Rate-Adaptive Atrial Pacing In Diastolic Heart Failure (RAPID-HF)
Phase: NA
Conditions: Heart Failure With a Preserved Ejection Fraction, Heart Failure, Diastolic, Chronotropic Incompetence
Sponsor: Mayo Clinic

 
 
Rate-Adaptive Atrial Pacing In 
Diastolic Heart Failure (RAPID-
HF) 
 
NCT02145351 
 
30SEP2021 

Rate-adaptive Atrial Pacing In Diastolic Heart Failure (RAPID-HF) 
 
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Mayo Clinic and Medtronic, Inc. 
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Rate-adaptive Atrial Pacing In Diastolic Heart Failure (RAPID-HF) 
A prospective, randomized, double-blind, crossover study of rate adaptive pacing for patients 
with chronotropic incompetence and heart failure with a preserved ejection fraction. 
 
 
Principal Investigator 
Dr. Barry Borlaug 
Mayo Clinic – Cardiovascular Diseases 
200 First Street SW Rochester, MN 55905 
 
Co-Investigator 
Dr. Margaret Redfield 
Mayo Clinic – Cardiovascular Diseases 
200 First Street SW Rochester, MN 55905 
Funding Sponsors: 
Primary Sponsor: 
Mayo Clinic 
200 First Street SW Rochester, MN 55905 
Secondary Sponsor: 
Medtronic, Inc. 
710 Medtronic Pkwy NE, Minneapolis, MN 55432 
 
Study Product: 
Dual-chamber pacemaker with rate adaptive pacing 
Azure XT DR® Pacemaker 
Protocol Number: (IRBe) 
13-008306 
 
 
 
Initial version: [2/27/2014] Version (1) 
Updated: 
07/Jan/2015, Version 2 
03/Jun/2016, Version 3: Removed loop diuretic from inclusion criteria. 
05/Jul/2016, Version 4: Prior version of protocol had an error in inclusion criteria, where PCWP was 
listed in criterion #3.4 at 15mmHg and at 20mmHg in criterion #8.2. The modification on 05Jul2016 corrected 
the PCWP in criterion 8.2 to indicate 15mmHg, the clinical standard used in this patient population. 
06/Jun/2017, Version 5: The protocol has been modified to increase the sample size from 30 to 50 to allow 
for subject drop out, incomplete/inadequate data. We aim to have complete endpoint data for 30 participants. 
Inclusion/exclusion criteria has been modified to reflect advancements in the current literature. We have clarified 
study procedures for the randomization visit and additional secondary endpoints. These data are collected through 
current study procedures, however, they were not included in the protocol as secondary endpoints 

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01/April/2019, Version 6: Remove Advisa DR pacemaker to the protocol and added Azure XT DR pacemaker. 
30/September/2021, Version 8: Change Inclusion Criteria (4.1, Page 13) – Resting PCWP from > 15 to ≥15 mmHG 
and PCWP/LV end-diastolic pressure from > 25 to ≥ 25 mmHG. Per PI, this was a typo and should be changed to 
reflect correctly. 

