Electrocardiogram for Programming in Cardiac Resynchronization Therapy
Phase: NA
Conditions: Systolic Heart Failure, Cardiac Resynchronization Therapy, Electrocardiography
Sponsor: Washington University School of Medicine

 
 
 
 
 
 
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1 
 
Title: Electrocardiogram for Programming in Cardiac Resynchronization Therapy 
Trial 
 
NCT #: NCT03936608 
 
Date: 2/13/2019 
 
 
 

 
 
 
 
 
 
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2 
 
 
Electrocardiography for Programming In Cardiac 
Resynchronization Therapy (EPIC) Trial 
 
 
Principal Investigator: Amit Noheria, MBBS, SM 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version Date/Number: 2/13/2019; 1.2 
 
CONFIDENTIAL: This document is the intellectual property of Amit Noheria, MD.  Acceptance of 
this document constitutes the agreement by the recipient that no unpublished information 
contained herein will be published or disclosed without prior written approval. 
 
 

 
 
 
 
 
 
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3 
TABLE OF CONTENTS 
 
A 
INTRODUCTION ..................................................................................................... 4 
A1 
STUDY ABSTRACT............................................................................................... 4 
A2 
PRIMARY HYPOTHESIS ........................................................................................ 5 
A3 
PURPOSE OF THE STUDY PROTOCOL ................................................................... 5 
B 
BACKGROUND ....................................................................................................... 5 
B1 
PRIOR LITERATURE AND STUDIES ........................................................................ 5 
B2 
RATIONALE FOR THIS STUDY ............................................................................... 7 
C 
STUDY OBJECTIVES ............................................................................................. 8 
C1 
SPECIFIC AIM #1................................................................................................. 8 
C2 
RATIONALE FOR THE SELECTION OF OUTCOME MEASURES ................................... 8 
D 
STUDY DESIGN ...................................................................................................... 9 
D1 
OVERVIEW OR DESIGN SUMMARY ........................................................................ 9 
D2 
SUBJECT SELECTION AND WITHDRAWAL ............................................................ 10 
2.a 
Inclusion Criteria ...................................................................................................... 10 
2.b 
Exclusion Criteria..................................................................................................... 10 
2.c 
Ethical Considerations ............................................................................................ 10 
2.d 
Subject Recruitment Plans and Consent Process ............................................. 10 
2.e 
Randomization Method and Blinding ................................................................... 10 
2.f 
Risks and Benefits................................................................................................... 11 
2.g 
Early Withdrawal of Subjects ................................................................................. 11 
2.h 
When and How to Withdraw Subjects .................................................................. 11 
2.i 
Data Collection and Follow-up for Withdrawn Subjects .................................... 12 
E 
STUDY PROCEDURES ......................................................................................... 12 
E1 
SCREENING FOR ELIGIBILITY ............................................................................. 12 
E2 
SCHEDULE OF MEASUREMENTS ......................................................................... 12 
E3 
SAFETY AND ADVERSE EVENTS ......................................................................... 12 
3.a 
Safety and Compliance, and Medical Monitoring ............................................... 12 
i 
Investigator .................................................................................................. 12 
ii 
Data and Safety Monitoring Committee ....................................................... 13 
E4 
STUDY OUTCOME MEASUREMENTS AND ASCERTAINMENT ................................... 13 
F 
STATISTICAL PLAN ............................................................................................. 13 
F1 
SAMPLE SIZE DETERMINATION AND POWER ....................................................... 13 
F2 
STATISTICAL METHODS ..................................................................................... 13 

 
 
 
 
 
 
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4 
G 
DATA HANDLING AND RECORD KEEPING ....................................................... 14 
G1 
CONFIDENTIALITY AND SECURITY....................................................................... 14 
G2 
RECORDS RETENTION....................................................................................... 14 
H 
STUDY MONITORING, AUDITING, AND INSPECTING ....................................... 15 
H1 STUDY MONITORING PLAN .................................................................................... 15 
I 
STUDY ADMINISTRATION ................................................................................... 15 
I1 
ORGANIZATION AND PARTICIPATING CENTERS ....................................................... 15 
I2 
FUNDING SOURCE AND CONFLICTS OF INTEREST ................................................... 15 
I3 
SUBJECT STIPENDS OR PAYMENTS ....................................................................... 15 
I4 
STUDY TIMETABLE ............................................................................................... 15 
J 
PUBLICATION PLAN ............................................................................................ 16 
K 
ATTACHMENTS .................................................................................................... 16 
K1 
INFORMED CONSENT DOCUMENTS ..................................................................... 16 
K2 
KCCQ-12 QUALITY-OF-LIFE QUESTIONNAIRE ...................................................... 16 
M 
REFERENCES ...................................................................................................... 16 
 
