez A, Peterson P, 
Turakhia MP, Masoudi FA. Does Age Influence Cardiac Resynchronization Therapy Use and 
Outcome? JACC Hear Fail. 2015;3:497–504. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CRT-P vs. CRT-D 
Protocol A 
Version v.0.6 
         24 MAY 2018 
PROTOCOL SUMMARY 
 
21 
 
 
 
 
 
RAND-36 HEALTH STATUS INVENTORY 
This section includes a wide variety of questions about your health and your life.  We are interested 
in how you feel about each of these issues. 
1. In general, would you say your health is: [Mark an 
 in the one box that best describes your 
answer.] 
 Excellent 
 Very good 
 Good 
 Fair 
 Poor 
2. Compared to one year ago, how would you rate your health in general now? 
 Much better now than one year ago 
 Somewhat better now than one year ago 
 About the same as one year ago 
 Somewhat worse now than one year ago  
 Much worse now than one year ago 
The following items are about activities you might do during a typical day.  Does your health now 
limit you in these activities?  If so, how much?  [Mark an 
 in a box on each line.] 
 
Yes, 
limited 
 a lot 
Yes, limited 
 a little 
No, not 
limited  
at all 
3. Vigorous activities, such as running, lifting 
heavy objects, participating in strenuous sports. 
 
 
 
4. Moderate activities, such as moving a table, 
pushing a vacuum cleaner, bowling, or playing 
golf. 
 
 
 
5. Lifting or carrying groceries. 
 
 
 
6. Climbing several flights of stairs. 
 
 
 
7. Climbing one flight of stairs. 
 
 
 
8. Bending, kneeling, or stooping. 
 
 
 
9. Walking more than a mile. 
 
 
 
10. 
Walking several blocks. 
 
 
 
11. 
Walking one block. 
 
 
 
12. 
Bathing or dressing yourself. 
 
 
 
During the past 4 weeks, have you had any of the following problems with your work or other regular 
daily activities as a result of your physical health? 
 
YES 
NO 
13. Cut down the amount of time you spent on work or other 
activities. 
 
 
14. Accomplished less than you would like. 
 
 
15. Were limited in the kind of work or other activities. 
 
 
16. Had difficulty performing the work or other activities (for 
 
 
APPENDIX 1 

CRT-P vs. CRT-D 
Protocol A 
Version v.0.6 
         24 MAY 2018 
PROTOCOL SUMMARY 
 
22 
 
example, it took extra effort) 
 
During the past 4 weeks, have you had any of the following problems with your work or other 
regular daily activities as a result of any emotional problems (such as feeling depressed or 
anxious)? 
 
YES 
NO 
17. 
Cut down the amount of time you spent on work or other 
activities. 
 
 
18. 
Accomplished less than you would like. 
 
 
19. 
Didn’t do work or other activities as carefully as usual. 
 
 
 
20. During the past 4 weeks, to what extent has your physical health or emotional problems 
interfered with your normal social activities with family, friends, neighbors, or groups? 
 Not at all 
 Slightly 
 Moderately 
 Quite a bit 
 Extremely 
21. How much bodily pain have you had during the past 4 weeks? 
 None 
 Very mild 
 Mild 
 Moderate 
 Severe 
 
 
 Very severe 
 
22. During the past 4 weeks, how much did pain interfere with your normal work (including both 
work outside the home and housework)? 
 Not at all 
 Slightly 
 Moderately 
 Quite a bit 
 Extremely 
These questions are about how you feel and how things have been with you during the past 4 
weeks.  For each question, please give the one answer that comes closest to the way you have 
been feeling.  How much of the time during the past 4 weeks… 
 
All of the 
time 
Most of 
the time 
A good 
bit of the 
time 
Some of 
the time 
A little of 
the time 
None of 
the time 
23. Did you feel full of 
pep? 
 
 
 
 
 
 
24. Have you been a very 
nervous person? 
 
 
 
 
 
 

CRT-P vs. CRT-D 
Protocol A 
Version v.0.6 
         24 MAY 2018 
PROTOCOL SUMMARY 
 
23 
 
25. Have you felt so down 
in the dumps that 
nothing could cheer 
you up? 
 
 
 
 
 
 
26. Have you felt calm 
and peaceful? 
 
 
 
 
 
 
27. Did you have a lot of 
energy? 
 
 
 
 
 
 
28. Have you felt 
downhearted and 
blue? 
 
 
 
 
 
 
29. Did you feel worn out? 
 
 
 
 
 
 
30. Have you been a 
happy person? 
 
 
 
 
 
 
31. Did you feel tired? 
 
 
 
 
 
 
 
32.  During the past 4 weeks, how much of the time has your physical health or emotional 
problems interfered with your social activities (like visiting with friends, relatives, etc.)? 
 All of the time 
 Most of the time 
 Some of the time 
 A little of the time 
 None of the time 
  
 
Please choose the answer that best describes how true or false each of the following statements 
is for you. 
 
