Spinal Cord Stimulation to Inhibit Afferent Feedback During Exercise in Heart Failure
Phase: NA
Conditions: Heart Failure
Sponsor: Mayo Clinic

 
SPINAL CORD STIMULATION TO 
INHIBIT AFFERENT FEEDBACK 
DURING EXERCISE IN HEART 
FAILURE 
 
NCT# 02659202 
 
February 5, 2016 

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Bruce D. Johnson, PhD 
 
CONFIDENTIAL 
 
 
SPINAL CORD STIMULATION TO INHIBIT AFFERENT 
FEEDBACK DURING EXERCISE IN HEART FAILURE 
 
 
Principal Investigator 
 
[Co-Investigator(s)] 
Bruce D. Johnson 
Division of Cardiovascular Diseases 
200 First St. SW Rochester MN 55901 
507-284-4375 
Funding Sponsor: 
Boston Scientific 
4100 Hamline Ave N 
St. Paul, MN 55112 
651-324-7352 
Study Product: 
Precision Spinal Cord Stimulator System 
Protocol Number: (IRBe) 
14-002521 
IDE Number: 
 
 
 
 
Initial version: 
4/03/2015 Version (1.0) 
Revised version:  
10/1/2015 (2.0)  
 
 
02/05/2016 Version (3.0) 
 
 

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Table of Contents 
STUDY SUMMARY ............................................................................................................................................ 5 
1 
INTRODUCTION ...................................................................................................................................... 6 
1.1 
BACKGROUND ...................................................................................................................................... 6 
1.2 
INVESTIGATIONAL DEVICE ................................................................................................................... 8 
1.3 
CLINICAL DATA TO DATE .................................................................................................................... 9 
1.4 
STUDY RATIONALE AND RISK/BENEFITS .......................................................................................... .10 
1.4.1 
Study Rationale ............................................................................................................................. 10 
1.4.2 
Anticipated Risks .......................................................................................................................... 10 
1.4.3 
Potential Benefits.......................................................................................................................... 11 
2 
STUDY OBJECTIVES ............................................................................................................................. 12 
2.1 
PRIMARY OBJECTIVE ......................................................................................................................... 12 
2.2 
SECONDARY OBJECTIVE .................................................................................................................... 12 
3 
STUDY DESIGN ...................................................................................................................................... 12 
3.1 
GENERAL DESIGN .............................................................................................................................. 12 
3.2 
PRIMARY STUDY ENDPOINTS ............................................................................................................. 13 
3.3 
SECONDARY STUDY ENDPOINTS ........................................................................................................ 13 
3.4 
PRIMARY SAFETY ENDPOINTS ............................................................................................................ 13 
4 
SUBJECT SELECTION, ENROLLMENT AND WITHDRAWAL.................................................... 13 
4.1 
INCLUSION CRITERIA ................................................................. ERROR! BOOKMARK NOT DEFINED.3 
4.2 
EXCLUSION CRITERIA ........................................................................................................................ 14 
4.3 
SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING .................................................................. 14 
4.4 
EARLY WITHDRAWAL OF SUBJECTS................................................................................................... 14 
4.4.1 
When and How to Withdraw Subjects .......................................................................................... 14 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects ............................................................. 15 
5 
STUDY DEVICE ...................................................................................................................................... 15 
5.1 
DESCRIPTION ..................................................................................................................................... 15 
5.2 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ........................................................... 18 
5.3 
PREPARATION AND ADMINISTRATION/IMPLANTATION OF INVESTIGATIONAL DEVICE ....................... 18 
5.4 
SUBJECT COMPLIANCE MONITORING ................................................................................................. 18 
5.5 
PRIOR AND CONCOMITANT THERAPY ................................................................................................ 18 
5.6 
PACKAGING AND LABELING ............................................................................................................... 18 
5.7 
BLINDING OF STUDY .......................................................................................................................... 19 
5.8 
RECEIVING, STORAGE, DISTRIBUTION AND RETURN .......................................................................... 19 
5.8.1 
Receipt of Investigational Devices................................................................................................ 19 
5.8.2 
Storage.......................................................................................................................................... 19 
5.8.3 
Distribution of Study Device ......................................................................................................... 19 
5.8.4 
Return or Destruction of Study Device ......................................................................................... 19 
6 
STUDY PROCEDURES .......................................................................................................................... 20 
6.1 
VISIT 1 ............................................................................................................................................... 20 
6.2 
VISIT 2 ............................................................................................................................................... 20 
7 
STATISTICAL PLAN .............................................................................................................................. 23 
7.1 
SAMPLE SIZE DETERMINATION .......................................................................................................... 23 
7.2 
STATISTICAL METHODS ..................................................................................................................... 24 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ........................................................................................... 25 
8 
SAFETY AND ADVERSE EVENTS ...................................................................................................... 25 

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8.1 
DEFINITIONS ...................................................................................................................................... 25 
8.2 
RECORDING OF ADVERSE EVENTS ..................................................................................................... 25 
8.3 
SPONSOR-INVESTIGATOR REPORTING OF UNANTICIPATED ADVERSE DEVICE EFFECTS AND 
UNANTICIPATED PROBLEMS ............................................................................................................................. 25 
8.3.1 
Sponsor-Investigator Reporting, Notifying Mayo IRB.................................................................. 25 
8.3.2 
Sponsor-Investigator Reporting: Notifying the FDA .................................................................... 28 
8.4 
UNBLINDING PROCEDURES (BREAKING THE BLIND) (AS NECESSARY IF THE STUDY IS BLINDED) ....... 29 
8.5 
STOPPING RULES ................................................................................................................................ 29 
8.6 
MEDICAL MONITORING ..................................................................................................................... 29 
9 
DATA HANDLING AND RECORD KEEPING ................................................................................... 29 
9.1 
CONFIDENTIALITY.............................................................................................................................. 29 
9.2 
SOURCE DOCUMENTS......................................................................................................................... 29 
9.3 
CASE REPORT FORMS ........................................................................................................................ 30 
9.4 
RECORDS RETENTION ........................................................................................................................ 31 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................ 31 
10.1 
STUDY MONITORING PLAN ................................................................................................................ 31 
10.2 
AUDITING AND INSPECTING ............................................................................................................... 31 
11 
ETHICAL CONSIDERATIONS ............................................................................................................. 31 
12 
STUDY FINANCES ................................................................................................................................. 32 
12.1 
FUNDING SOURCE .............................................................................................................................. 32 
12.2 
CONFLICT OF INTEREST ...................................................................................................................... 32 
12.3 
SUBJECT STIPENDS OR PAYMENTS ..................................................................................................... 32 
13 
PUBLICATION PLAN ............................................................................................................................ 32 
14 
REFERENCES ......................................................................................................................................... 32 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IDE 
Investigational Device Exemption 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
UADE 
Unanticipated Adverse Device Effect 
HF 
Heart Failure 
MOA 
Mechanism of Action 
 
 
 
 

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Study Summary 
Title 
Spinal Cord Stimulation to Inhibit Afferent Feedback during 
Exercise in Heart Failure 
Running Title 
SCS during exercise in HF 
IRB Protocol 
Number 
14-002521 
Phase 
Pilot 
Methodology 
Single blinded, randomized-order study 
Overall Study 
Duration 
Two years 
Subject 
Participation 
Duration 
Two visits, at least one week apart, total time = 28-30 hours, 
includes one overnight stay 
Objectives 
To determine the influence of lumbar epidural spinal cord 
stimulation and optimal frequency parameters on blood pressure 
and its components (cardiac output and systemic vascular 
resistance) during exercise in HF patients. 
Number of Subjects 
40 
Diagnosis and Main 
Inclusion Criteria 
Heart failure: Inclusion criteria for HF patients includes: no history 
of dangerous arrhythmia’s, not pacemaker dependent, body mass 
index ≤35kg/m2, current non-smokers with <15 pack year history, 
non-pregnant women, and individuals who are able to exercise (i.e. 
without orthopedic limitations or musculoskeletal disorders). 
Study Device 
Device: PrecisionTM stimulation system (or equivalent) , MOA: 
blocking locomotor afferent feedback to reduce blood pressure and 
systemic vascular resistance during exercise 
Duration of 
Exposure 
Temporary use. Device will be inserted on morning of visit 2, day 
one and will remain in place until the next morning after exercise: 
approximate 26-28 hours 
Reference therapy 
Reference is a placebo 
Primary Endpoint 
Mean arterial pressure as quantified as the mean computed over the 
last minute of each frequency challenge on Day 1 and Day 2 
Statistical 
Methodology 
The primary outcome measure will be tested using t-tests at the 
alpha=0.05 level of significance (two-sided). No interim analyses 
are planned.  
 
 
 

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1 Introduction 
• This document is a clinical research protocol for human research that investigates the 
use of spinal cord stimulation to reduce systemic vascular resistance and blood 
pressure in heart failure patients during exercise. 
• The described study will be conducted in compliance with the protocol, Good 
Clinical Practices standards and associated Federal regulations, and all applicable 
institutional research requirements.   
1.1 
Background 
 
HF is a complex clinical syndrome involving multiple physiologic systems and is a leading 
cause of death in North America 1. It has recently been suggested that the average life-span of 
a HF patient at the time of hospital discharge is ~5.5 years, with over 17% and 25% of patients 
having average life-spans of less than six months and one year respectively 2. The average life-
span varies considerably according to age, gender, baseline predicted mortality risk, left 
ventricular function, and comorbidity burden.  
 