 
 

 
 
 
 
 
 
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5 
 
Protocol Revision History 
 
 
Initial Approval Version 
 
Protocol v1.0 
 
XX/XX/XXXX 
 
 

 
 
 
 
 
 
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6 
 
Electrocardiography for Programming In Cardiac Resynchronization 
Therapy (EPIC) Trial 
 
 
Principal Investigator’s Signature Page 
 
 
The study will be conducted in accordance with the International Conference on Harmonisation 
guidelines for Good Clinical Practice (ICH E6), the Code of Federal Regulations on the Protection 
of Human Subjects (45 CFR Part 46), and the NIDCR Clinical Terms of Award. All personnel 
involved in the conduct of this study have completed human subject’s protection training. 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
 
 
Signed: 
 
Date: 
 
 
Name: Amit Noheria, MD 
 
Title: 
Principal Investigator 
 
 
 
 

 
 
 
 
 
 
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7 
A Introduction 
A1 Study Abstract 
Heart failure with reduced ejection fraction is a major global health problem. Every year, over 
200,000 patients with heart failure receive pacing device implants for cardiac resynchronization 
therapy (CRT). However, one-third of the patients receiving CRT do not derive any benefit, a large 
population with refractory heart failure symptoms, high mortality, and tremendous healthcare 
costs. Our overall objective is to reduce heart failure by physiological individualized optimization 
of CRT pacing therapy guided by 12-lead electrocardiography (ECG).  
Patients with heart failure and left bundle branch block benefit from CRT. This delivers pacing 
from right ventricle (RV) and left ventricle (LV) synchronously, the resultant ventricular electical 
resynchrony leading to improved cardiac mechanics and acute hemodynamics, and subsequent 
reverse structural cardiac remodeling. This leads to reduced heart failure symptoms, 
hospitalizations and death. It is not known if programming an individually optimized RV-LV pacing 
offset to maximize electrical resynchrony can improve benefit from CRT.  
The proposed study is a randomized controlled trial in patients undergoing implant of a CRT 
pacemaker/defibrillator device for clinical indications to evaluate benefit of RV-LV offset 
programming using ECG vs. standard nominal CRT programming without RV-LV offset. Patients 
receiving CRT devices will be randomized to either (A) active intervention of programming 
individualized RV-LV pacing offset to optimize ECG or to (B) active control of nominally 
programming CRT device without RV-LV offset. The patients will be followed to evaluate changes 
in heart failure endpoints including echocardiography, quality-of-life, functional performance and 
a blood biomarker. 
A2 Primary Hypothesis 
Among patients receiving CRT, individualized RV-LV offset programming using ECG will result in 
improvement of heart failure endpoints. 
A3 Purpose of the Study Protocol 
The results of this study will provide key mechanistic insights on the salutary effects of CRT on 
reverse cardiac remodeling. Physiologically-tailored individually-optimized CRT therapy would 
improve individual patient health by improving heart failure outcomes, and decrease the economic 
burden of refractory heart failure. 
 
B Background 
B1 Prior Literature and Studies 
CRT can be lifesaving for heart failure patients with left bundle branch block (LBBB) and delayed 
electrical activation of the LV lateral wall. A pacing device is used to resynchronize the LV with 
electrical stimulation from implanted electrodes in the RV and in a LV coronary vein.1-3 CRT results 
in improved hemodynamics, beneficial reverse cardiac remodeling, and reduction in adverse 
outcomes like heart failure hospitalizations and death.4-10 Every year, over 200,000 CRT 
procedures are performed in heart failure patients worldwide.11 However, one-third of CRT 
patients fail to show a clinical response to CRT with a large implication for the quality and quantity 
of life, and economic healthcare burden.6-10,12 Non-response to CRT can be attributed to factors 

 
 
 
 
 
 
