Rate Response With CLS Versus Accelerometer and Effect on Both Subjective Symptoms and Objective Outcomes in a Heart Failure Population Implanted With Cardiac Resynchronization With Defibrillator Device: The CLASS Trial
Phase: NA
Conditions: Heart Failure, ICD, Chronotropic Incompetence
Sponsor: University of California, San Diego

Cover Page: 
 
 
Comparing Rate Response With CLS Versus Accelerometer ICD Settings in Heart 
Failure Patients With BIOTRONIK CRT-Ds 
 
 
NCT 02693262 
 
 
Date 3/20/2016 
 

9. 
RESEARCH DESIGN AND METHODS 
Study Design 
This study is a prospective, randomized, single-blind crossover study intended to enroll patients who are 
implanted or are scheduled to be implanted with a Biotronik CLS and accelerometer capable CRT-D device. 
Patients will serve as their own control group with regard to modes of rate-adaptive pacing. Patients with a 
previously implanted Biotronik CRT-D device with CLS-capability will be recruited from health care 
institutions in San Diego and all dedicated functional testing will be performed at the University of California, 
San Diego (UCSD).  The goal enrollment target for analysis will be 15 patients, with up to 20 patients enrolled 
to allow for withdrawals.  
 
Patients with suspected CI would include those with a blunted atrial sensing histogram that would justify to a 
treating clinician enabling a rate response feature, or objective evidence of chronotropic incompetence (e.g., 
low average heart rate during telemetry monitoring, or <85% MPHR on exercise treadmill testing) before or 
after CRT-D implantation.  Patients who have or are scheduled for implantation of a Biotronik CLS-capable 
device will be enrolled. Then each patient will complete an initial run-in period of one week whereby no rate 
response is programmed into the CRT-D device.  One week later, patients will then be randomized to either 
CLS or an accelerometer mode. CPET and 6-minute walk testing scheduled one week after the initial mode is 
set (CLS or accelerometer).  At the conclusion of the initial CPET and 6-minute walk assessments, the initial 
device setting (CLS or accelerometer) will be programmed to the opposite setting for a period of one week, at 
which point repeat CPET and 6-minute walk tests will be conducted.  Results will be collected and compared.  
Patient preferences regarding quality of life and symptoms in each mode will be assessed immediately after 
study completion.  Quality of life information will be gathered by a RAND-36 questionnaire at the baseline 
visit and at each setting change.  At the final encounter, the patient will be asked to pick which setting of the 2 
they felt improved their overall well-being and exercise performance during testing.. This is a proof of concept 
design, with cross-sectional analysis, purposefully designed to reduce costs of prolonged follow-up, but also 
answer the appropriate clinical question. 
 
Study Overview 
This study is designed to evaluate patients who have been implanted with a cardiac resynchronization therapy 
with defibrillator (CRT-D) therapy capable of closed loop stimulation (CLS) as a comparator to an 
accelerometer setting.  Patients with CRT-D and CI will undergo cardiopulmonary exercise stress testing 
(CPET) and six-minute walk assessments in a randomized crossover study design to evaluate patient 
performance and preference regarding CLS compared to use of an activated accelerometer.  Numerous studies 
have described the utility of CPET in patients with congestive heart failure and chronotropic 
incompetence.4,5,6,7. 
 
CI as seen on remote or in-person monitoring would be defined as a blunted atrial sensing histogram that would 
prompt the treating physician to utilize the rate response feature.  Patients with CI would then serve as their 
own controls and undergo testing with CPET and six-minute walk assessments with activation of accelerometer 
for rate response and again with CLS driven rate response as a comparative arm.  Randomization will be 
performed to determine the order of accelerometer versus CLS driven rate response. Randomization will be 
performed in computer generated blocks of 5, with sealed envelopes revealing the order of testing.  Patients will 
be blinded to randomization, until study completion at which point unmasking to the patient will occur, and the 
patient will be set to the patient preferred setting for rate responsive pacing. 
 

Patients would serve as their own controls to increase the study power as an effort to examine whether CLS 
improves exercise performance and patient satisfaction as compared to use of an accelerometer. 
 
CPET Testing 
CPET testing will be performed by trained health professionals proficient in CPET testing. Those individuals 
performing CPET testing and reporting information will be blinded to rate responsive pacing settings, so as not 
to introduce bias into interpretation 
 
All patients will undergo CPET testing at the dedicated stress lab or clinical research institute at the University 
of California, San Diego.  Patients will be scheduled after their initial clinic visit when device interrogation and 
programming is made. Upon presentation to the stress lab, patients will be asked to perform a progressive test 
(16.7 W/min) on an electrically braked cycle ergometer (or treadmill) until subjective exhaustion, plateauing of 
oxygen intake, or if any clinical contraindication precludes continuing. All testing will be supervised.  
 
The modified Naughton protocol will be used for treadmill exercise testing in patients.  This protocol is 
designed to increase the workload by approximately 1 metabolic equivalent (MET) (3.5 mL O2/kg/min) for 
each two-minute stage.  Patients will have continuous electrocardiogram monitoring and frequent blood 
pressure measurements during exercise testing.  The ventilator threshold (VAT) or the Vo2 at the onset of 
anaerobic metabolism is visually identified as the onset of a disproportionate rise in VE/Vo2 relative to 
VE/Vco2.  
 