Exercise Intolerance in Heart Failure 
Heart failure patients often are burdened with comorbidities involving the pulmonary, 
metabolic and neuromuscular systems 3, 4. For example, exercise intolerance, manifested by 
symptoms of fatigue and dyspnea, is a hallmark feature in HF and is likely influenced by a 
hyper-active sympathetic nervous system (driven in part by afferent feedback from locomotor 
muscles). Although mechanisms contributing to exercise intolerance in HF are not completely 
understood, there is strong evidence to suggest that symptom limited exercise capacity may be 
an indirect result from alterations in skeletal muscle 5. 
 
Skeletal Muscle Myopathy in Patients with Heart Failure 
Skeletal muscle in HF patients demonstrates significant myopathy as the disease progresses, 
although some of these changes may be inherently due to deconditioning 6. Alterations in 
skeletal muscle in HF, including atrophy of muscle fibers, a loss of type I (fatigue-resistant) 
and gain in type II (fast-fatigable) fiber area and decreased oxidative capacity 7, result in greater 
glycolytic metabolism during exercise. Enhanced glycolytic metabolic activity in the muscle 
will consequently increase the firing of mechano- (group III) and metabo- (group IV) receptors 
which send signals centrally via dorsal column of the spinal cord 8. A unifying term for the 
combined influence of mechano- and metabo-reflex mediated responses is the ergoreflex. 
Globally, this reflex is known to contribute to the cardiovascular and ventilatory responses to 
exercise in health and disease.  
 
Afferent feedback from Skeletal Muscle Contributes to Increases in Blood pressure 
The idea that signals from contracting muscles govern cardiovascular response to exercise 
dates to seminal studies in the 1930’s. Alam and Smirk showed that the increased arterial 
pressure during exercise was augmented by skeletal muscle ischemia and this response was 
maintained when exercise stopped but ischemia continued9. Since that time, numerous studies 
in animals10-12 and humans13, 14 have established the importance of afferent signaling from 
skeletal muscle in mediating the increase of sympathetic nerve activity and blood pressure 
during exercise. Importantly, skeletal muscle afferent activation has been shown to have a 

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stimulatory effect on sympathetic activity that is greater in HF compared with healthy 
controls15. For example, our laboratory has demonstrated that HF patients on optimal 
pharmacological treatments demonstrate an increased blood pressure response to metaboreflex 
stimulation after lower extremity exercise (Figure 1)16. In fact, it has been suggested that the 
ergoreflex in HF patients is closely linked to exercise intolerance resulting in increased 
dyspnea and sensations of fatigue (muscle hypothesis) 17. 
 
Evidence of Blocking Afferent Feedback with Fentanyl on Ventilation in HF 
HF patients demonstrate a greater ventilation for a given level of CO2 production when 
compared to those without heart failure (high VE/VCO2 = low ventilatory efficiency). Reduced 
ventilatory efficiency in HF patients is known to be related to reduced exercise tolerance, poor 
prognosis, and increased mortality18-20. Recently, we have shown that the increased ventilatory 
response in HF patients during exercise is driven by augmented afferent feedback from 
locomotor muscles21. When locomotor muscle afferent feedback to the supraspinal centers is 
inhibited (via intrathecal injection of fentanyl), the ventilatory response to exercise is 
significantly reduced22. These studies demonstrate that locomotor afferent feedback is an 
important signal in modulating physiological responses during exercise and when blocked can 
be attenuated and potentially improve exercise capacity.  
 
Impaired Peripheral Vascular Hemodynamics during Exercise in HF 
Several studies have indicated that the ability for HF patients to vasodilate peripheral 
vasculature during exercise is impaired23-27. Patients with HF have an increased systemic 
vascular resistance and reduced limb blood flow during dynamic exercise when compared with 
healthy controls23, 25. Importantly, LeJemtel et al. (1986) demonstrated that maximal limb 
blood flow did not increase in HF after regional administration of phentolamine, α-adrenergic 
blockade, during exercise, suggesting the ability of the muscle vasculature to vasodilate is 
impaired25. Overactivation of the sympathetic nerve activity contributes to the reduced ability 
of the vasculature to vasodilate and thereby limits the reduction in the peripheral vasculature 
during exercise28. Group III/IV muscle afferents are a strong contributor to this excessive 
sympathoexcitation29. Further, spinal cord stimulation of the lumbar spine may inhibit 
locomotor group III/IV afferent feedback and ultimately improve systemic vascular resistance 
during exercise in HF. 
 
Modulating Afferent Feedback via Epidural Spinal Cord Stimulation 
             
D iffe re n c e  in  M A P  (% )
-2 0
-1 5
-1 0
-5
0
5
1 0
C TL
HF
                           
D iffe re n c e  in  S B P   (% )
-2 0
-1 5
-1 0
-5
0
5
1 0
 
Figure 1. Blood pressure increased more so for heart failure (HF, n= 11) patients compared with healthy controls (CTL, n = 
11) with two minutes of metaboreflex stimulation (regional circulatory occlusion, RCO) of the lower extremity after a 
 A. 
B. 
NR
RCO 
NR
RCO 

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Modulation of afferent feedback via spinal cord stimulation has been used successfully for 
decades as a therapeutic approach for chronic pain; however, this is a novel therapeutic 
approach for use in patients with HF who demonstrate excessive cardiovascular responses to 
exercise. Several studies have demonstrated improvements in peripheral blood flow to the 
lower limbs in patients with peripheral vascular disease. Mechanisms causing the increase in 
blood flow are currently unclear, but two theories exist. One mechanism is that spinal cord 
stimulation attenuates sympathetic outflow, reduces vascular resistance and thus increases 
peripheral blood flow30, 31. The second mechanism is that spinal cord stimulation activates the 
ERK and AKT intracellular signaling pathways and releases GABA in the spinal gray matter 
that in turn, antidromically activates dorsal root afferent fibers32. These fibers increase 
peripheral vasodilation by releasing calcitonin gene-related peptide (CGRP) onto receptors on 
the blood vessel walls. In addition, CGRP activates nitric oxide-induced endothelium 
dependent vasodilation33-35. Recent studies also revealed that the capsaicin-sensitive sensory 
nerves (transient receptor potential vanilloid receptor (TRPV1) containing fibers; including 
unmyelinated C fibers and thin myelinated Aδ fibers are important in producing the spinal cord 
stimulation-induced vasodilation36-38. This proposal will be the first to investigate the influence 
of epidural spinal cord stimulation on peripheral locomotor afferent feedback during exercise 
in HF. Our preliminary results clearly demonstrate that spinal cord stimulation is safe and 
effective in healthy humans during exercise (Figure 2).  In addition, we will identify specific 
stimulation parameters that will optimize inhibition of locomotor afferent feedback and 
promote optimal cardiovascular responses. In addition, there is also some evidence that 
somatic afferents from skeletal muscle and the kidney are tonically active and drive a number 
of cardiovascular and respiratory derangements in resting patients with HF and resistant 
hypertension, and these afferents are also a target for the proposed therapeutic stimulation. 
1.2 
Investigational Device 
 
The Precision system will consist of a pulse generator that will not be implanted (external 
trial stimulator), temporary percutaneous leads, lead extensions, each packaged as a separate 
kit. The percutaneous leads function as a component of the Precision SCS system by 
delivering electrical stimulation to the nerve structures in the dorsal aspect of the spinal cord. 
Although this has typically been indicated for reductions in pain in chronic lumbar and lower 
leg pain patients, we will implant the leads in the same region of the lumbar spine, but will 
assess how spinal cord stimulation modulates blood pressure and systemic vascular 
resistance in heart failure patients. 
 
Class III Device - a device with the following characteristics: 
• Risk: high; devices that present serious risk; most typically are implanted and life-
supporting or life-sustaining, e.g. replacement heart valves, silicone gel-filled breast 
implants, cerebral stimulators 
• Special FDA controls through Pre-market review: The pre-market review involves a 
comprehensive evaluation, including data from clinical studies, and is required to 
ensure safety and effectiveness prior to marketing of the devices. This involves bench 
and animal tests, clinical trials, the submission of a Premarket Approval Application 
(PMA). 
 

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Category A Device 
A Category A device refers to an innovative device believed to be in Class III for which 
"absolute risk" of the device type has not been established (that is, initial questions of safety 
and effectiveness have not been resolved, and the FDA is unsure whether the device type can 
be safe and effective).  Note: Category A devices ARE NOT eligible for Medicare coverage. 
1.3 
Clinical Data to Date 
Keller-Ross ML, Johnson, BD, Joyner, MJJ, Olson, TP. Influence of the metaboreflex on 
arterial blood presure in heart failure patients. Am Heart J. In press. Heart failure patients 
(n=11, 51±15 yrs, mean ± SD)  and CTLs (n=11, 43±9 yrs) completed two sessions. For both 
sessions, participants exercised at 60% of peak work for 4 minutes and then were randomized 
to either 2 minutes of normal passive recovery (NR) or 2 minutes of RCO. Our results 
demonstrated 
that 
metaboreflex 
stimulation (via regional circulatory 
occlusion, 
RCO) 
of 
the 
lower 
extremities increased blood pressure for 
HF patients but not for controls (Figure 
1).  
 
