A Randomized Trial of Closed Loop Stimulation After Epicardial Pacemaker Implantation for Congenital Heart Disease
Phase: PHASE2
Conditions: Congenital Heart Disease, Bradycardia Sinus
Sponsor: University of California, Los Angeles

 
 
Ahmanson/UCLA Adult Congenital Heart Disease Center 
Dedicated to the Future of Children 
 
David Geffen School ofMedicine 
Departments ofMedicine, Pediatrics & Surgery 
UCLA Centerfor the Health Sciences 
650 Charles E. Young Drive South 
Room A2-237Cf1S, Los Angeles, CA 90095-1679 
Patient Related (310) 794-9629 *Administrative once (310) 825-2019 *Far: (310) 825-6346 
Medical and Surgical Faculty 
Jamil Aboulhosn, M.D., Director 
Leigh Reardon, M.D. 
Jeannette Lin, M.D. 
Jeremy Moore, MD. 
Kevin Shannon, M.D. 
Gentian 
Lluri, 
M.D., 
PhD 
Kalyanam 
Shiykumar, 
M.D., 
PhD Daniel Levi, M.D. 
John Moriarty, M.D. 
Paul Finn, M.D. 
Pierangelo Renella, M.D. 
Hillel Laks, M.D. 
Brian Reemtsen, M.D. 
Reshma Biniwale, M.D. 
Richard Shemin, M.D. 
John S. Child, 
Director 
Nursing Pamela D. Miner, 
RN, MN, NP 
Linda Houser, RN, MS, NP 
Jennifer Doliner, RN, BSN 
Mary Canobbio, RN, MN 
Social Work 
David Highfìll, MSW, LCS"' 
Research Coordinators 
Abbie Hageman, B.S. 
Rachel Bolanos, MPH Jana 
Tarabay, M.D. 
Administrative Sta 
Yvonne Jose 
Veronica Olmedo 
Administrative Manager 
Evelyn Garcia 
E-mail: ACHDC@pnednet.uc1a.edu 
Website: www.heart.ucla.edu/achdc 
Date: 11/14/2022 
RE: A Randomized Trial of Closed Loop Stimulation after Pacemaker Implantation 
for 
Congenital heart Disease 
NCT: NCT03361189 
Protocol ID: 17-000932 
 
Please find attached the protocol. 
Sincerely, 
 
Jeremy P. Moore, MD, MS, CCDS, CEPS, FHRS 
Fellowship Program Director I Director of Clinical Research I Division of 
Pediatric Cardiology 
Clinical Faculty I Ahmanson-UCLA, Adult Congenital Heart Disease 
Program 
100 Medical Plaza Drive, Suite 770 
Los Angeles, CA 90095 
 
 
 
 

Title: Closed Loop Stimulation after Epicardial Pacemaker Implantation for patients with CHD 
Revised 01/11/2017 
1 
A Randomized Trial of Closed Loop Stimulation 
after Epicardial Pacemaker Implantation for 
Congenital Heart Disease 
 

Title: Closed Loop Stimulation after Epicardial Pacemaker Implantation for patients with CHD 
Revised 01/11/2017 
2 
Table of Contents: 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 Animal Studies and Previous Human Studies 
4.0 
Inclusion/Exclusion Criteria 
5.0 
Enrollment/Randomization 
6.0 
Study Procedures 
7.0 
Risks 
8.0 Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others 
9.0 
Study Withdrawal/ Discontinuation 
10.0 Statistical Considerations 
11.0 Privacy/Confidentiality Issues 
12.0 Follow-up and Record Retention 
 