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like irreversible scarring of the heart muscle, absence of sufficient baseline electrical 
dyssynchrony that is amenable to CRT, suboptimal pacing electrode location, non-adherence to 
heart failure medications, competing cardiac arrhythmias limiting CRT delivery, and importantly, 
suboptimal CRT delivery due to non-individually optimized programming of the device.13-15 
Optimizing RV-LV offset: Previous techniques have been evaluated to individually program RV-
LV offset to acutely optimize cardiac mechanics and hemodynamic performance with variable 
results. These methods included transthoracic echocardiography,16-18 gated SPECT perfusion 
imaging,19 
invasive 
hemodynamic 
measurements,20,21 
non-invasive 
digital 
photoplethysmography,22 and pacemaker lead sensors to measure peak endocardial 
acceleration.23,24 However, these techniques have failed on account of being cumbersome, non-
standardized, lacking reproducibility, and failure to show improvement in clinical outcomes. 
Echocardiography to prospectively guide RV-LV offset optimization has not been demonstrated 
to be superior to simultaneous biventricular pacing without RV-LV offset.25,26 The aforementioned 
techniques for RV-LV offset optimization focus on acute mechanical and hemodynamic effects, 
without any evaluation of the resulting electrical resynchrony. The disappointing results have led 
experts to surmise that “an electrical problem requires an electrical solution”.27 We hypothesize 
that the salutary long-term effects of CRT are dependent on its impact on electrical rather than 
mechanical function. 
Commercial device algorithms for RV-LV offset: Some device manufacturers have proprietary 
algorithms that use the RV-LV activation delay to make a recommendation for RV-LV offset 
programming.28-30 An adaptive algorithm for fusion of intrinsic right bundle branch conduction with 
LV only pacing has also been developed.31,32 These algorithms are based on relative local 
activation differences at the RV and LV pacing electrodes, and fail to incorporate activation of 
bulk of the heart muscle. Further limitations include inability to use thse algorithms in setting of 
atrioventricular block or atrial fibrillation, and lack of validation to assess impact on clinical 
outcomes. 
ECG for optimizing RV-LV offset: 12-lead ECG is a readily available tool to evaluate the electrical 
activation of the heart and has been retrospectively used to evaluate CRT in many studies (Table 
1). It is, however, unclear whether the absence of ECG markers that predict a good response to 
CRT in an individual patient is due to remediable RV-LV offset programming, or is a result of non-
programmable factors like electrode location and scarring of heart muscle; and how many patients 
will convert to a favorable ECG with RV-LV offset optimization.48 
Table 1. Retrospectively using ECG after CRT to correlate with good clinical response.  
QRS duration 
Lead V1 
(or V2) 
Lead I 
(or aVL) 
Frontal plane QRS 
 Shorter QRSd 
(absolute or indexed 
to baseline QRSd); 
QRSd shortening 
≥25 ms33-40 
 QRS normalization34 
 R wave34,37,41,42 
 R/S ≥143 
 R wave amplitude (V1 
or V2)44 
 Shortening of RS 
interval; RS 
shortening ≥10 ms45 
 S wave41 
 R/S ≤143 
 Reversal from 
positive to 
negative (lead I 
& aVL)46 
 Right axis deviation 
(from baseline left 
axis deviation)44 
 Vectorcardiogram 
QRS amplitude half 
way between LBBB 
and LV pacing47 

 
 
 
 
 
 
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ECG has been evaluated prospectively in limited-scope small studies for RV-LV offset 
optimization.18,39 A shorter biventricular paced QRS duration (QRSd) has been associated with 
good CRT response.33-40 However, RV-LV offset programming to minimize the QRSd is not the 
most suitable method for RV-LV offset optimization.39 In a study by Vidal et al., RV-LV offset (-30 
ms, 0, +30 ms) determined by shortest QRSd did not predict acute mechanical left ventricular 
resynchrony on tissue Doppler echocardiography.49 Other “summed” ECG parameters like 3-
dimensional QRS area (voltage-time integral) are conceptually appealing but yet to be evaluated 
prospectively for CRT programming.50,51  
B2 Rationale for this Study 
We propose to study the heart failure effects of ECG-guided RV-LV offset optimization. In a 
randomized controlled trial, we will determine whether such individualized RV-LV offset 
optimization using ECG results in improved reverse cardiac remodeling and other heart failure 
endpoints. 
 
C Study Objectives 
C1 Specific Aim 
To determine the impact of individualized RV-LV pacing offset to optimize ECG on reverse 
cardiac remodeling and other heart failure surrogate endpoints: 
After CRT implant, we will randomize patients to either (A) active intervention of programming 
individualized RV-LV offset to optimize ECG or to (B) active control of nominally programming 
CRT device without RV-LV pacing offset. The primary outcome will be the reverse cardiac 
remodeling after 3-12 months, as assessed by LV end-systolic volume on echocardiography.52 
The secondary outcomes will include quality-of-life (Kansas City Cardiomyopathy Questionnaire-
12, KCCQ-12), functional performance (6-minute hall walk distance) and a prognostic biomarker 
(serum NT-proBNP). 
C2 Rationale for the Selection of Outcome Measures 
The primary outcome is echocardiographic LV end-systolic volume. LV end-systolic volume is a 
reliable surrogate for clinical outcomes in clinical heart failure trials.52 Secondary outcomes 
include quality-of-life (KCCQ-12), functional performance (6-minute hall walk distance) and a 
prognostic biomarker (serum NT-proBNP). KCCQ-12 and 6-minute hall walk are standard metrics 
to assess quality-of-life and functional status in heart failure research.53-55 Serum NT-ProBNP 
strongly predicts improvement in cardiac function and favorable prognosis after CRT.56  
 