Furthermore, preliminary data from our 
laboratory demonstrates that the use of 
spinal cord stimulation at 100 and 1000 
Hz during ischemic exercise and 
ergoreflex stimulation (RCO) caused a 
slight decrease in systemic vascular 
resistance and an increase in cardiac 
output with no changes in blood 
pressure.  Data is not significant, 
however due to small sample size. 
Seven healthy adults (25 ± 2 yrs) 
participated in 3 sessions of performing 
ischemic calf-raises for two minutes and 
then RCO for two minutes (without 
exercise). Ischemia was produced by 
use of RCO of the proximal thigh 
bilaterally (Figure 2). The stimulator 
frequency was randomized to 100 Hz, 
1000 Hz and off for the three separate 
sessions with 15 minutes separating the 
sessions. Hence, all sessions occurred 
on the same day. The spinal cord 
stimulator leads were inserted at L2-L3 
interspace and advanced to the inferior 
aspect of T11. An 8-contact trial spinal 
cord stimulator was used.  
 
Figure 2. Mean arterial pressure (MAP) (A), cardiac output (B) 
and systemic vascular resistance (SVR) (C) during exercise 
and ergoreflex stimulation in 7 (2 females) healthy adults. 
Base, resting conditions; ENDEX1, the end of the first minute of 
ischemic calf-raises; ENDEX2, end of the second minute of 
ischemic calf-raises; RCO1, end of the first minute of regional 
circulatory occlusion; RCO2, end of second minute RCO; REC 1, 
2 and 3 are recovery time points at one, two and three minutes. 

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1.4 
Study Rationale and Risk/Benefits 
1.4.1 Study Rationale 
 
Spinal cord stimulation is used clinically to treat chronic pain disorders 39, 40 and works by 
modulating afferent input at the dorsal column of the spinal cord 41. Recently, evidence 
suggests that lumbar spinal cord stimulation produced a marked improvement in blood flow to 
lower limbs in patients with peripheral vascular disease 42, 43.  Therefore, the use of spinal cord 
stimulation may be an innovative technique to reduce the systemic effects of 
sympathoexcitatory afferent feedback from the active muscle causing a potential reduction in 
sympathetic activation or an increase in peripheral vasodilation. In this context, the purpose of 
this proposal is to determine whether epidural spinal cord stimulation can modulate 
cardiovascular control during exercise in HF. A secondary purpose is to develop optimal 
stimulation parameters to attenuate sympathoexcitation by attenuating the blood pressure 
response or reducing systemic vascular resistance during exercise and ultimately improve 
exercise tolerance in HF. Our rationale is two-fold: first, we seek to develop an experimental 
tool which will permit us to study the contributions of muscle afferents to cardiovascular 
control during exercise without administering narcotics; and second, we seek to explore 
technologies that may ultimately lead to “device therapy” that will improve exercise tolerance 
in HF and other patients with excessive sympathoexcitation at rest and during exercise. 
Currently, there are no minimally invasive devices that provide anti-hypertensive treatment to 
clinical patients. The risks associated with spinal cord stimulation are very low. Dr. Lamer has 
implanted over 1000 stimulators in adults at the Mayo Clinic with no adverse events. In 
addition, we have completed 8 spinal cord stimulation insertions on healthy adults for the 
intended purposes of this study without adverse effects. The benefits of the outcomes of this 
study significantly outweigh the risks. This device could prove to be an effective treatment 
modality for hypertension in clinical patients as well as improve tolerance to exercise 
(symptoms of dyspnea and fatigue upon exertion) in HF patients.  
1.4.2 Anticipated Risks 
 
Exercise: The risks associated with vigorous exercise, usually defined as exercise requiring an 
oxygen uptake ≥6 METS or 21 ml/kg/min44 is associated with an increased risk of acute MI45, 
46 and sudden cardiac death47, 48 compared with less vigorous and sedentary activity. The risk 
of an acute myocardial infarction (heart attack) during or immediately after an exercise test in 
patients with suspected cardiac disease is less than or equal to 0.04%. 
 
Arterial Catheters: There is a minor risk of blood vessel spasm, formation of a clot, bruise, 
infection, or interruption of blood flow to the hand. In the event of a major clot formation in 
the vessels, surgical treatment may be required. In the event the arterial catheter cannot be 
successfully placed or needs to be removed, we will be utilizing a finger cuff for non-invasive 
blood pressure measurements. There are no known risks of this cuff, although, there may be 
mild discomfort similar to when a blood pressure cuff is inflated around the upper arm. 
 
Blood draw: The risks of drawing blood include pain, bruising, or in rare cases, infection at 
the site of the needle stick. 

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Breathing Gases: There are no known risks associated with breathing the cardiac output gas 
in the small amounts used in the study. 
 
ECG Electrodes: The adhesives from the electrodes may cause slight irritation to the skin. In 
rare occasions, the adhesive electrodes may cause an allergic reaction. The subject will be 
encouraged to let the principal investigator or study personnel know if they are feeling any 
itching or burning sensations from the electrodes. 
 
Thigh Cuffs: There are no known risks associated with the use of blood pressure cuffs on the 
thighs as used in this study, although there may be some mild discomfort similar to when you 
have a blood pressure cuff inflated on your arm. 
 
Spinal Cord Stimulator Placement: Placement of spinal cord stimulator will occur under 
local anesthesia (2% lidocaine). Therefore minimal pain will be felt with electrode placement. 
There may be bruising or bleeding at the needle puncture site. There is a risk for infection at 
the insertion site which is extremely rare in healthy patients. Soreness at the needle site may 
occur once the local wears off. This is typically very minor and either requires no treatment or 
simple over-the-counter treatments. On an extremely rare occasion, nerve root/spinal cord 
trauma with the placement may occur that may lead to paralysis. Dr. Lamer has implanted over 
1000 stimulators in adults at the Mayo Clinic with no adverse events. There is also a less than 
1% risk of dural puncture and a “spinal headache.” Spinal headaches may be present for 1-5 
days and usually resolve with conservative therapy (rest, fluids, and analgesics such as 
ibuprofen or acetaminophen). In some cases, a procedure known as a “blood patch” may be 
needed where the subject’s own blood will be injected using similar techniques as the 
placement of the stimulator. This procedure is safe and very effective in treating spinal 
headaches. This risk is lower when the procedure is performed by a highly experienced 
individual. 
 
Spinal Cord Stimulation: Patients may feel mild discomfort from the electrical stimulation. 
 
X-ray and Fluoroscopy: The spinal cord stimulator placement will occur under fluoroscopy. 
Patients will be exposed to low-levels of radiation. The amount of radiation that will be used 
has a low risk of harmful effects. 
 
Magnetic Resonance Imaging: There is no radiation associated with MRI, but people who 
have metal devices like pacemakers cannot have an MRI and will not be able to participate in 
the study. Some people with claustrophobia may feel too closed in and may not tolerate MRI 
scanning. If participants feel too confined in the MRI scanner, they can inform the technologist 
and the MRI scan will be stopped. The MRI machine makes loud knocking sounds when it is 
scanning. Because of this the subject will be asked to wear earplugs while getting the scan. 
The earplugs minimize discomfort from noise and keep the noise levels within the safety range. 
 
If a patient is regularly taking blood thinners or anticoagulant medications, to participate they 
will need to be able to come off them for the study. Their primary care physician will be 

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contacted to discuss if it is possible for the patient to come off this medications temporarily for 
the following time periods: 
• Coumadin- 6 days prior to the procedure. The INR needs to be normal.  Then the patient 
needs to be off the medication for the trial (2 days), for a total of 8 days off 
• Clopidogrel (Plavix)-7 days prior to the procedure. Then the patient needs to be off for 
the trial (2 days), for a total of 9 days off 
• Dabigatran (Pradaxa) -5 days prior to the procedure (total of 7 days off) 
• Rivaroxiban (Xarelto) -4 days prior to the procedure (total of 6 days off) 
• Apixiban (Eliquis)- 5 days prior to the procedure (total of 7 days off) 
• Ticagrelor (Brilinta)- 5 days prior to the procedure (total of 7 days off) 
• Aggrenox (Dipyridamole) - 7 days prior to the procedure (total of 9 days) 
• Aspirin (ASA) - 6 days prior to procedure. This is a shared decision process. If the 
patient is taking ASA for secondary prophylaxis, they may remain on ASA 
1.4.3 Potential Benefits 
 
We are studying a group of highly symptomatic patients with HF. Spinal cord stimulation 
may improve exercise capacity, daily activity tolerance, and overall quality of life by 
reducing fatigue and allowing patients to be more active. Future patients with symptomatic 
exercise intolerance may also benefit from the results of this study (i.e. other cardiovascular 
diseases, COPD, etc...) If spinal cord stimulation is found to significantly improve symptoms 
in HF, without excessive risk, it may become common practice for this population. 
 