Title: Closed Loop Stimulation after Epicardial Pacemaker Implantation for patients with CHD 
Revised 01/11/2017 
3 
1.0 Background 
Sinus node dysfunction is highly prevalent among patients with congenital heart disease, 
manifesting as resting bradycardia or chronotropic incompetence. As children and adults 
with congenital heart disease are now expected to have increasing lifeexpectancy; with 
well over 1 million adult patients currently living in North America, 1 issues such as mental 
health, acquired comorbidities and their impact on overall cardiovascular health have 
assumed increased scrutiny. 
It is now understood that objective measures of aerobic capacity, such as peak \/02, peak 
VENC02, and heart rate reserve predict all-cause mortality for adult patients with 
congenital heart disease. As the chronotropic response during exercise is a key 
determinant of aerobic capacity, improvement in sensor-based technology for heart rate 
support is expected to have a significant impact on functional capacity and longevity in 
this population. Some forms of congenital heart disease, such as single ventricle 
physiology after the Fontan population are especially likely to benefit, as cardiac output 
is determined almost exclusively by heart rate during exertion due to limited ability to 
augment cardiac stroke volume. 2 
It is also becoming increasingly clear that sedentary behaviors are highly relevant to 
overall cardiovascular health in the general adult population. Adult patients with 
congenital heart disease are at especially high risk for sedentary behavior as a result of I) 
chronic restriction for physical activities based on ill-founded medical advice, 2) 
chronotropic incompetence resulting from prior surgical palliations and hemodynamic 
stressors, and 3) overestimation of physical activity. 
The closed-loop stimulation (CLS) algorithm developed by Biotronik Inc. is a novel 
sensor-based technology that relies on the change in myocardial systolic impedance for 
modulation of the heart rate during physical and emotional stress. 3 The pacing algorithm 
has been shown to be highly effective for a wide range of clinical scenarios. Despite the 
fact that congenital heart disease (CHD) patients are likely to derive significant benefit in 
terms of functional ability and aerobic capacity using this novel technology, the CLS 
system has not been adequately studied in this population. As many CHD patients also 
undergo epicardial placement of pacing systems at the time of concomitant cardiac 
surgery, CLS has been less often utilized in this population given almost no data in the 
setting of surgical electrode placement. The present study intends to examine the benefits 
of the Biotronik CLS algorithm in the CHD population, employing the use of epicardial 
pacemaker systems in the study protocol. 
2.0 
Rationale and Specific Aims 
Improvement in sensor-based rate adaptation for sinus node dysfunction is needed in the 
CHD population. Emerging data suggest that greater aerobic capacity and heart rate 

Title: Closed Loop Stimulation after Epicardial Pacemaker Implantation for patients with CHD 
Revised 01/11/2017 
4 
reserve are independently associated with superior outcomes in this population. 
Improvements in these parameters can be expected with the use of the Biotronik CLS 
algorithm and this pacing system may therefore be particularly well-suited to patients 
with CHD. 
The Specific Aims of this protocol are: 
Primary Aim: To determine the performance of CLS for CHD patients after both 
transvenous and epicardial pacemaker implantation 
Hypothesis: CLS after either pacemaker implantation strategy will result in equivalent 
improvements in autonomic control of chronotropic response as compared to standard 
sensor based rate modulation 
Primary outcome: Objective change in autonomic modulation of heart rate while 
randomized to CLS pacing with mental stress and ANSAR testing 
Secondary outcomes: Increase in aerobic capacity, non-sedentary behavior, and quality of 
life while randomized to CLS pacing 
This will be a single-blind (blinded subjects) randomized cross-over study, in which each 
patient will receive treatment A (CLS-on or CLS-off) for 3 months followed by treatment 
B (CLS-0ff or CLS-on). 
3.0  Previous Human Studies 
The Biotronik CLS alrogithm has been studied extensively in the clinical setting. 
Notable findings include improvements in heart rate response during mental stress4 5 
reliable tracking of the sympathetic tone 6' 7 and excellent performance despite beta-
blocker therapy. 8 In addition, most patients prefer CLS pacing as opposed to traditional 
accelerometer-based pacing in a ratio of 2:1 after sequential randomization to both 
pacing modes 4 However, there is almost no data supporting the use of this algorithm in 
the congenital heart disease population. 9 In addition, there is a very limited amount of 
clinical data (essentially limited to isolated case reports) describing the use of CLS after 
epicardial pacemaker implantation. 9 10 
4.0 Inclusion/Exclusion Criteria 
Inclusion criteria: 
o Congenital heart disease 
o Simple, moderate, or complex congenital heart disease o Adolescent or 
adult age group (age >14 and <65 years) o Significant sinus node dysfunction 
o Atrial pacing percentage
 