D Study Design  
D1 Overview or Design Summary 
Once the eligibility for the study is determined and patient has consented for participation, all 
study participants will undergo a baseline evaluation (within 6 weeks prior to 2 weeks after CRT 
device implant/upgrade). Echocardiogram, quality-of-life questionnaire, 6-minute hall walk, blood 
test, vital signs, ECGs, device interrogation and baseline demographic and medical history 
including chart review will be obtained. After CRT device implant/upgrade, participants will 

 
 
 
 
 
 
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10
undergo physiologic evaluations at various (up to 10 or more) RV-LV offset settings including 
ECGs and echocardiography. A randomized assignment using a random allocation table in 
REDCap will be used to program patients to (A) intervention or (B) control RV-LV offset setting. 
Patients will return for study follow-up between 3-12 months. Follow-up evaluations will include 
echocardiography, quality-of-life questionnaire, 6-minute hall walk test, blood test, vital signs, 
ECGs, device interrogation, and follow-up medical history including chart review. The patients will 
continue to be in extended follow-up through review of their medical charts till the end of the study 
(12 months from date of CRT implant/upgrade of the the last study participant). 
Treatment and control arms: All study patients will receive standard of care clinically indicated 
medical and device therapy per their treating physicians. After implant of a clinically indicated 
CRT device or upgrade of a preexisting pacemaker or defibrillator device to CRT system, 
participants will be randomized 1:1 to treatment arms (A) active intervention of programming 
individualized RV-LV pacing offset to optimize ECG or to (B) active control of nominally 
programming CRT device without RV-LV offset. Of note, both intervention and control treatment 
are active FDA-approved CRT therapies and no investigational device or programming will be 
used, and no clinically indicated treatment will be withheld from any patient. At any time, if in the 
judgment of the patient’s treating physicians or the research team, any treatment including CRT 
programming different from the study protocol is necessitated for clinical reasons, the appropriate 
clinically indicated changes will be made. At the end of the study, if the participant is clinically 
doing well and the programmed CRT settings are deemed clinically appropriate they will be 
retained, else the CRT programming may be changed as per standard of care.  
Enrolled participants who have a failed or unsatisfactory LV lead implant will not be randomized.  
D2 Subject Selection and Withdrawal  
2.a Inclusion Criteria  
1. Patients ≥18 years of age who are able to give consent. 
2. Diagnosis of systolic heart failure.  
3. Planned to undergo new CRT device implant (or upgrade of preexisting pacemaker or 
defibrillator device to CRT system) for standard clinical indications. 
4. Expected to have over 95% heart beats resynchronized with CRT (absence of competing 
arrhythmias or plans to not immediately activate CRT therapy). 
2.b Exclusion Criteria  
1. Unable to comply with the study follow-up. 
2. Life expectancy ≤1 year. 
2.c Ethical Considerations  
This is a patient-oriented research plan to optimize delivery of CRT in humans. Patients with 
heart failure undergoing clinically indicated CRT device implant/upgrade would form the 
study population. Human subjects receiving clinically indicated CRT are needed to evaluate 
the clinical impact of individulzied RV-LV offset programming of CRT.  
2.d Subject Recruitment Plans and Consent Process 
 
Subjects will be enrolled from patients undergoing CRT device implant/upgrade at Barnes-
Jewish Hospital. Patients will provide a signed informed consent prior to participation in the 
study. Enrollment will be voluntary. No children will be enrolled.  
 
Informed consent will be obtained by study personel in person with ample opportunity to ask 
questions, consider options and decline participation. Participants will be educated about 

 
 
 
 
 
 
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11
the rationale of the research, logistics and follow-ups for the study, and risks associated with 
the study. The subjects will sign a Washington University Institutional Review Board 
approved informed consent document prior to being enrolled in the study. Only adult patients 
who are personally able to provide informed consent will be enrolled. If a patient is unable 
to consent, they will not be enrolled.  
 