2 Study Objectives 
 
2.1 Primary Objective 
To determine the influence of lumbar epidural spinal cord stimulation on blood pressure 
during exercise in HF patients. We will measure the influence of spinal cord stimulation on 
blood pressure response to lower extremity dynamic exercise with vascular occlusion (to 
stimulate the mechano- and metabo- reflex, i.e. ergoreflex). We hypothesize that blood 
pressure will be lower with spinal cord stimulation during exercise and activation of ergoreflex 
compared to without stimulation. 
 
2.2 Secondary Objective 
To develop optimal frequency parameters for attenuating blood pressure during 
exercise in HF patients. We will determine the optimal stimulation frequency parameters to 
attenuate the pressor response in HF. We hypothesize that blood pressure will be lower 
during higher frequencies of stimulation (~ 1 KHz) vs lower frequencies (100 Hz).  
3 Study Design 
3.1 
General Design 
Forty HF (>18 yrs. of age) will be recruited. The study will include a total of 2 visits. All 
experiments will take place at the Mayo clinic; at the outpatient radiology for MRI screening, 

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the Charlton CRU for surgical suite for spinal cord stimulation placement and the Saint Mary’s 
Hospital CRU for clinical exercise laboratory for the exercise protocol and overnight stay.  
 
Study visit 1 will include eligibility screening, consenting process, completion of an activity 
questionnaire and health questionnaire and performance of a peak VO2 test. Additionally, 
subjects will undergo a screening lumbar MRI to ensure that there are no anatomical anomalies 
in or around the epidural area consistent with standard clinical practice for epidural stimulator 
lead placement associated with chronic pain syndromes.  Study day one will take 
approximately 3 hours. 
Study visit 2 will include an overnight stay in the CRU. Patients will check in to the CRU in 
the morning of day 1, visit 2. Prior to placement of stimulating electrodes an INR will be 
checked to ensure safe clotting. An INR of < 1.5 will be required in order to continue with 
study procedures. An anesthesiologist will place the electrodes in the lumbar/thoracic epidural 
space in a manner that is standard for the clinical placement of temporary electrodes in humans. 
This will be done using local anesthesia with (2%) lidocaine and fluoroscopy to guide lead 
placement. After electrode placement, an arterial catheter will be placed in the radial artery for 
arterial blood pressure measurements by an anesthesiologist or respiratory therapist from the 
Anesthesia Clinical Research UnitThe participants will then transfer to the clinical exercise 
laboratory to start the exercise protocol. Participants will rest 15 minutes prior to starting 
exercise. Exercise will take place on a vertical bike where they will perform a submaximal 
cycling exercise at 30% of peak work for 29 minutes. In order to stimulate the mechano- and 
metabo-reflex (ergoreflex), thigh tourniquets will be placed on the proximal thigh bilaterally 
and inflated intermittently to pressures of 80 mmHg (See figure 3). In addition, the stimulator 
frequency will be turned on at two different frequencies ((~100 Hz – ~ 1 KHz, randomized) 
throughout the exercise. Studies performed in humans with use of spinal cord stimulation have 
indicated that frequencies up to 10 KHz are safe for humans 49-51. Measures of arterial blood 
pressure, heart rate, ventilation (VE) and gas exchange will be measured continuously 
throughout the exercise. Cardiac output (via the open-circuit acetylene wash-in technique), 
arterial blood gases, catecholamines and lactate will be measured intermittently throughout 
(see experimental paradigm). Systemic vascular resistance will be quantified by calculating 
MAP/CO. 
On day two of visit two, participants will repeat testing from day one with new randomization 
to determine reliability of testing performed on day one. After the exercise on day two of visit 
two, the spinal cord stimulator leads will be removed by an anesthesiologist (Dr. Lamer or Dr. 
Hoelzer). The radial arterial catheter will be removed by an anesthesiologist or a respiratory 
therapist from the Anesthesia Clinical Research Unit.  . Patients are free to leave the hospital 
once they feel recovered from exercising. 
3.2 
Primary Study Endpoint 
• Mean Arterial Pressure (see operationalized definition in Section 7) 
3.3    Secondary Efficacy Endpoint 
• Systemic Vascular Resistance 

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3.4 
Primary Safety Endpoints 
Data will be collected to determine: 
• Incidence of all serious adverse events including unanticipated adverse device effects 
• Incidence of device failures and malfunctions 
4 Subject Selection, Enrollment and Withdrawal 
4.1 
Inclusion Criteria 
 
Heart Failure patients with reduced ejection fraction: 
• 18-90 yrs. 
• Men and women 
• History of ischemic or idiopathic dilated cardiomyopathy (duration > 1 yr.), stable for 
>3 mo and New York Heart Association Class I-III. 
• Not pacemaker dependent 
• BMI ≤35 kg/m2 
• EF < 40% 
• Stable on optimal medications for > 3 mo. 
• Current nonsmokers with < 15 pack year history 
• Individuals who are able to exercise (i.e. without orthopedic limitations or 
musculoskeletal disorders) 
 
Patient Management/Cardiac Medications: Patients will need to be on standardized, 
state of the art, optimized therapy.  This was the approach taken by the large successful 
NIH supported HF Action Trial (Mayo was one of many sites)52.  Any potential subject 
that has not been on state of the art therapy will be put on optimized therapy and 
subsequently maintained on this for a minimum of 3 mo prior to study entry.  Changes 
to the management for whatever reason after “optimization” will require an additional 
30 days prior to entry. The standard of care for patients with stable class II - III HF due 
to systolic dysfunction generally includes the use of ACE inhibitors, diuretics, digoxin 
and beta-blockers.  A-II receptor blockers are frequently used for patients who cannot 
tolerate ACE inhibitors, usually due to cough. The majority of our preliminary data has 
been collected on local patients managed at Mayo who are on standard HF medications, 
although the population and etiology of HF was not as homogenous as proposed in 
these studies.  Although these medications may influence cardiopulmonary interactions 
in various ways, we feel it is important, practical and safe to study these patients under 
conditions of optimal care.  All standard pharmacotherapeutic agents for HF have 
effects on the neurohormonal modulation of this disorder. However, concurrent 
withdrawal of ACE-inhibitor, beta-blocker, digoxin and diuretic would likely be 
associated with modest decompensation in a high proportion of patients.  Accordingly, 
the impact of our studies will be applicable to a HF population receiving standard 
optimized therapy. All patients will be managed by their primary care physician or 
cardiologist with additional review by Dr. Barry Borlaug (Co-Investigator) prior to 
enrollment to ensure inclusion and exclusion criteria have been satisfied and 
participation in exercise testing is safe.  

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4.2 
Exclusion Criteria 
 
All participants:  
• History dangerous arrhythmias  
• Women that are currently pregnant 
• Patients taking prescribed opioid medications or have had a fusion or laminectomy at 
L3 or above. 
• Patients with a recent drug-eluding stent  
• History of spinal stenosis, lumbar radiculopathy, or peripheral neuropathy will be 
excluded from this study due to potential complications associated with the spinal cord 
lead implantation. 
• Must not currently be taking blood thinners or anticoagulant medications. If a patient 
is on such medications, their primary care physician will be contacted to discuss if it 
is possible for the patient to come off this medications temporarily for the following 
time periods: 
o Coumadin- 6 days prior to the procedure. The INR needs to be normal.  Then the 
patient needs to be off the medication for the trial (2 days), for a total of 8 days off 
o Clopidogrel (Plavix)-7 days prior to the procedure. Then the patient needs to be off 
for the trial (2 days), for a total of 9 days off 
o Dabigatran (Pradaxa) -5 days prior to the procedure (total of 7 days off) 
o Rivaroxiban (Xarelto) -4 days prior to the procedure (total of 6 days off) 
o Apixiban (Eliquis)- 5 days prior to the procedure (total of 7 days off) 
o Ticagrelor (Brilinta)- 5 days prior to the procedure (total of 7 days off) 
o Aggrenox (Dipyridamole) - 7 days prior to the procedure (total of 9 days) 
o Aspirin (ASA) - 6 days prior to procedure. This is a shared decision process. If the 
patient is taking ASA for secondary prophylaxis, they may remain on ASA. 
 