Title: Closed Loop Stimulation after Epicardial Pacemaker Implantation for patients with CHD 
Revised 01/11/2017 
5 
o Intrinsic dysfunction resulting from congenital lesion or cardiac surgery  
Secondary sinus node dysfunction due to antiarrhythmic drug therapy o Existing, 
fully functional Biotronik pacemaker or ICD with CLS capability o Epicardial or 
transvenous route of pacemaker implantation 
Exclusion criteria: 
 Unable to complete cardiopulmonary exercise testing (CPET) o 
Contraindication to CPET 
 Decreased mental capacity or known psychiatric disorder 
 Congestive heart failure, NY HA cass IV 
 Total atrial tachyarrhythmia burden >20% 
5.0 
Enrollment]Randomization 
Patient Enrollment: The treating physician will identify potential subjects with a 
previously implanted Biotronik pacemaker and present a brief overview of the study; if 
the subject is interested, the study will be described in detail. Informed consent will be 
obtained by the investigator after discussing the study, including the voluntary nature of 
participation and notification the subject can withdraw at any time. Ample time for 
questions and answers will be allowed. The investigator will give the subject and his/her 
legal guardian the opportunity to take the consent home to think about it more, with the 
option to call or meet with the investigator to ask additional questions. If the subject 
and/or his/her parent/legal guardian agree to participate, the investigator will ask them to 
sign a written, informed consent and assent. A copy of the assent and consent will be 
given to the subject and/or his/her parent/legal guardian. 
Randomization Procedure: This will be a single-blind placebo-controlled 
randomized crossover study with 2 treatments: CLS-on versus CLS-off (accelerometer 
only). Each enrolled patient will receive both treatments for 3 months. The order of 
treatments will be randomized 1 :1. 
6.0 Study Procedures 
All patients enrolled in the study will undergo the following baseline assessment and data 
collection: 
 
Demographics (age, gender, race/ethnicity) 
 
Review of data confirming the presence of sinus node dysfunction with 
chronotropic incompetence (prior exercise stress test and/or Holter monitor results) 
 
Review of clinical history, including age at diagnosis, congenital diagnosis, 
surgical history, and cardiac device implant procedure 
 
Antiarrhythmic drugs prescribed and the respective dosages 
 
Prior ECG and echocardiography and advanced imaging reports 

Title: Closed Loop Stimulation after Epicardial Pacemaker Implantation for patients with CHD 
Revised 01/11/2017 
6 
Randomization 
There will be a 50:50 randomization, with half the subjects randomized to CLS-on then 
CLS-off, and half randomized to CLS-off then CLS-on. 
Subjects previously receiving rate-responsive pacing with CLS that are randomly 
selected to CLS-on will continue with the identical programmed parameters. For 
subjects not previously receiving rate-responsive pacing with CLS that are randomly 
selected to CLS-on nominal programming will be utilized with a base rate of 60 beats 
per minute. 
Subjects will then initiate treatment A (CLS-on or CLS-off) in a blinded fashion. During 
the testing period, subjects will be tracked with the implanted device accelerometer to 
quantify physical activity. At 3 months, all subjects will undergo testing as noted below. 
 24 hour Hotter monitoring with spectral analysis 
 Cycle-ergometer stress with cardiopulmonary gas exchange analysis  Free form 
activities with cardiopulmonary gas exchange analysis (staircase  walking, 
sweeping, suitcase lifting with right and left arms, etc.) 
 ANSAR testing (hand grip, Valsalva, deep breathing, and orthostatic challenge) 
 Mental stress test with continuous electrocardiographic recording 
 Quality of life questionnaire (SF-36/Somerville index) 
After 3 months of treatment A, subjects will be reprogrammed to treatment B. Tracking 
of physical activity with the device accelerometer will continue during this period. After 
3 months of treatment B, repeat testing will be repeated as described above. At the 
conclusion of the study, patients will be asked which pacing mode is preferred. 

Title: Closed Loop Stimulation after Epicardial Pacemaker Implantation for patients with CHD 
Revised 01/11/2017 
7 
Cardiac surgery or catheter 
based pacemaker implantation 
(Biotronik) 
 
 
Enrollment/consent 
Randomization 
 
Accelerometer CLS 
 
(3 mos) 
(3 mos) 
 Test period #1 
CLS Accelerometer (3 
mos) 
(3 mos) 
 Test period #2 
Unblinding 
Study completion 
Patients will be followed during both treatment phases per usual clinical routine. 
Patients who experience significant symptoms (extreme fatigue, debilitating palpitations, 
or other clinically relevant symptoms) will be evaluated by their treating physician. 
Subjects that have any adverse events during treatment A will discontinue treatment A 
and immediately crossover to treatment B. Subjects with events during treatment B will 
be removed from the study and unblinded. Further treatment will be determined by the 
treating physician. 
7.0  Risks. 
All enrolled subjects will have a clinical diagnosis of congenital heart 
disease with sinus node dysfunction as defined in the inclusion criteria. 

