Arrhythmia Burden in Patients With Impulse Dynamics Optimizer Cardiac Contractility Modulation (CCM) Device Implantation: Retrospective and Prospective Evaluation
Conditions: Atrial Fibrillation, Arrythmia
Sponsor: Hackensack Meridian Health

CLINICAL STUDY PROTOCOL 
 
 
 
 
 
 
 
 
 
Arrhythmia Burden in Patients with Impulse Dynamics Optimizer Smart 
Device Implantation: Retrospective and Prospective Evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Version 
12/23/2022 
version 1.0 
 
 
 

 
Study Number  
12/20/2022 
 
2 
Study Authors  
 
Dr. Sameer Jamal 
Lead Study Principal Investigator: Dr. Sameer Jamal 
Hackensack University Medical Center, 
Hackensack Meridian School of Medicine 
 
Abbreviations 
Abbreviation  
Explanation 
 
AF=Atrial fibrillation 
CCM= Cardiac Contractility Modulation 
CHF=congestive heart failure 
CIED= cardiovascular implantable electronic device 
FDA=Food and Drug Administration 
HFrEF=heart failure with reduced ejection fraction 
ICD=Internal Cardioverter Defibrillator 
ILR=implantable loop recorder 
PPM=Permanent pacemaker 
LVEF=left ventricular ejection fraction 
NYHA=New York Heart Association  
VA=Ventricular arrhythmia 
VF=Ventricular fibrillation 
VT=Ventricular tachycardia 
 
 
 
 
 
 

 
Study Number  
12/20/2022 
 
3 
Summary  
The Impulse Dynamics Optimizer Device is a Food and Drug Administration (FDA) approved, 
commercially available device indicated for patients with heart failure with reduced ejection fraction 
(HFrEF), currently being implanted per FDA recommendation.  Many candidates of this device have 
a previously implanted cardiovascular implantable electronic device (CIED)- internal cardioverter 
defibrillator (ICD) or permanent pacemaker (PM).  Patients with heart failure are at high risk for both 
atrial and ventricular cardiac arrhythmias. 
 
The aim of this study is to evaluate up to 200 patients for Atrial fibrillation (AF) burden episode data 
obtained from interrogation of their CIED 8 months or greater after Optimizer implant, and compare 
arrhythmia burden 6 months before Optimizer Cardiac Contractility Modulation (CCM) device 
insertion to 6 months or greater after Optimizer insertion, after an immediate implantation blanking 
period of 2 months. 
 
 
 
 

 
Study Number  
12/20/2022 
 
4 
1 – Introduction    
The Impulse Dynamics Optimizer is indicated for patients with New York Heart Association 
(NYHA) class III congestive heart failure (CHF) with left ventricular ejection fraction (LVEF) 
between 25 and 45% who are not candidates for cardiac resynchronization therapy.  The Optimizer 
device requires a minimally invasive implant by a cardiac electrophysiologist with two transvenous 
pacemaker wires implanted into the right ventricular septum and attached to a generator in an 
infraclavicular region, much like a pacemaker.  The Optimizer device provides CCM through 
improved calcium handling and has been shown to reverse the negative remodeling of the left 
ventricle seen in HFrEF and improve left ventricular contractile strength.  
 
We plan to enroll a maximum of 200 patients with existing or newly implanted Impulse Dynamics 
Optimizer with concurrent previously implanted CIED. 
 
 
2 – Background 
AF demonstrates an average prevalence of 25% in HFrEF, and is the most common sustained 
arrhythmia encountered in the HFrEF population (1).  AF burden in HFrEF is estimated at 35%. AF 
increases risks of CHF hospitalizations and mortality in HFrEF (2).  Episodes of AF longer than 24 
hours in a non HFrEF population substantially increased risk of stroke (3). Sudden cardiac death, 
most often a result of ventricular arrhythmia (VA), accounts for 30-50% of the deaths in heart failure 
patients (4-5).  CCM is a novel therapy for patients with heart failure with a variety of short and long-
term benefits.  While CCM has been shown to improve health status and reduce hospitalization rates 
in those with AF (6), there is a paucity of data examining the impact of CCM therapy on arrhythmia 
burden.   
  