4.3 
Subject Recruitment, Enrollment and Screening 
 
Subject Recruitment: The majority of HF patients will be recruited from the Heart Failure (HF) 
Clinic and the Cardiovascular Health Clinic (CVHC) in the Division of Cardiovascular 
Diseases of Mayo Clinic, as well as from the surrounding community. Presently, the HF Clinic 
averages over 150 new patients per month, assesses over 2,000 HF patients per year, and admits 
over 700 HF patients to the hospital practice per year. The CVHC performs over 40 treadmill 
exercise tests with gas exchange monthly on patients with reduced LV function. In addition, 
approximately 30% of our rehabilitation population has reduced LV function.  
4.4 
Early Withdrawal of Subjects 
4.4.1 When to Withdraw Subjects 
 
A patient may be withdrawn from the study at any time, before or after implantation of the 
spinal cord stimulator, and prior to that subject completing all of the study related 
procedures. Because of the invasive nature of this study, investigators will do everything 

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possible to avoid withdrawing patients from this study after implantation. Some reasons to 
withdraw may include: 
• Subject safety issues and adverse device effects or complications 
• Failure of the subject to adhere to protocol requirements 
• Subject decides to withdraw from the study (withdrawal of consent) 
 
Investigators may choose to replace that subject with a newly enrolled subject in order to 
maintain sample size.  
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
 
If a patient withdraws from the study for any reason, and cannot or will not complete the 
investigational aspects of the study, they will be withdrawn from the study with immediate 
follow-up to be sure of no adverse events related to study procedures.  
5 Study Device 
 
The precision system will consist of a pulse generator that will not be implanted, temporary 
percutaneous leads, surgical paddle leads and lead extensions, each packaged as a separate 
kit. The percutaneous and surgical paddle leads function as a component of the Precision 
SCS system by delivering electrical stimulation to the nerve structures in the dorsal aspect of 
the spinal cord. Although this has typically been indicated for reductions in pain in chronic 
lumbar and lower leg pain patients, we will implant the leads in the same region of the 
lumbar spine, but will assess how spinal cord stimulation modulates blood pressure and 
systemic vascular resistance in heart failure patients. 
5.1 
Description 
 
Features of the Precision SCS System Include: 
• Stimulation electrode field navigation 
• Sixteen independent current-controlled electrodes 
• High-range parameter capability 
• No detectable latex 
 
Implantable Pulse Generator 
The precision implantable pulse generator is intended to electrically stimulate the spinal cord. 
The multi-channel, multi-electrode device capability provides flexibility in conjunction with 
ease of programming. Because this device is intended for permanent placement in chronic 
pain patients it is implantable. The device will not be implanted in this study, but will be 
secured to the patient’s skin by adhesive tape until the study procedures are completed. 
 
Percutaneous Leads 
The eight-contact percutaneous leads are available in lengths of 30 cm, 50cm, and 70cm. 
Each lead has eight electrode contacts located near the distal end. Each contact is 3 mm from 
the adjacent contact. The Infinion™ 16 percutaneous lead is available in lengths of 50 cm 

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and 70 cm. Each lead has 16 contacts located near the distal end. Each contact is 3 mm in 
length and is spaced 1 mm from the adjacent contact. 
 
The intended purpose of this device is to investigate if spinal cord stimulation of the lumbar 
spine can modulate blood pressure and systemic vascular resistance in heart failure patients. 
The physician will be provided with a new Precision Kit for each participant. The physician 
that will be inserting the leads has been adequately trained to do so and has performed this 
procedure on over 1000 patients at the Mayo Clinic for chronic pain indications. 
 
Percutaneous Lead Placement in the Epidural Space 
1. Position, prep and drape the patient in the usual accepted manner. Inject a local anesthetic 
at the needle insertion site. 
 
2. Under fluoroscopic guidance, place the insertion needle into the epidural space with the 
bevel facing up using an angle of 45° or less. 
WARNING: The angle of the insertion needle should be 45° or less. Steep angles increase 
the insertion force of the stylet and also present more of an opportunity for the stylet to pierce 
the lead and cause tissue damage. 
 
3. Remove the needle stylet from the insertion needle and verify entry into the epidural space 
using the standard technique. 
 
4. OPTIONAL. Under fluoroscopic guidance, insert the lead blank through the insertion 
needle and into the epidural space. Advance the lead blank to verify entry into the epidural 
space, and then withdraw the blank. 
 
5. While holding the lead stylet handle, place the steering cap over the proximal end of the 
stylet handle with moderate force until it is held in place. Then slowly insert the lead, with 
stylet, through the insertion needle. The lead stylet should extend to the tip of the lead. 
 
6. OPTIONAL. If exchange of the lead stylet is desired, carefully pull out the existing stylet 
and insert the preferred stylet. While inserting the stylet into the lead, if resistance is 
encountered, withdraw the stylet approximately 3 cm, rotate the lead and/or stylet, and gently 
advance the stylet. If resistance is still encountered, repeat the above procedure. 
 
Connecting the OR cable Assembly 
The OR cable assembly is designed for temporary connection of a lead to the Trial 
Stimulator. A cable extension is provided. When using a Splitter 2x8 prepare two OR Cable 
Assemblies. 
 
CAUTION: Do not immerse the OR cable connector or plug in water or other liquids. The 
OR Cable Assembly is intended for one-time only use; do not resterilize. 
 
1. If two leads are being implanted, wrap the non-sterile “1-L” and “2-R” labels around the 
cables at the Trial Stimulator to identify lead connections. 
 

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2. Verify that the Trial Stimulator is off. 
 
3. Check that the locking lever on the OR cable connector is in the open position, marked 
“0”. 
 
4. For Percutaneous Leads, remove the steering cap from the stylet and slide the proximal 
end of the lead with stylet, or splitter, into the open port on the OR cable connector. 
 
5. Push the end of the lead or splitter into the port until it stops. Hold the lead in place while 
sliding the lever to the locked position, marked “1”. 
 
6. Plug the OR Cable Assembly into the corresponding Trial Stimulator port(s) labeled “1-L” 
(left) and “2-R” (right). Superior (upper or left) leads connect to port “1-L”. Inferior (lower 
or right) leads connect to port “2-R”. If only a single lead is being used, connect it to “1-L”. 
 
Note: If using a Splitter 2x8, connect the cable labeled “1-L” to the laser-marked tail, and 
the cable labeled “2-R” to the unmarked tail. 
 
7. Proceed to the instructions for “Intraoperative Stimulation Testing” page 23. 
 
Intraoperative Stimulation Testing 
 
Note: The following steps are for procedural reference only. Please refer to the 
BionicNavigator Software Guide for detailed stimulation testing procedures and guidelines. 
 
1. If using a splitter: 
• Visually check splitter to leads connection 
• Check impedance 
Note: If using the 2x4 Splitter, make note of splitter configuration in the 
BionicNavigator™ software per Splitter Programming Guide. 
 
2. After linking the Clinician Programmer to the Trial Stimulator, check impedances to verify 
that components are properly connected. Lead impedance is measured and displayed for each 
of the IPG’s 16 electrode contacts. Impedances over 4500 Ohms are considered to be 
resultant from open or unconnected wires, displayed with an X. 
 
3. Using test stimulation, enlist patient feedback to verify lead placement and pain coverage. 
 
Note: If lead repositioning is necessary, turn stimulation off before proceeding. 
 
4. Reposition leads as necessary. If using a splitter, gently pull on lead attached to splitter to 
reposition caudal or disconnect splitter from leads, re-insert stylet, and advance leads to 
reposition cephalad. 
 
CAUTION: Do not force stylet into lead. 
 

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5. Steer lead to new position. 
 
6. Remove stylet, wipe proximal ends of leads and reconnect splitter. 
 
7. Check impedances. 
 
8. Repeat steps 1-3 if lead has been repositioned. 
 
9. When the desired paresthesia is achieved: 
a) Turn the Trial Stimulator off. 
b) Unlock each OR cable connector and disconnect from the lead(s). 
c) For percutaneous lead(s) – slowly withdraw the stylet(s). 
 
10. Record the lead position by capturing a fluoroscopic image to be sure the leads have not 
moved. Retest if necessary. 
 
11. If using a splitter, disconnect splitter from leads. Insert the hex wrench and turn the set 
screw counter clockwise to loosen. 
 
Note: • The set screw should only be loosened to an amount sufficient to insert a lead. 
 
• Do not excessively loosen the set screw. This may cause the set screw to dislodge, 
rendering the splitter unusable. 
 
5.2 
Method for Assigning Subjects to Treatment Groups 
 
• The participants (both HF and Controls) will all undergo the same procedures. The 
stimulation frequency will be randomized within each trial. 
5.3 
Preparation and Administration/Implantation of Investigational Device 
 
All participants will receive the same device; there will not be a sham procedure or device. 
On study visit day one, consent for the study will be obtained as well as other study 
procedures (Refer to figure 1). On study visit 2, day one, the spinal cord stimulator leads will 
be implanted in the morning in the CRU at the Mayo Clinic. The device will be on during 
exercise periods. Participants will exercise on day one and two of study visit two and then the 
leads will be removed before the patient is released from the study. 
5.4 
Subject Compliance Monitoring 
 
Subjects will remain in the hospital overnight and will be monitored throughout. 
5.5 
Prior and Concomitant Therapy 
 

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We will collect information on current medications at the baseline visit. There will not be 
restrictions on medications for heart rate/rhythm and blood pressure that can be used during 
the study in heart failure patients. 
5.6 
Packaging and Labeling 
 
All devices and components to be used in this study are market-approved, and will be 
obtained from the manufacturer Boston Scientific in their original packaging. Labeling 
includes the device model and serial number. 
 