Title: Closed Loop Stimulation after Epicardial Pacemaker Implantation for patients with CHD 
Revised 01/11/2017 
8 
Supporting evidence for the clinical diagnosis will be reviewed by the principal 
investigator prior to enrollment. Patients with sinus node dysfunction are often 
more s m tomatic and likel to ex erience adverse cardiovascular outcomes b 
nature of the disease. Those with pacemakers are at risk for lead malfunction and 
are other forms of pacemaker system malfunction. These risks are inherent to the 
patient population studied here. 
There are risks associated with exercise testing in patients with ACHD, including the risk 
of provoking both atrial and ventricular arrhythmias. Nevertheless, exercise testing is 
routinely used to assess clinical status in the adult congenital heart disease population. 
There are risks of loss of confidentiality related to the study procedures. Privacy issues 
are discussed in greater detail in section 1 1 .0. 
8.0 Reporting of Adverse Events (AE) or Unanticipated Problems involving Risk 
to Participants or Others 
AES will be reported to the IRB according to the IRB policies and procedures. 
9.0 Study Withdrawal/Discontinuation 
Subjects may withdraw from the study at any time. Subjects will be unblinded at the time 
of withdrawal. 
10.0 Statistical Considerations 
Sample Size Estimation and Power Analysis 
The primary endpoint of this randomized controlled 2x2 cross-over trial will be to 
measure the influence of autonomic function on heart rate response, and to show an 
equivalent response for both epicardial and transvenous CLS pacemaker systems. The 
objective of this study is to evaluate changes in heart rate in response to the CLS 
algorithm versus a standard accelerometer during various tests of autonomic function. 
Previous studies of adults with chronotropic incompetence using the CLS algorithm 
have demonstrated a mean increase in heart rate of 16.1 ± 1 .1 beats/minute during 
mental stress with CLS-on versus 5.8 ± 0.6 beats/minute with standard accelerometer 
 
A further pilot study using ANSAR demonstrated a mean increase in 12.5 beats/minute 
during isometric hand-grip with CLS-on versus 2.9 beats/min with standard 
accelerometer (p=0.004), 13.2 beats/minute during deep breathing versus 2.9 
beats/minute (p=0.004), 16.0 beats/minute during Valsalva maneuver versus 4.5 
beats/minute (p=0.004), and 14.9 beats/minute for postural change versus 6.2 
beats/minute 
The results of the prior pilot study are summarized below. 

Title: Closed Loop Stimulation after Epicardial Pacemaker Implantation for patients with CHD 
Revised 01/11/2017 
9 
ANSAR HEART 
RATE 
Baseline  
DOD-CLS 
DDDR T test 
Wilcoxon test 
Resting 
55.8 
70.0 
60.8 
<0.001 
0.004 
Isometric Handgrip 
59.4 
71.9 
62.3 
<0.001 
0.004 
Deep Breathing 
58.0 
71.2 
60.9 
<0.001 
0.004 
Valsalva maneuver 
57.1 
73.1 
61.6 
<0.001 
0.004 
Postural Change 
58.1 
73.0 
64.3 
0.015 
0.039 
From Pavri et al. Circulation 
 749. 12 
A two-sided t-test achieves 80% power to infer that the mean difference is not 0 when 
the total sample size of a  cross-over design is 40 (or 81% when n=24 and 96% when 
n=30) assuming a 5% type I error. The actual difference and the square root of the 
within mean square error are assumed to be 10. Considering a drop-out rate of 30%, a 
total of 57 patients will need to be enrolled to achieve the target sample number. 
Statistical Analysis Plan 
Descriptive statistics, including means, standard deviations, and ranges for continuous 
variables, as well as percentages and frequencies for categorical variables, will be 
provided to describe the study sample. Differences between group means for continuous 
variables will be examined using ANOVA or Kruskal-Wallis Test. Point estimates along 
with the corresponding p-values and 95% confidence intervals will be reported. The 
adjusted p-values and the corresponding 95% confidence interval will be reported for 
multivariate analyses. Statistical analysis will be done with JMP version 12.0 (SAS 
Corporation, Cary, NC). 
11.0 PrivacylConfidentiality Issues 
Only individuals directly involved with the study will have access to data. Information is 
for research purposes only and will be used for publication purposes. All participants 
will have their names concealed. Access to identified patient information will be limited 
to the investigators listed within this IRB application. De-identified information with 
HIPPA identifiers removed will be available to other investigators following appropriate 
IRB approval. Confidentiality and security will be maintained for the database. The 
database is stored behind a firewall (in addition to the institutional firewall) with the 
highest level of protection, i.e. the same level of protection as the on-line hospital 
information system at UCLA. This means that users must logon to a web server that sits 
between the institutional firewall and the firewall to the database, and only this 
application server is allowed to query the database. Only users approved through our 
institutional review board will be allowed access to patient identifiers. Other levels of 
authorization may exist for future approved users following IRB approval, e.g. access to 
de-identified data. 