3 – Rationale, Objectives and Hypothesis  
3.1 Study Rationale 
 
There are no studies that assess the impact of the Optimizer device on atrial and ventricular 
arrhythmias, and any investigation is unique and may add value.  The study will be performed in two 
arms. The first arm will be retrospective and the second arm will be prospective. We will perform a 
retrospective review of atrial and ventricular arrhythmias that occur 6 months before and 8 months 
after the Optimizer device is implanted in patients with a CIED with the ability to interpret atrial 
signals. The 8 months post implant period will include a 2 month blanking period which will allow 
for the therapeutic effects of CCM. Patients who have undergone Optimizer implantation, but do not 
have at least 8 months of follow up, can be enrolled in the retrospective arm and signed informed 
consent will be required. The prospective arm will include patients who have had a CIED with the 
ability to interpret atrial signals for at least 6 months and have a clinical indication for CCM therapy 
as per standard of care. These patients will be followed for 8 months post Optimizer implant, 
including an initial 2 month post Optimizer implant blanking period.  
 
3.2 Hypothesis  
 
We hypothesize that treatment with Optimizer will result in a 20% reduction of AF burden. 
 

 
Study Number  
12/20/2022 
 
5 
3.3 Primary Objective 
 
The primary objective for both the retrospective and prospective arms of the study is to compare the 
AF burden noted 6 months pre Optimizer implant to 6 post Optimizer months (post Optimizer months 
3-8), after 2 month blanking period 
.  
 
3.4 Exploratory Objectives 
All exploratory objectives will be performed for both retrospective and prospective arms separately 
and together with comparisons to be made between the following groups: 
1. 6 months pre Optimizer to 6 post Optimizer months (post Optimizer months 3-8), after 2  
month blanking period 
2. 6 months pre Optimizer to 6 post Optimizer months (post Optimizer months 1-6) 
3. 3 months pre Optimizer to 3 post Optimizer months (post Optimizer months 3-5), after 2 
month blanking period 
4. 3 months pre Optimizer to 3 post Optimizer months (post Optimizer months 6-8), after 2 
month blanking period 
5. 3 months pre Optimizer to 3 post Optimizer months (post Optimizer months 1-3)  
6. 3 months pre Optimizer to 3 post Optimizer months (post Optimizer months 4-6)  
  
 
3.4.1 Exploratory Objective One 
 
Exploratory objective one is to compare the AF burden between groups 2-6 noted above. 
 
3.4.2 Exploratory Objective Two 
 
Exploratory objective two is to compare the number of VA episodes between all groups noted above. 
 
3.4.3 Exploratory Objective Three  
 
Exploratory objective three is to compare the AF burden after censoring subjects who underwent 
cardioversion or catheter ablation of AF during entire study period between all groups noted above. 
 
3.4.4 Exploratory Objective Four  
 
Exploratory objective four is to compare the AF burden after censoring subjects who had addition of 
antiarrhythmic drug, underwent cardioversion, or underwent catheter ablation during entire study 
period between all groups noted above.  
 
3.4.5 Exploratory Objective Five  
 
Exploratory objective five is to compare the number of hospitalizations between all groups noted 
above. 
 
3.4.6 Exploratory Objective Six 
 
Exploratory objective six is to compare the number of stroke events between all groups noted above. 
 
3.4.7 Exploratory Objective Seven 

 
Study Number  
12/20/2022 
 
6 
 
Exploratory objective seven is to compare the number of catheter ablations between all groups noted 
above.  
 
3.4.8 Exploratory Objective Eight 
 
Exploratory objective eight is to compare the number of cardioversions between all groups noted 
above.  
 
3.4.9 Exploratory Objective Nine 
 
Exploratory objective nine is to compare the number of AF events ≥ 24 hours between all groups 
noted above.  
 
 
 
4 - Study Design 
4.1 General Design 
 
The study will be conducted in two arms. The retrospective arm will be an observational evaluation 
of subjects with a CIED with the ability to interpret atrial signals implanted at least 6 months prior to 
Optimizer implantation. Additionally, these subjects will be at least 8 months post Optimizer implant 
at the time of study approval.  Subjects with an appropriate CIED and who have undergone Optimizer 
implantation, but do not have at least 8 months of post Optimizer implantation follow up, can be 
enrolled in the retrospective arm, but signed informed consent will be required.  
 