No special vulnerable populations will be enrolled. 
2.e Randomization Method and Blinding 
A 1:1 randomization scheme using a random allocation table in REDCap will be used. The 
patient and personel assessing study outcomes will be blinded to the randomized 
assignment.  
2.f 
Risks and Benefits 
 
Participation in the research study requires a commitment of time by the participants. Every 
subject will undergo, both at enrollment and at the follow-up visit, evaluations including 
echocardiography, quality-of-life questionnaire, 6-minute hall walk test, blood test, vital 
signs, ECGs, device interrogation, and clinical history including chart review. After CRT 
implant/upgrade, participants will have a physiological assessment of various (up to 10 or 
more) RV-LV offset settings including ECGs and echocardiography. During study related 
CRT device evaluation, there is an extremely small risk of inducing cardiac arrhythmias that 
is similar to the risk entailed in standard routine clinical device interrogations. In the 
improbable event of an unstable cardiac arrhythmia, the patient will be immediately 
cardioverted using the implanted pacemaker/defibrillator or using an external defibrillator. A 
trained clinical electrophysiologist will be present in person during all study related 
interrogation and programming of CRT device.  
 
The alternative for human subjects to research participation is to not enroll for the study and 
undergo standard care with RV-LV offset programming at the discretion of the treating 
physician. The research question is a state of equipoise where it is not clear whether RV-
LV pacing offset optimization using ECG is superior to nominally programming CRT device 
without any RV-LV offset. It is the intention of this research to investigate if there is any 
additional CRT benefit with individualized optimization of RV-LV offset.  
 
Potential benefits of the research to participants include close follow-up required for the trial 
post CRT system implant. Potential benefit of this research to other CRT recipients would 
be determination of individualized optimal RV-LV offset programming for maximizing CRT 
benefit and alleviation of heart failure.  
 
This outcome of this research will impact >200,000 heart failure patients who receive CRT 
every year, with more individually optimized delivery of CRT.11 This will be especially 
impactful for the large group of patients with refractory heart failure who currently derive no 
benefit from CRT. Improvement in CRT response would ultimately impact individual patient 
health by improving heart failure outcomes and reduce the economic burden on healthcare 
systems.12 
2.g Early Withdrawal of Subjects  
 
The participants may withdraw by telling the study team they are no longer interested in 
participating in the study or by sending in a withdrawal letter.  
 
The investigator might end a subject’s participation in this research study earlier than 
planned. This may happen for no reason, because in the treating physician or study team’s 
judgment it would not be beneficial for the participant to continue, because the participant’s 
condition has become worse, or because the research has ended. 

 
 
 
 
 
 
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2.h When and How to Withdraw Subjects  
Subjects can be withdrawn from the study at any time by communicating directly to the study 
team or sending a withdrawl letter.  
2.i 
Data Collection and Follow-up for Withdrawn Subjects  
All data collection and follow-up for the purposes of the study will be terminated for subjects 
withdrawn from the study. At the time of withdrawal, if the participant is clinically doing well 
and the programmed CRT settings are deemed clinically appropriate they will be retained, 
else the CRT programming may be changed as per standard of care. 
 
E Study Procedures  
E1 Screening for Eligibility 
Patients for this study will be screened and approached for participation prior to or after a clinical 
CRT implant/upgrade procedure at Barnes-Jewish Hospital Clinical. 
E2 Schedule of Measurements 
The baseline evaluation will encompass one, two or more visits in the time window 6 weeks prior 
to 2 weeks after CRT device implant/upgrade date. If the patient passes the eligibility screening 
and signs informed consent, their baseline evaluation will include echocardiogram, quality-of-life 
questionnaire, 6-minute hall walk, blood test, vital signs, ECGs, device interrogation and baseline 
demographic and medical history including chart review. After CRT device implant, participants 
will undergo physiologic evaluations at various (up to 10 or more) RV-LV offset settings including 
ECGs and echocardiography. The randomized CRT pacing assignment will be programmed. 
The follow-up evaluation (usually 3-12 months) will encompass one or more visits and include 
echocardiography, quality-of-life questionnaire, 6-minute hall walk test, blood test, vital signs, 
ECGs, device interrogation, and follow-up medical history including chart review. The patients will 
continue to be in extended follow-up through review of their medical charts till the end of the study 
(12 months from date of CRT implant/upgrade of the the last study participant). 
 