Definitely 
true 
Mostly  
true 
Don’t 
know 
Mostly 
false 
Definitely 
false 
33. I seem to get sick a little easier 
than other people. 
 
 
 
 
 
34. I am as healthy as anybody I know. 
 
 
 
 
 
35. I expect my health to get worse. 
 
 
 
 
 
36. My health is excellent. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CRT-P vs. CRT-D 
Protocol A 
Version v.0.6 
         24 MAY 2018 
PROTOCOL SUMMARY 
 
24 
 
 
MINNESOTA LIVING WITH HEART FAILURE QUESTIONNAIRE 
 
The following questions ask how much your heart failure (heart condition) affected your life 
during the past month (4 weeks).  After each question, circle the 0, 1, 2, 3, 4 or 5 to show 
how much your life was affected.  If a question does not apply to you, circle the 0 after that 
question. 
 
Did your heart failure prevent 
you from living as you wanted during 
 
 Very 
 Very 
the past month (4 weeks) by -  
No  
Little  
Much  
 
1. causing swelling in your ankles or legs? 
0 
1 
2 
3 
4 
5 
2. making you sit or lie down to rest during 
the day? 
0 
1 
2 
3 
4 
5 
3. making your walking about or climbing 
stairs difficult? 
0 
1 
2 
3 
4 
5 
4. making your working around the house 
or yard difficult? 
0 
1 
2 
3 
4 
5 
5. making your going places away from 
home difficult? 
0 
1 
2 
3 
4 
5 
6. making your sleeping well at night 
difficult? 
0 
1 
2 
3 
4 
5 
7. making your relating to or doing things 
with your friends or family difficult? 
0 
1 
2 
3 
4 
5 
8. making your working to earn a living 
difficult? 
0 
1 
2 
3 
4 
5 
9. making your recreational pastimes, sports 
or hobbies difficult? 
0 
1 
2 
3 
4 
5 
10. making your sexual activities difficult? 
0 
1 
2 
3 
4 
5 
11. making you eat less of the foods you 
like? 
0 
1 
2 
3 
4 
5 
12. making you short of breath? 
0 
1 
2 
3 
4 
5 
13. making you tired, fatigued, or low on 
energy? 
0 
1 
2 
3 
4 
5 
14. making you stay in a hospital? 
0 
1 
2 
3 
4 
5 
15. costing you money for medical care? 
0 
1 
2 
3 
4 
5 
16. giving you side effects from treatments? 
0 
1 
2 
3 
4 
5 
17. making you feel you are a burden to your 
family or friends? 
0 
1 
2 
3 
4 
5 
18. making you feel a loss of self-control 
in your life? 
0 
1 
2 
3 
4 
5 
19. making you worry? 
0 
1 
2 
3 
4 
5 
20. making it difficult for you to concentrate 
or remember things? 
0 
1 
2 
3 
4 
5 
21. making you feel depressed? 
0 
1 
2 
3 
4 
5 
 
APPENDIX 2 

CRT-P vs. CRT-D 
Protocol A 
Version v.0.6 
         24 MAY 2018 
PROTOCOL SUMMARY 
 
25 
 
 
THE SATISFACTION WITH DECISION SCALE 
 
Strongly 
Disagree 
 
 
[1] 
Disagree 
 
 
 
[2] 
Neither 
Agree 
nor 
Disagree 
[3] 
Agree 
 
 
 
[4] 
Strongly 
Agree 
 
 
[5] 
I am satisfied that I am adequately informed 
about the issues important to my decision 
□ 
□ 
□ 
□ 
□ 
The decision I made was the best decision 
possible for me personally 
□ 
□ 
□ 
□ 
□ 
I am satisfied that my decision was 
consistent with my personal values 
□ 
□ 
□ 
□ 
□ 
I expect to successfully carry out (or 
continue to carry out) the decision I made 
□ 
□ 
□ 
□ 
□ 
I am satisfied that this was my decision to 
make 
□ 
□ 
□ 
□ 
□ 
I am satisfied with my decision 
 
□ 
□ 
□ 
□ 
□ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX 3