The prospective arm will be an observational evaluation of subjects with an appropriate CIED 
implanted at least 6 months prior and scheduled to undergo Optimizer implantation as per standard of 
care.  Informed consent will be obtained from all subjects in the prospective arm at a recommended 
time of 2-4 weeks before scheduled Optimizer implant date.  A CIED interrogation (remote or in-
person) is to be performed 2-4 weeks prior to Optimizer implant date as per standard of care.  If AF 
burden is noted to be between 1% and 99% (reported for any time equal to or less than the prior 6 
month period), the patient can be enrolled into the prospective arm of the study.  Arrhythmia burden 
data from the CIED manufacturer will also be requested; if this data does not corroborate AF burden 
between 1% and 99% then the patient will be considered a screen failure.  AF burden and VA 
episodes will be assessed remotely through the CIED manufacturer and compared from the pre 
implantation period to the post implantation period, as defined above.  The prospective arm will allow 
attainment of information prospectively during 8 months of follow up after Optimizer implantation, 
including an initial 2 month post Optimizer implant blanking period.  
 
Evaluation for both arms will include: 
1. Pre-6 months to Optimizer implant (will be subcategorized into pre-6 to pre-3 months, 
and pre-3 months to Optimizer implant) 
2. Optimizer implant date to post-8 months [will be subcategorized into Optimizer  
implant to post 2 months (blanking period), post-2 months to post-5 months, and post-5 
months to post-8 months], and if applicable every 3 months thereafter.    

 
Study Number  
12/20/2022 
 
7 
In terms of arrhythmia reporting, AF burden will be reported as (1) hours of AF/day (2) percent AF 
per day and (3) number of AF episodes ≥24 hours/1 month period, including in the 2 month blanking 
period. 
VA episodes will be categorized into types and number of events as reported by the CIED as (1) 
treated VT and treated VF together and (2) untreated non-sustained VT, treated VT, and treated VF 
together. 
 
4.1.1 Study Duration  
 
The study will last approximately 2 years to allow for enrollment.  
 
4.1.2 Number of Study Sites 
 
The study will be performed at the primary site, Hackensack University Medical Center, and up to 50 
additional subsites in the USA currently implanting Impulse Dynamics Optimizer devices per 
standard of care. 
 
4.2 Study Population 
 
The population will include adult patients, at least 18 years of age. 
  
1. Retrospective study 
a. CIED with the ability to interpret atrial signals implanted at least 6 months prior to 
Optimizer implantation AND Optimizer implantation at least 6 months post CIED 
implantation and with at least 8 months of post Optimizer implantation follow up. 
b. OR if the patient has an appropriate CIED with at least 6 months of follow up prior to 
Optimizer implantation, but less than 8 months of follow up after Optimizer 
implantation (will require a signed informed consent form). 
 
2. Prospective study 
 
CIED with the ability to interpret atrial signals implanted at least 6 months prior to CCM 
implantation AND scheduled CCM implant which was prescribed for standard clinical 
indications. 
  
   
4.2.1 Number of Participants 
 
We would like to evaluate up to 200 subjects from up to 50 subsites. 
 
4.2.2 Eligibility Criteria 
 
The population will include subjects with the following for the: 
1. Retrospective arm 
a. Optimizer implantation at least 6 months post CIED implantation and with at least 8 
months of post Optimizer implantation follow up 
b. Patient has an appropriate CIED with at least 6 months of follow up prior to 
Optimizer implantation, but less than 8 months of follow up after Optimizer 
implantation (will require a signed informed consent form). 

 
Study Number  
12/20/2022 
 
8 
2. Prospective arm 
a. CIED with the ability to interpret atrial signals implanted at least 6 months prior to 
Optimizer implantation; 
b. Scheduled Optimizer implant which was prescribed for standard clinical indications. 
 