Table 2.  
EPIC Study Calendar 
Baseline 
Evaluation 
CRT 
Evaluation  
Follow-up 
Evaluation 
Extended 
Follow-up 
Timeline (w.r.t. date of CRT 
device implant/upgrade) 
-6 to +2 
weeks 
0 to +2 
weeks 
3 to 12 
months 
Till study 
completion 
Informed Consent 
 
 
 
 
Medical History 
 
 
 
 
Vital Signs 
 
 
 
 

 
 
 
 
 
 
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Echocardiogram 
 
 
 
 
KCCQ-12 
 
 
 
 
6-Minute Hall Walk 
 
 
 
 
Blood Testing 
 
 
 
 
Device Interrogation 
 
 
 
 
12-lead ECGs 
 
 
 
 
Randomization 
 
 
 
 
Adverse Event Monitoring 
 
 
 
 
 
E3 Safety and Adverse Events  
3.a 
Adverse Events and Reporting Requirements 
Any adverse or significant events including heart failure hospitalizations, incident arrhythmias, 
complications and deaths will be tracked during the study participation (i.e. from time of consent 
through completion of the study).  A baseline evaluation of all subjects’ current medical problems 
will be documented and evaluated using the reporting classifications below prior to any baseline 
procedures.  Any exacerbation of these medical problems will be documented as an adverse 
event.  All adverse events will be tracked from time of consent through completion of the study. 
i 
Adverse Event Definitions 
Term 
Definition 
Adverse Event (AE) 
An unfavorable medical occurrence in a human subject 
including any abnormal sign, symptom, or disease. 
Serious Adverse Event 
(SAE) 
An adverse experience occurring that results in any of the 
following outcomes: 
a. Death 
b. A life-threatening adverse experience 
c. Inpatient hospitalization or prolongation of existing 
hospitalization 
d. A persistent or significant disability/incapacity (i.e. a 
substantial disruption of a person’s ability to conduct 
normal life functions) 
e. A congenital anomaly/birth defect 
f. Any other experience which, based upon appropriate 
medical judgment, may jeopardize the subject and may 
require medical or surgical intervention to prevent one of 
the outcomes listed above 

 
 
 
 
 
 
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Life-Threatening 
An adverse experience that places the subject (in the view of 
the investigator) at immediate risk of death from the reaction as 
it occurred, i.e. it does not include a reaction that, had I 
occurred in a more severe form, might have caused death. 
ii 
Attribution, Anticipation, and Expectedness of AEs 
The terms for attribution, expectedness, and severity are defined as follows: 
1) Attribution 
Classification 
Description 
Definitely Related 
The adverse event, incident, experience or outcome was 
definitely caused by the procedures involved in the research. 
Probably Related 
There is a reasonable probability that the adverse event, 
incident, experience or outcome may have been caused by the 
procedures involved in the research. 
Possibly Related  
There is a reasonable possibility that the adverse event, 
incident, experience or outcome may have been caused by the 
procedures involved in the research. 
Unlikely Related 
The adverse event, incident, experience or outcome was 
unlikely caused by the procedures involved in the research. 
Unrelated 
The adverse event, incident, experience or outcome was 
unrelated to the procedures involved in the research. 
2) Anticipation 
Classification 
Description 
Anticipated 
Any incident, experience, or outcome that is anticipated to 
occur due to the research (i.e. procedures, investigational 
medication, etc.). 
Unanticipated 
Any incident, experience, or outcome that meets all of the 
following criteria: 
a. unexpected (in terms of nature, severity, or frequency) 
given (a) the research procedures that are described in 
the protocol-related documents, such as the IRB-
approved research protocol and informed consent 
document; and (b) the characteristics of the subject 
population being studied; 
b. related or possibly related to a subject’s participation in 
the research; and 

 
 
 
 
 
 
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15
c. suggests that the research places subjects or others at 
a greater risk of harm (including physical, 
psychological, economic, or social harm) related to the 
research than was previously known or recognized. 
3) Expectedness 
Classification 
Description 
Expected 
Any adverse event that is a known or foreseeable risk 
associated with the procedures involved in the research or is 
an expected natural progression of any underlying disease, 
disorder, or condition. 
Unexpected 
Any adverse event occurring in one or more subjects in a 
research protocol, the nature, severity, or frequency of which is 
not consistent with either: 
a. the known or foreseeable risk of adverse events 
associated with the procedures involved in the research 
that are described in (a) the protocol–related 
documents, such as the IRB-approved research 
protocol, any applicable investigator brochure, and the 
current IRB-approved informed consent document, and 
(b) other relevant sources of information, such as 
product labeling and package inserts; or 
b. the expected natural progression of any underlying 
disease, disorder, or condition of the subject(s) 
experiencing the adverse event and the subject’s 
predisposing risk factor profile for the adverse event. 
 