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Table of Contents 
STUDY SUMMARY ............................................................................................................................................ 6 
1 
INTRODUCTION ......................................................................................................................................... 7 
1.1 
BACKGROUND ................................................................................................................................................................................... 7 
1.2 
INVESTIGATIONAL DEVICE ............................................................................................................................................................ 7 
1.3 
STUDY RATIONALE AND RISK/BENEFITS .................................................................................................................................. 7 
1.3.1 
Study Rationale ................................................................................................................................8 
1.3.2 
Anticipated Risks ..............................................................................................................................9 
1.3.3 
Potential Benefits .......................................................................................................................... 10 
2 
STUDY OBJECTIVES ............................................................................................................................... 10 
3 
STUDY DESIGN ......................................................................................................................................... 11 
3.1 
GENERAL DESIGN ........................................................................................................................................................................... 11 
3.2 
PRIMARY STUDY ENDPOINTS ..................................................................................................................................................... 12 
3.3 
PRIMARY SAFETY ENDPOINTS .................................................................................................................................................... 12 
4 
SUBJECT SELECTION, ENROLLMENT AND WITHDRAWAL ...................................................... 12 
4.1 
INCLUSION CRITERIA ..................................................................................................................................................................... 13 
4.2 
EXCLUSION CRITERIA ................................................................................................................................................................... 13 
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 ........................................................................................ 16 
5.3 
PREPARATION AND ADMINISTRATION/IMPLANTATION OF INVESTIGATIONAL DEVICE ........................................... 16 
5.4 
SUBJECT COMPLIANCE MONITORING ...................................................................................................................................... 16 
5.5 
PRIOR AND CONCOMITANT THERAPY ...................................................................................................................................... 17 
5.6 
PACKAGING AND LABELING........................................................................................................................................................ 17 
5.7 
BLINDING OF STUDY ...................................................................................................................................................................... 17 
5.8 
RECEIVING, STORAGE, DISTRIBUTION AND RETURN .......................................................................................................... 17 
5.8.1 
Receipt of Investigational Devices ................................................................................................ 17 
5.8.2 
Storage .......................................................................................................................................... 17 
5.8.3 
Distribution of Study Device ......................................................................................................... 17 
5.8.4 
Return or Destruction of Study Device .......................................................................................... 18 
6 
STUDY PROCEDURES ............................................................................................................................. 18 
6.1 
VISIT 1: SCREENING TO DETERMINE ELIGIBILITY + BASELINE VISIT .............................................................................. 18 
6.2 
VISIT 2: PACEMAKER IMPLANTATION ...................................................................................................................................... 18 
6.3 
VISIT 3: RANDOMIZATION ........................................................................................................................................................... 18 
6.4 
VISIT 4: FOLLOW-UP 1 ................................................................................................................................... 18 
6.5 
VISIT 5: FOLLOW-UP 2 ................................................................................................................................... 19 
6.6 
VISIT 6: FOLLOW-UP 3 ................................................................................................................................... 19 
7 
STATISTICAL PLAN ................................................................................................................................ 19 
7.1 
SAMPLE SIZE DETERMINATION .................................................................................................................................................. 19 
7.2 
STATISTICAL METHODS ................................................................................................................................................................ 20 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ............................................................................................................................... 21 
8 
SAFETY AND ADVERSE EVENTS ......................................................................................................... 21 

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8.1 
DEFINITIONS ..................................................................................................................................................................................... 21 
8.2 
RECORDING OF ADVERSE EVENTS ............................................................................................................................................ 23 
8.3 
SPONSOR-INVESTIGATOR REPORTING 
OF 
UNANTICIPATED 
ADVERSE 
DEVICE 
EFFECTS 
AND 
UNANTICIPATED PROBLEMS ................................................................................................................................................................... 24 
8.3.1 
Sponsor-Investigator Reporting, Notifying Mayo IRB .................................................................. 24 
8.3.2 
Sponsor-Investigator Reporting: Notifying the FDA .................................................................... 24 
8.4 
UNBLINDING PROCEDURES (BREAKING THE BLIND) (AS NECESSARY IF THE STUDY IS BLINDED)................... 25 
8.5 
STOPPING RULES ............................................................................................................................................................................ 25 
8.6 
MEDICAL MONITORING ................................................................................................................................................................ 25 
9 
DATA HANDLING AND RECORD KEEPING ..................................................................................... 26 
9.1 
CONFIDENTIALITY .......................................................................................................................................................................... 26 
9.2 
SOURCE DOCUMENTS .................................................................................................................................................................... 26 
9.3 
CASE REPORT FORMS.................................................................................................................................................................... 26 
9.4 
RECORDS RETENTION ................................................................................................................................................................... 27 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................ 28 
10.1 
STUDY MONITORING PLAN ....................................................................................................................................................... 28 
10.2 
AUDITING AND INSPECTING ...................................................................................................................................................... 28 
11 
ETHICAL CONSIDERATIONS............................................................................................................. 28 
12 
STUDY FINANCES ................................................................................................................................. 29 
12.1 
FUNDING SOURCE ........................................................................................................................................................................ 29 
12.2 
CONFLICT OF INTEREST .............................................................................................................................................................. 29 
13 
PUBLICATION PLAN ............................................................................................................................ 29 
14 
REFERENCES ......................................................................................................................................... 29 

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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 