4.2.3 Inclusion Criteria 
 
1. 1%≤AF burden≤99% in the 6 month period prior to Optimizer implant as documented the 
patient’s CIED 
2. 18 years of age or older on day of signing consent 
3. Any gender 
4. Functional dual chamber pacemaker or ICD and using remote follow up for their CIED 
5. Not scheduled for planned catheter ablation or cardioversion 
6. Ability to sign consent in English or Spanish 
 
4.2.4 Exclusion criteria 
 
1. Permanent atrial fibrillation 
2. Pregnancy (in prospective arm only)  
3. Expected survival <1 year 
 
4.3 Study procedures 
 
AF burden and VT episodes will be remotely accessed from the CIED manufacturer. 
The prospective arm will allow prospective data collection for 8 months after Optimizer implantation, 
including a 2 month blanking period immediately after Optimizer implantation.     
 
For the retrospective and the prospective arms, the data will be evaluated in the same manner, except 
as noted below, and will be performed as follows: 
 
1. Pre-6 months to Optimizer implant (will be subcategorized into pre-6 to pre-3 months, and pre-3 
months to Optimizer implant), to ensure 1%≤AF burden≤99% (otherwise subjects will be excluded). 
2. Optimizer implant date will be followed by a 60 day blanking period. The patients will be followed 
for 8 months [will be subcategorized into Optimizer implant to post-2 months (blanking period), post-
2 month blanking period to post-5 months, and post-5 months to post-8 months, and every 3 months 
thereafter until the study is completed).    
AF burden will be reported as (1) hours of AF/day (2) percent AF per day and (3) number of AF 
episodes ≥24 hours/1 month period, including the blanking period. 
Demographics, development of medical events (hospitalization, stroke) and arrhythmia related 
history (presence/absence of medications) and interventions, such as cardioversion, antiarrhythmic 
drug administration, or catheter ablation will be recorded. 
VA episodes will be categorized into types and number of events as reported by the CIED as (1) 
treated VT and treated VF together and (2) untreated non-sustained VT, treated VT, and treated VF 
together. 
 
 
 

 
Study Number  
12/20/2022 
 
9 
4.4 Risks and Benefits  
 
The subjects will not obtain any direct benefit from participation.  Conducting this study may help 
identify new benefits of the Optimizer implant on arrhythmia burden and as a result help patients with 
AF in the future.   
 
There are no physical risks related given the nature of this study and the fact that all procedures took 
place as per standard of care. The only foreseeable risk is related to breach of confidentiality since 
data is accessed for research purposes. All measures will be taken to minimize this risk and data will 
be stored in a coded manner and only de-identified data will be shared across institutions (see details 
in section 6).  
 
 
 
5 – Methods  
5.1 Sample Size Justification 
 
The sample size is based on a statistical test of whether AF burden is reduced after Optimizer implant 
compared to the pre-implant period. We assume median pre-Optimizer implant AF burden of 
approximately 25%, which may be a conservative estimate given similar or higher reported device-
monitored AF burden over 24 weeks in a genetically-defined group of heart failure patients (6). We 
hypothesize a 20% change in post-Optimizer AF burden (5% absolute reduction). The sample size 
calculation is based on a non-parametric Wilcoxon signed-rank test of the paired change in pre-
Optimizer to post-Optimizer AF burden. Assuming a mean reduction of 5% and a standard deviation 
of 15% for the paired change in AF burden, alpha of 0.05 and power of 0.8, the required sample size 
is 77 patients. This sample size provides power >0.8 for a paired t-test. Based on a missing data rate 
of up to approximately 20% (e.g. due to dropout or unavailable device AF burden data), we plan to 
include up to 15 more subjects for a total of up to 92 subjects per arm. 
 
 The sample was calculated using PASS (Kaysville, UT) 2022 software. 
 
5.2 Analysis Population 
 
All patients identified and enrolled will be included in the analyses.  
 
5.3 Statistical Methods 
Descriptive statistics will be calculated for patient characteristics [age, gender (female/male), 
race/ethnicity (American Indian or Alaska Native, Asian, Black or African American, Hispanic, 
Native Hawaiian or Other Pacific Islander, White), body-mass index, presence of comorbid 
conditions (asthma, cancer, chronic obstructive pulmonary disease, coronary artery disease, diabetes 
mellitus, renal insufficiency, stroke), prior rhythm controlling strategies for AF or VT 
(antiarrhythmics, cardioversion, catheter ablation). For continuous variables, visual inspection of q-q 
plots for skewness and outliers along with the Shapiro-Wilk test (p>0.05 indicates no deviation from 
normality and p<0.05 indicates deviation from normality) will be used to evaluate normality or 
normal continuous variables, the mean, standard deviation, and range will be calculated. For non-
normal continuous variables, the median, interquartile range, and range will be calculated. For 
categorical variables, counts and percentages will be reported. 