iii 
Noncompliance and Exceptions 
Term 
Definition 
Noncompliance 
Failure to follow an applicable regulation or institutional policies 
that govern human subjects research or failure to follow the 
determinations of the IRB.  Noncompliance may occur due to 
lack of knowledge or due to deliberate choice to ignore 
regulations, institutional policies, or determinations of the IRB. 
Serious Noncompliance 
Noncompliance that materially increases risks, that results in 
substantial harm to subjects or others, or that materially 
comprises the rights or welfare of participants. 
Protocol Exceptions 
A planned deviation from the approved protocol that are under 
the research team’s control.  Exceptions apply only to a single 
participant or a singular situation. 

 
 
 
 
 
 
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16
 
Washington University central IRB pre-approval of all protocol 
exceptions must be obtained prior to the event for both the 
coordinating center and all participating sites.  Participating 
sites must also follow their local IRB’s guidelines for any 
submission that needs to be made to their local IRB. 
All incidences of noncompliance and protocol exceptions will be tracked from time of IRB approval 
until the close of the study. 
iv 
Reporting Requirements 
The Washington University Human Research Protection Office (HRPO) requires that all events 
meeting the definition of unanticipated problem or serious noncompliance be reported as outlined. 
The PI is required to promptly notify the IRB of the following events: 
 
Any unanticipated problems involving risks to participants or others which occur at WU or 
any BJH or SLCH institution that impacts participants or the conduct of the study. 
 
Noncompliance with federal regulations or the requirements or determinations of the IRB. 
 
Receipt of new information that may impact the willingness of participants to participate or 
continue participation in the research study 
These events must be reported to the IRB within 10 working days of the occurrence of the event 
or notification to the PI of the event.  The death of a research participant that qualifies as a 
reportable event should be reported within 1 working day of the occurrence of the event or 
notification to the PI of the event. 
3.b 
Safety and Compliance, and Medical Monitoring 
i 
Investigator  
 
In the unlikely event of any acute adverse events during device programming during study 
participation, they will be addressed in person by the investigator and plans communicated 
to the treating team. Any significant adverse events related to the research project will be 
reported to the data safety monitoring committee and the Washington University IRB. The 
above sections describes the plan for data and safety monitoring of the clinical trial and 
adverse event reporting to the IRB, to ensure the safety of subjects. 
 
No investigational treatments will be used for the study. Participants will receive a clinically 
indicated CRT device per routine care. The only treatment intervention is optimization of 
RV-LV offset (programmable setting of CRT system) guided by ECG within parameters 
on CRT devices and programming approved by the FDA. 
ii 
Independent Data and Safety Monitoring Committee 
An independent data and safety monitoring committee (DSMC) chaired by Dr. Edward 
Geltman will be appointed. Dr. Geltman will choose 2 additional members including a 
statistician and an electrophysiologist. All members of the DSMC will be completely 
independent and not involved in the conduct of the study. The committee will have access 
to the study data, in order to determine patient safety.  
Dr. Edward Geltman: Dr. Geltman is an experienced advanced heart failure expert and 
Professor of Medicine at Washington University. In his clinical practice he follows many 
advanced heart failure patients and patients with CRT devices. He will be able to 

 
 
 
 
 
 
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17
adjudicate if heart failure outcomes are attributable to participation in the research study. 
He has experience in leading DSMC for other cardiovascular research studies.  
Electrophysiologist: The electrophysiologist will be experienced in implantation and 
management of CRT devices. They will be able to adjudicate if any CRT related outcomes 
or other complications are attributable to participation in the research study.  
Statistician: The statistician will be knowledgable in interim safety analyses. 
E4 Study Outcome Measurements and Ascertainment 
The primary outcome of LV end-systolic volume will be evaluated by blinded study personel with 
echocardiography. For secondary outcomes, the patients will fill out quality-of-life KCCQ-12 
questionnaire, undergo 6-minute hall walk test, and have blood draw for serum NT-proBNP.  
 