An objective grading system that is based upon values of Vo2max and the anaerobic threshold will be used to 
evaluate each patient’s functional capacity:  
Class A:  None to mild; VO2 max >20 mL/kg/min 
Class B:  Mild to Moderate; VO2 max 16-20 mL/kg/min 
Class C:  Moderate to Severe; VO2 max 10-15 mL/kg/min 
Class D:  Severe; VO2 max 6-9 mL/kg/min 
Class E:  Very severe; VO2 max < 6 mL/kg/min 
 
During CPET testing, data collected will include minimum, maximum, average heart rate, peak VO2 during 
exercise and associated functional class, and peak and average METs achieved with exercise.   
 
Six-minute Walk Testing 
Six-minute walk testing (6MWT) will be performed by trained sub-investigators, including research staff. 
Those individuals performing six-minute walk testing and reporting information will be blinded to rate 
responsive pacing settings, so as not to introduce bias into interpretation. 
 
The 6MWT assessment will be performed at the University of California, San Diego at the Thornton Hospital.   
A practice walk will be performed to orient the patient to the procedure.  In addition to total distance walked, 
the magnitude of desaturation and timing of heart rate recovery will be metrics for clinical outcomes. 
 
Standard protocol will be followed, including:  a flat, straight corridor with 100 feet in length; turnaround 
points demarcated with orange cones; patient rest period of 10 minutes prior to the walk assessment; patients 
will be instructed to wear comfortable shoes and clothes; Record baseline heart rate and pulse oxygen 
saturation (SpO2); monitoring pulse oxygen saturation during test is optional; lap counter will be set to zero and 
timer to six minutes; patients will be instructed that the object is to walk AS FAR AS POSSIBLE for 6 minutes, 

but don't run or jog;  at the end of the test, the floor will be marked where the patient stopped; after the test 
record the Borg dyspnea and fatigue levels will be recorded; the distance walked will be recorded.  During 
6MWT, average and peak heart rate immediately following exercise will be measured, as well as maximum 
distance walked.   
 
Quality of Life and Patient Preference Testing 
 
A RAND-36 patient questionnaire will be administered to the patient after both CPET testing and six-minute 
walk testing have been performed at the end of each of the 2 rate responsive pacing settings. 
Patient preference regarding rate response pacing modality (CLS versus accelerometer) will also be collected at 
the end of the study. 
 
 
Enrollment  
Patients will be recruited from local hospitals in San Diego with all formal testing and data analysis performed 
at UCSD.  
 
Main Inclusion Criteria 
1.) Patients with a Biotronik CRT-D device (capable of both CLS and accelerometer rate responsive pacing).   
2.) Patients ≥ 18 years of age 
3.) Patients who have plausible symptoms of CI based on previous monitoring and clinical symptoms 
 
Exclusion Criteria 
1.) Pregnant patients 
2.) Patients who are unwilling or unable to provide informed consent 
3.) Patients who are unable to complete study related procedures 
 
 
 
Study Procedures 
Medical records and device interrogation results of patients who have clinical device interrogations and clinical 
suspicion of CI will be screened to determine eligibility for the study.  Subjects who meet the 
inclusion/exclusion criteria will be asked to participate in the study and sign the approved informed consent 
prior to initiating any study related procedures including further patient contact.  
 
As part of the research study, medical history, demographic information (age, race, sex, and date of birth) and 
baseline information will be obtained from the patient and/or patient chart. 
 
After a minimum of three months post implantation of a Biotronik CLS-capable CRT-D device, patients 
enrolled will undergo a run-in period with use of no rate response pacing for one week.  They will then be 
randomized to CLS or accelerometer turned on with testing performed after one week in the initial mode set.  
After CPET and 6-minute walk assessments are performed on the initial device setting (CLS or accelerometer), 
the device will be programmed to the opposite setting for a period of one week, at which point repeat CPET and 
6-minute walk tests will be conducted. Results will be collected and compared.  Patient preferences will be 
assessed immediately after study completion. 
 

The following information will be collected for research purposes: 
• Baseline demographic and clinical information 
• Any cardiac medication prescription 
• Antiarrhythmic drug prescription 
• Procedural evaluation (ablation, device implantation, etc.) 
 
Study Duration 24 months 
 
 
Waiver of consent for recruitment 
From clinical data gathered during the main study time period, we will review electronic medical records to 
collect information the population of patients screened. The study will require a waiver of consent to collect 
data for patients evaluated The waiver of consent is necessary to meet the specific aims of the trial to ascertain 
whether patients are reasonable candidates for inclusion in the study.  
 
Data Analysis 
All the data for the study will be entered into case report forms and then entered into a database. All variables 
of interest including subject demographics, baseline characteristics, device information and endpoints will be 
summarized descriptively. Normally distributed continuous variables will be expressed as means and standard 
deviations and will compared by unpaired t-tests whereas continuous variables not normally distributed will 
expressed as medians and interquartile ranges (IQR), and will be compared by the Wilcoxon rank-sum test. 
Categorical variables will be expressed as percentages and were compared by the χ2 test.  For univariate and 
multivariable analysis, logistic regression will be used.  Analyses will be performed using Stata version 11.0 
(StataCorp, College Station, Texas).