 
Study Number  
12/20/2022 
 
10 
 All statistical analyses will be performed using SAS 9.4 (SAS Institute Inc., Cary, NC). All 
hypothesis tests will be two-sided with significance level α=0.05. Any p-value below 0.05 will be 
deemed statistically significant.  
 
 
5.3.1 Statistical Methods for Primary Objective 
 
Primary Objective: The primary objective for both the retrospective and prospective arms of the 
study is to compare the AF burden noted 6 months pre Optimizer implant to 6 post Optimizer months 
(post Optimizer months 3-8), after 2 month blanking period 
 
A patient’s AF burden is measured as the cumulative time spent in AF over the assessment period 
divided by the cumulative follow-up time of the assessment period. The difference in AF burden 
between the post-Optimizer and pre-Optimizer AF assessment periods will be analyzed as a 
continuous variable. Visual inspection of q-q plots for skewness and outliers along with the Shapiro-
Wilk test (p>0.05 indicates no deviation from normality and p<0.05 indicates deviation from 
normality) will be used to evaluate normality. If the distribution of changes in AF burden is 
approximately normally distributed, a paired t-test will be used for analysis and the mean, standard 
deviation, and range will be reported. Otherwise, if the distribution is non-normal, a Wilcoxon 
signed-rank test will be performed and the median, interquartile range, and range will be reported. 
 
5.3.2 Statistical Methods for Exploratory Objectives 
 
All exploratory objectives will be performed for both retrospective and prospective arms separately 
and together with comparisons to be made between the following groups: 
1. 6 months pre Optimizer to 6 post Optimizer months (post Optimizer months 3-8), after 2  
month blanking period 
2. 6 months pre Optimizer to 6 post Optimizer months (post Optimizer months 1-6) 
3. 3 months pre Optimizer to 3 post Optimizer months (post Optimizer months 3-5), after 2 
month blanking period 
4. 3 months pre Optimizer to 3 post Optimizer months (post Optimizer months 6-8), after 2 
month blanking period 
5. 3 months pre Optimizer to 3 post Optimizer months (post Optimizer months 1-3)  
6. 3 months pre Optimizer to 3 post Optimizer months (post Optimizer months 4-6)  
  
 
Exploratory objective one is to compare the AF burden between groups 2-6 noted above. 
 
Exploratory objective two is to compare the number of VA episodes between all groups noted above. 
 
Exploratory objective three is to compare the AF burden after censoring subjects who underwent 
cardioversion or catheter ablation of AF during entire study period between all groups noted above.  
 
Exploratory objective four is to compare the AF burden after censoring subjects who had addition of 
antiarrhythmic drug, underwent cardioversion, or underwent catheter ablation during entire study 
period between all groups noted above.  
 
Exploratory objective five is to compare the number of hospitalizations between all groups noted 
above. 
 
Exploratory objective six is to compare the number of stroke events between all groups noted above. 

 
Study Number  
12/20/2022 
 
11 
 
Exploratory objective seven is to compare the number of catheter ablations between all groups noted 
above.  
 
Exploratory objective eight is to compare the number of cardioversions between all groups noted 
above.  
 
Exploratory objective nine is to compare the number of AF events ≥ 24 hours between all groups 
noted above.  
 
A patient’s AF burden is measured as the cumulative time spent in AF over the assessment period 
divided by the cumulative follow-up time of the assessment period. The difference in AF burden 
between the post-Optimizer and pre-Optimizer AF assessment periods will be analyzed as a 
continuous variable. Visual inspection of q-q plots for skewness and outliers along with the Shapiro-
Wilk test (p>0.05 indicates no deviation from normality and p<0.05 indicates deviation from 
normality) will be used to evaluate normality. If the distribution of changes in AF burden is 
approximately normally distributed, a paired t-test will be used for analysis and the mean, standard 
deviation, and range will be reported. Otherwise, if the distribution is non-normal, a Wilcoxon 
signed-rank test will be performed and the median, interquartile range, and range will be reported. 
 