“CAUTION – Investigational Device. Limited by Federal (or United States) law to 
investigational use”  
 
The label shall describe all relevant contraindications, hazards, adverse effects, interfering 
substances or devices, warnings and precautions and be affixed to the investigational device. 
5.7 
Masking/Blinding of Study 
 
Participants will be blinded to the frequency of stimulation as well as other stimulation 
parameters during the study. 
5.8 
Receiving, Storage, Distribution and Return 
5.8.1 Receipt of Investigational Devices 
 
The Precision kit will be obtained from the manufacturer Boston Scientific. Upon receipt of 
the devices, inventory and logs will be managed by study personnel to maintain device 
accountability. Any damaged or unusable devices will be exchanged and documented.  
5.8.2 Storage 
 
The precision kit will be stored in their original packaging at room temperature in containers 
by study personnel. They will be marked with the required labels and relevant 
contraindications, hazards, adverse effects, interfering substances or devices, warnings and 
precautions. 
5.8.3 Distribution of Study Device 
 
The precision kit will be distributed to the implanting physicians and their team before the 
procedure. The specific serial numbers will be documented. Devices will only be distributed 
immediately before the procedure. 
5.8.4 Return or Destruction of Study Device 
 
At routine intervals and at the completion of the study, there will be a reconciliation of 
devices shipped, devices utilized, and devices remaining.  This reconciliation will be logged 

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on the Device Accountability form, signed and dated.  Any discrepancies noted will be 
documented, the sponsor-investigator will be notified and an investigation will be conducted 
to determine the cause of the discrepancy.  Devices destroyed on site will be documented in 
the study files. 
6 Study Procedures 
6.1 
Visit 1 
 
Study visit 1 will include eligibility screening, consenting process, completion of an activity 
questionnaire and health questionnaire and performance of a peak VO2 test. Additionally, 
subjects will undergo a screening lumbar MRI to ensure that there are no anatomical anomalies 
in or around the epidural area consistent with standard clinical practice for epidural stimulator 
lead placement associated with chronic pain syndromes.  Study day one will take 
approximately 3 hours. 
6.2 
Visit 2 
Study visit 2 will include an overnight stay in the CRU. Patients will check in to the CRU in 
the morning of day 1, visit 2. An anesthesiologist will place the electrodes in the 
lumbar/thoracic epidural space in a manner that is standard for the clinical placement of 
temporary electrodes in humans. This will be done using local anesthesia with (2%) lidocaine 
and fluoroscopy to guide lead placement. After electrode placement, an arterial catheter will 
be placed in the radial artery for arterial blood pressure measurements by an anesthesiologist 
or a respiratory therapist from the Anesthesia Clinical Research Unit. The participants will 
then transfer to the clinical exercise laboratory to start the exercise protocol. Participants will 
rest 15 minutes prior to starting exercise. Exercise will take place on a vertical cycle ergometer 
where they will perform a submaximal cycling exercise at 30% of peak work for approximately 
30 minutes. In order to stimulate the mechano- and metabo-reflex (ergoreflex), thigh 
tourniquets will be placed on the proximal thigh bilaterally and inflated intermittently to 
pressures of 80 mmHg at 3 min intervals and deflated for 5 min to allow for wash out (See 
figure 3). In addition, the stimulator frequency will be turned on at two different frequencies, 
a high (~1 KHz) and low (~100 Hz) frequency throughout the exercise. Measures of arterial 
blood pressure, heart rate, ventilation (VE) and gas exchange will be measured continuously 
throughout the exercise. Cardiac output (via the open-circuit acetylene wash-in technique), 
arterial blood gases, catecholamines and lactate will be measured intermittently throughout 
(see experimental paradigm). Systemic vascular resistance will be quantified by calculating 
MAP/CO. Barry Borlaug, a HF cardiologist will be available during the experimental sessions. 
On day two of visit two, participants will repeat testing from day one with new randomization 
to determine reliability of testing performed on day one. After the exercise on day two of visit 
two, the spinal cord stimulator leads will be removed by an anesthesiologist (Dr. Lamer or Dr. 
Hoelzer).. The radial arterial catheter will be removed by the supervising physician or a 
respiratory therapist from the Anesthesia Clinical Research Unit. Patients are free to leave the 
hospital once they feel recovered from exercising. 
Follow-up: A phone call to the participant will be placed 2-3 days after the study to confirm 
that no adverse events have taken place as a result of the study.  

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At least one week will take place between study visit one and two.  
Study Procedures 
 
Peak Oxygen Consumption Testing (VO2 peak) (Visit 1): We will use a modified graded cycle 
ergometry protocol with increases in intensity of 20 watts / 3 minutes (HF patients) or 40 watts 
every 3 minutes (CTL) to volitional fatigue. We will use this test to determine specific 
submaximal workload intensities (30% of peak VO2) for the subsequent individual study visit. 
Our laboratory has extensive experience with exercise testing in clinical HF patients. 
 
Measurement of Blood Pressure (Visit 2): We will use an indwelling 20 gauge arterial catheter 
placed in the radial artery of the non-dominant hand. The catheter will be placed (after an 
Allen's test demonstrates adequate ulnar blood flow) using aseptic technique via ultrasound 
guidance after local anesthesia with lidocaine. It will be flushed continuously at 3 cc/hr 
w/sterile saline. This catheter will allow for continuous real-time intra-arterial measurement of 
beat-to-beat blood pressure. In the event that an arterial line cannot be placed, or it has to be 
removed during the overnight stay of visit 2, non-invasive continuous blood pressure 
measurements will be made using the Finapres or Nexfin monitoring systems. Either system 
utilizes a finger cuff to provide beat by beat blood pressure determination as well as other 
hemodynamic parameters. 
 
Measurement of Cardiac Output and Systemic Vascular Resistance (All Visits): During the 
measurement of gas exchange and ventilation as described above, cardiac output will be 
measured using the open-circuit acetylene (C2H2) gas wash-in technique as described by Stout 
et al. 53 and refined by Gan et al. 54 and Nielson et al. 55 and validated in our laboratory 56. We 
have demonstrated that the open-circuit technique for measurement of cardiac output is 
accurate, reproducible, and sensitive. Systemic vascular resistance will be calculated by 
MAP/CO. 
 
Measurement of Gas Exchange and Ventilation (All Visits): Volume of oxygen consumed 
(VO2), volume of carbon dioxide produced (VCO2), breathing frequency (fb), tidal volume 
(VT), minute ventilation (VE), partial pressure of end-tidal oxygen and carbon dioxide (PETO2 
and PETCO2, respectively) and derived variables (e.g. VE/VO2 and VE/VCO2) will be measured 
using a low resistance open circuit automated metabolic system (Medical Graphics Co., St. 
Paul, MN) integrated with a mass spectrometer (Perkin Elmer, model 1100). A formal 
validation of this system has been performed using Douglas bags, Tissot, and calibration gases 
for measurement of VE, VO2 and VCO2. Volume calibration will be performed with a 3-liter 
syringe and gas calibration performed with manufacturer recommended gases of known 
concentration.  
 
Measurement of Arterial Blood Gases, catecholamines, lactate, and heart rate (Visit 2, Day 1 
& 2): We will use an indwelling 20 gauge arterial catheter placed in the radial artery of the 
non-dominant hand. The catheter will be placed (after an Allen's test demonstrates adequate 
ulnar blood flow) using aseptic technique via ultrasound guidance after local anesthesia with 
lidocaine. It will be flushed continuously at 3 cc/hr w/sterile saline. This catheter will provide 
access to arterial blood for measurement of blood gases (pH, PaCO2, PaO2, and oxygen 

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saturation), catecholamines and lactate. Participants will be instrumented with a 12 lead ECG 
for the measurement of heart rate and rhythm. Participants will be verbally encouraged to reach 
maximal effort, determined by the respiratory exchange ratio (RER >1.10) and a rating of 
perceived exertion ≥ 18 on the Borg 6-20 scale 57. 
 
Measurement of Perceived Exertion and Dyspnea (All Visits): Dyspnea will be measured using 
the modified Borg analog/visual scale. Because perception of dyspnea consists of sensory 
(intensity) and affective (unpleasantness) dimensions we will use a scale which provides a 
number, text description, and picture description of each progressive level of dyspnea during 
exertion as previous described 58-60. In addition, we will include measurements of total body 
fatigue and specific leg fatigue. For this we will use the traditional and well validated Borg 
scale of perceived exertion. These scales has been used extensively over the last 40 years and 
are validated for the determination of dyspnea and fatigue during exercise 57. In addition, we 
will use the Faces Pain Scale-Revised (FPS-R) during visit 2. 
 
Figure 3. Study Procedures 
 
 
 
 

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7 Statistical Plan 
7.1 
Sample Size Determination 
 
The sample size is estimated to be 40 participants. The calculation and assumptions made are 
detailed below. 
 
Statistical Hypotheses 
Null hypotheses: The one minute mean MAP measured at times 12, 20 and 28 minutes on 
day 1 will be equal. 
 
Alternative hypothesis: The contrast testing if the MAP averaged over frequencies 1 and 2 is 
different than the MAP measured with the device inactive.  
 