F Statistical Plan  
F1  Sample Size Determination and Power 
We plan to randomize 200 patients that may require enrollment of up to 250 patients. This gives 
us 80% power to detect a between-treatment difference of ≥2±5% in the % reduction in LV end-
systolic volume from baseline with a 2-sided α-error 0.05. Previous studies have shown that a 
reduction in LV end-systolic volume from baseline is associated with an improvement in clinical 
outcomes.52 As both the study and control arms will receive CRT, albeit with different approach 
to programming RV-LV offset, any statistical difference in reverse cardiac remodeling between 
the two RV-LV offset programming strategies will be clinically important.  
F2  Statistical Methods  
The primary outcome of interest is the LV end-systolic volume.52 Secondary outcomes include 
quality-of-life (KCCQ-12), functional performance (6-minute hall walk distance) and a prognostic 
biomarker (serum NT-proBNP).53-55 We will perform t-tests to assess for differences in the % 
change from baseline in primary and secondary endpoints between treatment groups. Sub-
analyses will evaluate for effect modification by subgroups based on ischemic vs. non-ischemic 
cardiomyopathy, sex, and magnitude of RV-LV offset based on ECG. We prespecify evaluation 
of the subgroup with ECG optimized RV-LV offset ≥40 msec. A two-tailed p-value 0.05 will be 
considered as threshold for statistical significance. 
 
G Data Handling and Record Keeping  
G1 Confidentiality and Security 
 
No specimens, records, or data will be collected from anyone not participating in the study.  
 
The human study subjects will provide baseline demographic and historical data related to 
their heart failure and related medical illnesses. This will be collected from their medical chart, 
patient interview, and patient questionnaire. The subjects will also provide echocardiography, 
quality-of-life questionnaire, 6-minute hall walk, blood sample, ECG, CRT device 
interrogation, and clinical information at baseline and follow-up.  

 
 
 
 
 
 
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18
 
Only the research staff and the data safety monitoring committee will have access to 
identifiable private information. Password-secured anonymized data will be stored on secure 
Washington University server (WUSTL BOX) and in REDCap, and kept in confidential study 
binders maintainded by the Washington Univeristy Cardiovascular Research core in a locked 
cabinet in a locked suite. 
 
The data related to the research project will be collected and managed using the standard 
protocols to protect PHI. Use of patient identifying information will be minimized and 
participant information will be identified by study ID number. The collection forms will be 
labeled only with the study ID number.  
G2 Records Retention 
The collection forms will be kept in confidential study binders at the Washington University 
Cardiovascular Research core in a locked cabinet in a locked suite. The data will be entered 
electronically and stored on secure server (WUSTL Box and REDCap). 
 
H Study Monitoring, Auditing, and Inspecting  
H1 Study Monitoring Plan  
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Data and Safety Monitoring Committee (DSMC) will meet to review data at least annually 
beginning six months after accrual has begun. The report will be prepared by the study statistician 
with assistance from the study team and will be reviewed by the DSMC.  The report will include: 
 
HRPO protocol number, protocol title, Principal Investigator name, research coordinator 
name, and statistician.  
 
Date of initial HRPO approval, date of most recent consent HRPO approval/revision, date 
of HRPO expiration, study status, and phase of study.  
 
History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason.  
 
Study-wide target accrual and study-wide actual accrual.  
 
Protocol activation date.  
 
Average rate of accrual observed in year 1, year 2, and subsequent years  
 
Expected accrual end date 
 
Objectives of protocol with supporting data and list the number of participants who have 
met each objective.  
 
Measures of efficacy.  
 
Abstract submissions/publications  
 
Summary of any recent literature that may affect the safety or ethics of the study 
 
Additional information the DSMC may request 
The following information will be monitored and provided to the DSMC: 
 
Enrollment and follow-up 
 
Adverse events occurring during follow-up, including hospitalizations and death 
The DSMC will have complete access to the raw study data throughout the duration of the study.  
The DSMC will have complete discretion for terminating the study for concerns of patient safety.  

 
 
 
 
 
 
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19
The investigator and the study coordinators will be responsible to report all Adverse Events, 
Serious Adverse Events (deaths, hospitalizations, life threatening events and any Unanticipated 
Problems) to the data safety monitoring committee and IRB as described above.  
 
I Study Administration 
I1 
Organization and Participating Centers 
This is a single centre study at Washington University/Barnes-Jewish Hospital.  
I2 
Funding Source and Conflicts of Interest 
This study is funded through Divisional support and American College of Cardiology Presidential 
Career Development Award to the PI.  
I3 
Subject Stipends or Payments  
None 
I4 
Study Timetable 
Subjects will be enrolled in 2019-2021 and complete study related follow-up by 2022.  
 
J Publication Plan  
The trial results will be submitted for publication in an reputed peer-reviewed cardiology journal. 
 
K  Attachments  
K1 Informed consent document 
K2 KCCQ-12 quality-of-life questionnaire 
 
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