VA episode counts will be tabulated for the pre-Optimizer and post-Optimizer assessment periods. A 
Poisson generalized estimating equation (GEE) analysis accounting for clustering of paired counts 
within subject may be performed to compare the rate of VA episodes between the pre-Optimizer and 
post-Optimizer assessment periods. 
 
 
5.4. Interim Analyses 
 
Descriptive interim analyses will be performed after the complete data for increments of 25 patients 
are available. Interim analyses will be conducted according to the primary and exploratory objective 
statistical methods. Stopping the study early on the basis of interim data analysis is not planned. 
 
5.5 Data Management 
 
All data will be entered into the HMH REDCap and imported into SAS 9.4 where all data queries will 
be generated for out of range values/invalid data until all data issues are resolved.  Each site’s team 
will be provided with temporary and restricted access to the HMH REDCap instance. Team members 
will enter data directly into the REDCap and will only have access to their own site data apart from 
HMH, the lead site, which will have overall access to all the deidentified datasets for analysis 
purposes (see section 6 for details).  
The HMH team will be responsible to build and maintain the REDCap database and provide access as 
per IRB approvals.  
Each site will be responsible for the quality of the data entered. At the end of the data collection, data 
will be reviewed for “outliers” and any inconsistencies will be reviewed with the local sites. 
 
6 - Trial Administration 
6.1 Ethical Considerations - Institutional Review Board (IRB) Review 
 

 
Study Number  
12/20/2022 
 
12 
The study will be conducted according to the International Conference on Harmonization (ICH), 
Good Clinical Practice (GCP), the Declaration of Helsinki, Institutional Review Boards (IRB) and in 
accordance with the U.S. Code of Federal Regulations on Protection of Human Rights (21 CFR 50). 
 
6.2 Institutional Review Board (IRB) Review (list the IRB of record) 
 
The final study protocol and data collection tools will be approved by the WIRB.  Approval will be 
received in writing before study initiation.  
Any changes to the study design will be formally documented in amendments and be approved by the 
IRB prior to implementation. 
 
6.3 Data management (collection, storage etc.) 
 
Data will be entered into REDCap, hosted at HMH, in a de-identified fashion with discrete variables 
(noted above). Subjects will be given a unique study ID number. The key linking the subject ID 
number to the medical record number and phone number will be kept separate from coded study data 
and will only be accessible by authorized study team members. The key will either be stored in a 
locked drawer or password protected spreadsheet. 
The REDCap project will be built using REDCap DataAccess groups (DAG), a REDCap feature in 
which only users within a given Data Access Group can access records created by users within that 
group. This feature may be useful in the case like this, of a multi-site or multi-group project that 
requires that groups not be able to access another group's data. Each group will only have access to its 
own data and only de-identified data can be shared with all necessary legal agreements in place.  
Identifying information will remain at each site.  
Non-HMH collaborators will be given temporary access to the HMH REDCap project and will be 
assigned to each DAG according to their site and needs.  
 
6.4 Informed consent  
 
A consent waiver for subjects enrolled in the Retrospective Arm.  Subjects enrolled in the Prospective 
Arm will be required to provide informed consent. Patients who underwent Optimizer implant and 
have < 8 months of follow up, will be included in the retrospective arm and will require informed 
consent.  Each site will be responsible to obtain consent for the prospective patients, document 
consent appropriately and monitor for compliance regarding the consenting process. Sites should 
perform an independent review of the Informed Consent Form and Process and document said review 
to provide to the Coordinating Site as requested.  
 
6.5 Study Records (retention etc.) 
 
Records will be retained in accordance with regulatory and organizational requirements, but for no less 
than six (6) years following the completion of the study.  Disposal of records will be performed 
according to regulations. 
 
6.6 Publication Plan  
 
This study is meant for publication. The PI holds the main responsibility for publication.  Interim 
analysis may also be published. If results of this study are to be reported or published, no information 
that could potentially identify patients will be included.  
 

 
Study Number  
12/20/2022 
 
13 
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