Statistical notation: Let mu_f1, mu_f2, and mu_f0ff denote the low, high and off frequencies 
for each patient. The hypotheses of interest, are then as follows: 
 
H0: (mu_f1 + mu_f2)/2 = mu_fOff 
Ha: (mu_f1 + mu_f2)/2 < mu_fOff 
 
Assumptions: 
. 
Schedule of Events 
Study Activity 
Visit 1 
Visit 2:day 1 
Visit 2:day 2 
 
 
 
 
Consent 
X 
 
 
History 
X 
 
 
Physical Exam 
X 
X 
X 
Case Report Forms 
X 
X 
X 
VO2 peak exercise test 
X 
 
 
Exercise 
X 
X 
X 
Rating of perceived exertion 
X 
X 
X 
Rating of dyspnea (labored breathing) 
X 
X 
X 
Rating of pain 
 
X 
X 
Device Implantation 
 
X 
 
Device in place 
 
X 
X 
Stimulation during exercise 
 
X 
X 
Device removal 
 
 
X 
EKG 
X 
X 
X 
Measurements of gas exchange 
X 
X 
X 
Measurement of cardiac output with open-circuit 
acetylene 
X 
X 
X 
Arterial line in place / finger cuff 
 
X 
X 
Concurrent Medications 
X 
X 
X 
Adverse Events 
 
X 
X 
Serious Adverse Events 
 
X 
X 
 

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• Primary endpoint: Mean arterial pressure (MAP) obtained as the one-minute mean 
pressure measured at the end of each frequency, 80% cuff challenge (12-13 minutes 
for f1, 20 – 21 minutes for fOff, and 28-29 minutes for f2).  
• Sample size formula for a one sample t-test  
• Two-sided testing at the alpha=0.05 level of significance 
• No interim analyses 
 
To estimate the sample size, we assume that the change between the device off setting 
and the mean MAP for the two active frequencies will be similar to the change observed 
in a recently completed study examining the effects of Fentanyl. In this study, the 
mean±SD MAPs at end exercise in the placebo and Fentanyl conditions were 111±13 and 
with 103±17, respectively. We expect the correlations in the within subject measurements 
to be high, but we conservatively estimate the correlation to be 0.5 (to allow the SD of 
the change to be equal to the SD of the pooled estimate) and assume the larger SD will be 
the pooled estimate (SD = 17) (i.e., estimated difference in HF will be 8±17). This effect 
size of 0.471 requires 38 participants to achieve 80% power with the assumptions listed 
above. To account for potential attrition and measurement issues, we will plan to enroll 
40 participants.  
 
7.2 Statistical Methods 
 
Descriptive Statistics 
 
Analysis / Interpretation 
 
General Statistical Methods. HF patients will undergo submaximal exercise and ergoreceptor 
activation with spinal cord stimulation at different frequency parameters to target afferent 
neural feedback. Continuous variables will be presented as mean±SD. Categorical variables 
will be presented as number (% population). Distribution normality will be assessed and 
transformations or non-parametric methods will be used as appropriate as sensitivity analyses 
to the planned primary analysis. Analyses will be conducted with SPSS (v19 or higher) and 
The SAS System (v9.4 or higher).  
 
Primary Outcome Analysis.  The one minute mean MAP measured at the end of the three 
frequency challenges on day 1 will be the compared using a blocked (on subject) ANOVA 
model. The estimated mean MAP for each of the three frequencies will be estimated by the 
model. The primary hypothesis will test if the pooled effect of the active frequencies (f1, f2) 
is statistically different from the MAP with the device inactive. This test will be conducted 
using a type III estimate of the contrast indicated above in the sample size section. This is 
considered the omnibus test of the device effect. Post hoc comparisons of the individual 
frequencies will also be conducted as a part of the optimization approach. It is not known if 
the “dose response” relationship is monotonic (i.e., higher frequency is strictly superior in all 
subjects). Therefore, further analysis will be done to determine the association between the 
MAP and frequency of spinal cord stimulation to understand the dose-response curve. 
 
Handling of Missing Data 

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Every effort will be made to ensure missing data is kept at a minimum. When entering data 
into the database, outliers or invalid data will be investigated to check accuracy. Because of 
the relatively small size of this study, it should be feasible to keep missing data below 5% 
and avoid the use of imputation.  
 
Level of Significance and Multiplicity Adjustment 
 
The primary outcome will be tested at the alpha=0.05 (two-sided) level of significance. No 
correction will be applied to secondary or exploratory analyses conducted (i.e., comparisons 
of each frequency to the inactive state).  
 
Interim Analysis 
 
There is no plan to conduct an interim analysis or stop early. This is a cross-over design so 
analysis would be difficult without participants having crossed over to the opposite group. 
7.3 
Subject Population(s) for Analysis 
 
Subject population for analysis will be any subject (HF patient or control participant) who is 
randomized, implanted with the device, and completed both halves of the crossover study. 
8 Safety and Adverse Events 
 
All adverse events occurring during the study, including those not meeting the criteria of an 
Unanticipated Adverse Device Effect (UADE) will be recorded on the appropriate case 
report form.  Records of these events will be maintained and reports submitted to the FDA 
and IRB according to the regulatory requirements.  Expected clinical adverse events and 
nonsignificant (not serious) clinical adverse events will not be reported. Expected clinical 
adverse events and anticipated adverse device effects are those listed in Section 1.5.2. 
8.1 
Definitions 
 
Unanticipated Adverse Device Effect (UADE) 
A UADE is any serious adverse effect on health or safety or any life-threatening problem or 
death caused by, or associated with, a device if that effect, problem or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan or 
IDE application (including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects. 
 
Adverse Effect (Event) 
Any untoward medical occurrence in a subject involved in clinical study of an investigational 
device; regardless of the causal relationship of the problem with the device or, if applicable, 
other study related treatment(s). 
 

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General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an adverse event must also be recorded and documented as an adverse 
event. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as an unanticipated adverse device effect unless specifically 
instructed otherwise in this protocol.  Any condition responsible for surgery should be 
documented as an adverse event if the condition meets the criteria for an adverse event. 
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At the 
last scheduled visit, the local investigator should instruct each subject to report, to the local 
investigator, any subsequent event(s) that the subject, or the subject’s personal physician, 
believes might reasonably be related to participation in this study.  The local investigator 
should notify the study regulatory sponsor of any death or adverse event occurring at any 
time after a subject has discontinued or terminated study participation that may reasonably be 
related to this study.  The sponsor should also be notified if the local investigator should 
become aware of the development of problems, cancer or of a congenital anomaly in a 
subsequently conceived offspring of a subject that has participated in this study. 
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets all of the following three criteria: 
• 
Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for the 
subject or others (including individuals who are not research subjects). These include: 
(1) death; (2) life threatening adverse experience; (3) hospitalization - inpatient, new, 
or prolonged; (4) disability/incapacity - persistent or significant; (5) birth 
defect/anomaly; (6) breach of confidentiality and (7) other problems, events, or new 
information (i.e. publications, DSMB reports, interim findings, product labeling 
change) that in the opinion of the local investigator may adversely affect the rights, 
safety, or welfare of the subjects or others, or substantially compromise the research 
data. 
• 
Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, consent document, not listed in the 
Investigator’s Brochure, or not part of an underlying disease. A problem or event is 
"unanticipated" when it was unforeseeable at the time of its occurrence. A problem or 

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event is "unanticipated" when it occurs at an increased frequency or at an increased 
severity than expected. 
• 
Related: A problem or event is "related" if it is possibly related to the research 
procedures. 
 
Adverse Event Reporting Period 
 
For this study, the study treatment follow-up period will end on day two of the final visit. No 
further monitory for adverse events will be performed after the final visit  
8.2 
Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Study subjects will be routinely 
questioned about adverse effects at study visits. Information on all adverse events should be 
recorded immediately in the source document, and also in the appropriate adverse event 
section of the case report form (CRF) or in a separate adverse event worksheet.  All clearly 
related signs, symptoms, and abnormal diagnostic, laboratory or procedure results should 
recorded in the source document. 
 
All adverse events occurring during the study period must be recorded.  All observed or 
volunteered adverse effects (serious or non-serious) and abnormal test findings, regardless of 
the treatment group if applicable or suspected causal relationship to the investigational device 
or if applicable other study treatment or diagnostic product(s) will be recorded in the 
subjects’ case history.  For all adverse effects sufficient information will be pursued and or 
obtained as to permit; an adequate determination of the outcome, an assessment of the casual 
relationship between the adverse effect and the investigational device or, if applicable other 
study treatment or diagnostic product.  The clinical course of each event should be followed 
until resolution, stabilization, or until it has been ultimately determined that the study 
treatment or participation is not the probable cause.  Serious adverse events that are still 
ongoing at the end of the study period must be followed up, to determine the final outcome.  
Any serious adverse event that occurs after the study period and is considered to be at least 
possibly related to the study treatment or study participation should be recorded and reported 
immediately. 
8.3 
Sponsor-Investigator Reporting of Unanticipated Adverse Device Effects and 
Unanticipated Problems 
When an adverse event has been identified, the study team will take appropriated action 
necessary to protect the study participant and then complete the Study Adverse Event 
Worksheet and log.  The sponsor-investigator will evaluate the event and determine the 
necessary follow-up and reporting required. 
 
The sponsor-investigator will promptly review documented Unanticipated Adverse Device 
Effects and as necessary shall report the results of such evaluation to FDA within 10 working 
days and Mayo IRB within 5 working days of initial notice of the effect.  Thereafter the 
sponsor-investigator will submit such additional reports concerning the effect as requested. 