Title: Closed Loop Stimulation after Epicardial Pacemaker Implantation for patients with CHD 
Revised 01/11/2017 
10 
Data is initially collected in the medical record for each individual study participant. The 
information will be extracted from the patient's medical record and then transferred into 
the Case Report Form (CRF). 
The CRFs will include personal identifiers for participant. However, this data will not be 
accessible as numbers and initials are assigned for each participant and these will 
become the identifying information for each study participant. A master list with 
patient demographics will only be accessible to the principle investigator and his senior 
coinvestigator. This data will not be available to others. 
13.0 Follow-up and Record Retention 
The study will continue for 5 years. The data will be maintained for 3 years after completion of 
the study. 
14.0 Reference List 
References 
1. 
Bouchardy J, Therrien J, Pilote L, lonescu-lttu R, Martucci G, Bottega N, Marelli A]. Atrial 
arrhythmias 
in adults 
with 
congenital heart disease. 
Circulation 
Oct 
27 
2009;120:16791686. 
2. 
Shachar GB, Fuhrman BPI Wang Y, Lucas RV, Jr., Lock JE. Rest and exercise hemodynamics 
after the Fontan procedure. Circulation Jun 1982;65: 1043-1048. 
3. 
Osswald S, Cron T, Gradel C, Hilti P, Lippert M, Strobel J, Schaldach M, Buser P, Pfisterer 
M. Closed-loop stimulation using intracardiac impedance as a sensor 
principle: Correlation of right ventricular dP/dt(max) and intracardiac 
impedance during dobutamine stress test, Pace Oct 2000;23: 1502-1508. 
4. 
Coenen M, Malinowski K, Spitzer W, et al. Closed loop stimulation and 
accelerometerbased rate adaptation: results of the PROVIDE study. Europace Mar 
2008;10:327-333. 
5. 
Chandiramani S, Cohorn LC, Chandiramani S. Heart rate changes during acute mental 
stress with closed loop stimulation: report on two single-blinded, pacemaker studies. 
Pacing Clin Electrophysiol Aug
 
6. 
Santini M, Ricci R, Pignalberi C, Biancalana G, Censi F, Calcagnini G, Bartolini P, Barbaro 
V. Effect of autonomic stressors on rate control in pacemakers using ventricular 
impedance signal, Pace Jan
 
7. 
Quaglione R, Calcagnini G, Censi F, Piccirilli F, lannucci L, Raveggl M, Biancalana G, 
Bartolini P. Autonomic function during closed loop stimulation and fixed rate pacing: 
heart rate variability analysis from 24-hour Holter recordings. Pacing Clin Electrophysiol 
Mar
 

Title: Closed Loop Stimulation after Epicardial Pacemaker Implantation for patients with CHD 
Revised 01/11/2017 
11 
8. 
Wojciechowski D, Fauser C, Brückner S, Griesbach L. Clinical Results of ContractilityBased 
Closed Loop Stimulation in Patients Treated with Beta-Blockers. Progress in Biomedical 
Research 2001;6:303-307. 
9. 
di Pino A, Caruso E, Censi F, Gaudenti G, Gargaro A, Calcagnini G. Physiological rate 
adaptation in a child with chronotropic incompetence through closed-loop stimulation 
using epicardial leads. HeartRhythm Case Reports 2016;2:36-39. 
10. 
Di Pino A, Agati S, Bianca I* Efficacy of closed-loop stimulation with epicardial leads in an 
infant with congenital atrioventricular block. Europace Mar 2008;10:334-335. 
11. 
Abi-Samra FM, Singh N, Rosin BL, Dwyer JV, Miller CD, Investigators CS, Effect of 
rateadaptive pacing on performance and physiological parameters during activities of 
daily living in the elderly: results from the CLEAR (Cylos Responds with Physiologic Rate 
Changes during Daily Activities) study. Europace Jun 2013;15:849-856. 
12. 
Pavri BB, Russell S. Abstract 3515: An Impedance Sensor is Superior to an 
Accelerometer for Chronotropically Incompetent Patients with Sinus Node Dysfunction: 
Results of a Pilot Study with a Dual Sensor Pacemaker, Circulation October 31, 2006 
749.