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8.3.1 Sponsor-Investigator Reporting, Notifying Mayo IRB 
The sponsor-investigator will report to the Mayo IRB any UPIRTSOs and Non-UPIRTSOs 
according to the Mayo IRB Policy and Procedures. 
8.3.2 Sponsor-Investigator Reporting: Notifying the FDA 
The sponsor-investigator will report to the FDA all unanticipated adverse device effects 
according to the required reporting timelines, formats and regulations. 
 
The sponsor-investigator will submit a completed FDA Form 3500A to the FDA’s Center for 
Devices and Radiological Health for any observed or reported adverse effect that is 
determined to be an unanticipated adverse device effect.  A copy of this completed form will 
be provided to the DSMB and all participating sub-investigators. 
 
The completed FDA Form 3500A will be submitted to the FDA as soon as possible and, in 
no event, later than 10 working days after the sponsor-investigator first receives notice of the 
adverse effect. 
 
If the results of the sponsor-investigator’s follow-up evaluation shows that an adverse effect 
that was initially determined to not constitute an unanticipated adverse device effect does, in 
fact, meet the requirements for reporting; the sponsor-investigator will submit a completed 
FDA Form 3500A as soon as possible, but in no event later than 10 working days, after the 
determination was made. 
 
For each submitted FDA Form 3500A, the sponsor-investigator will identify all previously 
submitted reports that that addressed a similar adverse effect experience and will provide an 
analysis of the significance of newly reported adverse effect in light of any previous, similar 
report(s). 
 
Subsequent to the initial submission of a completed FDA Form 3500A, the sponsor-
investigator will submit additional information concerning the reported adverse effect as 
requested by the FDA. 
 
Reporting Process 
Unanticipated Adverse Device Effect reports will be submitted on FDA Form 3500A. 
The contact information for submitting reports is: 
 
Food and Drug Administration 
Center for Devices and Radiological Health 
Document Mail Center - WO66-G609 
10903 New Hampshire Avenue 
Silver Spring, Maryland 20993-0002 
Deviations from the investigational plan. 
 
The sponsor-investigator shall notify Mayo IRB (see 21 CFR 56.108(a) (3) and (4)) of any 
deviation from the investigational plan to protect the life or physical well-being of a subject 

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in an emergency. Such notice shall be given as soon as possible, but in no event later than 5 
working days after the emergency occurred. Except in such an emergency, prior approval by 
the sponsor-investigator is required for changes in or deviations from a plan, and if these 
changes or deviations may affect the scientific soundness of the plan or the rights, safety, or 
welfare of human subjects, FDA and IRB notification in accordance with 21 CFR 812.35(a) 
also is required. 
8.4 
Unblinding Procedures (Breaking the Blind) (as necessary if the study is blinded) 
 
Every effort will be made to maintain blinding of patient in this study. The study participant 
will not be able to determine the differences in stimulation frequency parameters of the 
device. 
8.5 
Stopping Rules 
The study may be stopped if it becomes apparent that patients in the trial (in either group) are 
developing worsening heart failure symptoms, or needing hospitalization for heart failure 
which is reasonably felt by the investigators to be related to the spinal cord stimulation. 
8.6 
Medical Monitoring 
It is the responsibility of the sponsor-investigator to oversee the safety of the study.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events 
as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan (see Section 10 Auditing, Monitoring and Inspecting).  Medical monitoring 
will include a regular assessment of the number and type of serious adverse events. 
9 Data Handling and Record Keeping 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the 
following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (long term 
survival status that the subject is alive) at the end of their scheduled study period. 

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9.2 
Source Documents 
Source data comprise all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents.  Examples of these original documents, and 
data records include: hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after verification 
as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic 
media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. When applicable, information 
recorded on the CRF shall match the Source Data recorded on the Source Documents. 
9.3 
Case Report Forms 
A Case Report Form (CRF) will be completed for each subject enrolled into the clinical 
study.  The investigator-sponsor will review, approve and sign/date each completed CRF; the 
investigator-sponsor’s signature serving as attestation of the investigator-sponsor’s 
responsibility for ensuring that all clinical and laboratory data entered on the CRF are 
complete, accurate and authentic. 
 
The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF must be recorded.  All missing data must be explained.  If a space 
on the CRF is left blank because the procedure was not done or the question was not asked, 
write “N/D”.  If the item is not applicable to the individual case, write “N/A”.  All entries 
should be printed legibly in black ink.  If any entry error has been made, to correct such an 
error, draw a single straight line through the incorrect entry and enter the correct data above 
it.  All such changes must be initialed and dated.  Do not obliterate, erase, or use “white-out” 
for errors.  For clarification of illegible or uncertain entries, print the clarification above the 
item, then initial and date it.  If the reason for the correction is not clear or needs additional 
explanation, neatly include the details to justify the correction. 
 
Data Management 
 
Data will be managed electronically in a secure database to maintain patient data 
confidentiality and compliance with the Health Insurance Portability and Accountability Act 
(HIPAA).  
 
Data Processing 
 
Data processing will be performed by study personnel via medgraphics for gas exchange data 
and lab chart for blood pressure and heart rate analysis. 
 
Data Security and Confidentiality 
 
Data will be encrypted and secured with individual logins and passwords for study personnel, 
with auditing and logging of changes and modification times. 
 

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Data Quality Assurance 
 
Data will be verified at the time of entry into the database using a combination of double-
entry, and computerized validation methods to ensure accuracy and reduce outliers or 
missing data. 
9.4 
Records Retention 
 
The sponsor-investigator will maintain records and essential documents related to the 
conduct of the study.  These will include subject case histories and regulatory documents. 
 
The sponsor-investigator will retain the specified records and reports for: 
1. Up to 2 years after the marketing application is approved for the drug; or, if a 
marketing application is not submitted or approved for the drug, until 2 years after 
shipment and delivery of the drug for investigational use is discontinued and the FDA 
has been so notified. OR 
2. As outlined in the Mayo Clinic Research Policy Manual –“Retention of and Access to 
Research Data Policy” http://mayocontent.mayo.edu/research-policy/MSS_669717, 
whichever is longer. 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
 
The investigator will allocate adequate time for such monitoring activities.  The Investigator 
will also ensure that the monitor or other compliance or quality assurance reviewer is given 
access to all the study-related documents and study related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.), and has adequate space to conduct the monitoring visit. 
 
As a service to the sponsor-investigator, this study will be monitored during the conduct of 
the trial by staff from the Mayo Clinic Office of Research Regulatory Support.  Clinical trial 
monitoring may include review of the study documents and data generated throughout the 
duration of the study to help ensure the validity and integrity of the data along with the 
protection of human research subjects.  This will assist sponsor-investigators in complying 
with Food and Drug Administration regulations. 
10.2 Auditing and Inspecting 
The sponsor-investigator will permit study-related monitoring, audits, and inspections by the 
IRB, the monitor, and government regulatory agencies, of all study related documents (e.g., 
source documents, regulatory documents, data collection instruments, study data etc.).  The 
sponsor-investigator will ensure the capability for inspections of applicable study-related 
facilities (e.g., pharmacy, diagnostic laboratory, etc.). 
 
Participation as a sponsor-investigator in this study implies acceptance of potential inspection 
by government regulatory authorities and applicable compliance offices. 

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11 Ethical Considerations 
This study is to be conducted according to United States government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted local 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study.  The decision of the IRB concerning the conduct of the study will be 
made in writing to the sponsor-investigator before commencement of this study. 
 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study.  This consent form will be submitted with the protocol for review 
and approval by the IRB for the study.  The formal consent of a subject, using the Approved 
IRB consent form, must be obtained before that subject undergoes any study procedure.  The 
consent form must be signed and dated by the subject or the subject’s legally authorized 
representative, and the individual obtaining the informed consent. 
12 Study Finances 
12.1 Funding Source 
This study is being financed primarily by Boston Scientific and Mayo Ventures. 
12.2 Conflict of Interest 
Any study team member who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) must 
have the conflict reviewed by a properly constituted Conflict of Interest Committee with a 
Committee-sanctioned conflict management plan that has been reviewed and approved by the 
study sponsor-investigator prior to participation in this study. 
12.3 Subject Stipends or Payments 
Subject remuneration will be $750.  
13 Publication Plan 
 
Mayo and Investigators reserve the right to publish the result of work completed under this 
protocol. Prior review of the proposed publication by Boston Scientific will be provided, but 
in the interest of free exchange of scientific information, Mayo and Investigators may publish 
after the expiration of thirty (30) days following mailing of the proposed publication to 
Boston Scientific. Publication of the results will not include Confidential Information of 
Boston Scientific without the permission of Boston Scientific. In addition, Boston Scientific 
shall have the right to publish independently the results of the Study, provided, however, 
Mayo shall be the first to publish. In addition, any publication of data from the Study by 
Boston Scientific shall be considered a joint publication with Mayo as the co-author. After 
the publication of the primary paper, further ancillary studies using data collected in the trial 
may be analyzed and published by Mayo and Investigators. 

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