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Study Summary 
Title 
Rate-adaptive Atrial Pacing In Diastolic Heart Failure (RAPID-HF) 
A prospective, randomized, double-blind, crossover study of rate 
adaptive pacing for patients with chronotropic incompetence and 
heart failure with a preserved ejection fraction. 
Running Title 
Rate-adaptive Atrial Pacing In Diastolic Heart Failure (RAPID-HF) 
IRB Protocol 
Number 
13-008306 
Phase 
Pivotal 
Methodology 
Prospective, randomized, double blind, cross-over study 
Overall Study 
Duration 
30 weeks 
Subject Participation 
Duration 
20 weeks 
Objectives 
Assess the effect of rate adaptive pacing on symptoms, exercise 
capacity, daily activity tolerance, biomarkers and quality of life in 
patients with chronotropic incompetence and heart failure with a 
preserved ejection fraction. 
Number of Subjects 
50 
Diagnosis and Main 
Inclusion Criteria 
Heart failure with ejection fraction ≥ 50% and current symptoms 
(New York Heart Association II-III), recent hospitalization or need 
for acute treatment. 
Chronotropic incompetence, defined as heart rate reserve <0.80 on 
clinical or screening exercise test within the past 6 months. 
Study Device 
Dual-chamber cardiac pacemaker, Azure XT DR®, with rate-adaptive 
pacing of the right atrium. There will be an associated right atrial lead 
and right ventricular lead. 
Duration of 
Exposure 
The device is intended to permanently remain in the body, unless 
there is a need to remove it. 
Reference therapy 
The reference is the device with pacing turned off (cross-over design), 
equivalent to placebo. 
Statistical 
Methodology 
The effect of rate-adaptive pacing on versus off will be compared 
within the same individual using paired t-tests for continuous data or 
McNemar Chi-square test for categorical data. 

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1 Introduction 
 
This document is a protocol for a human research study to evaluate the effect of rate adaptive 
atrial pacing in patients with chronotropic incompetence and heart failure with a preserved 
ejection fraction. This study will be carried out in accordance with the procedures described 
in this protocol, applicable United States government regulations, good clinical practice 
standards and Mayo Clinic policies and procedures. 
 
1.1 
Background 
 
Heart failure (HF) is the leading cause of hospitalization among Americans >65 years of age, 
with an annual healthcare cost in excess of $37 billion in 2009.1 Half of patients with HF 
have preserved EF (HFpEF) with a left ventricular EF of ≥50%. The prevalence of HFpEF 
relative to HF with reduced EF (HFrEF) is increasing by 1% per year.2 In contrast to HFrEF, 
where 7 drugs/devices have been shown to improve mortality, there is no proven treatment 
that improves outcomes in HFpEF.3 Recent clinical trials have tested therapies effective in 
HFrEF, yet each of these trials has failed to detect a benefit in HFpEF. One possible reason 
for the failure of prior clinical trials is the complex and heterogeneous pathophysiology of 
HFpEF, and enrolling patients with different underlying mechanisms into the same study 
may mask any real benefits.3–6 
 
While multiple cardiovascular abnormalities are known to contribute to the pathophysiology 
of exercise intolerance in HFpEF, chronotropic incompetence (CI) is one consistently 
observed finding across studies.7–12 CI is diagnosed during an exercise stress test when a 
subject is unable to increase their heart rate appropriately to achieve a set percentage of their 
predicted maximum. Single center studies from our group and others have identified CI in 
20-57% of HFpEF patients, and in the recently completed RELAX trial, the prevalence of CI 
was 77%.12 
1.2 
Investigational Device 
 
There are no investigational devices used in this study. Medtronic Azure XT DR™ is a 
market-approved dual-chamber pacemaker (pulse generator), Class III Device, Category B. It 
will be used with atrial and ventricular leads, Medtronic CapSureFix MRI™ model number 
5086. 
 
Medtronic Azure XT DR MRI™ model W1DR01 is a permanent, dual-chamber cardiac 
pacemaker with the ability to continuously monitor and record patient activity, and respond 
to activity by pacing faster and increasing the heart rate (rate adaptive atrial pacing). It will 
be programmed in AAIR mode to pace the right atrium. 
 
1.3 
Study Rationale and Risk/Benefits 

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1.3.1 Study Rationale 
 
Heart rate (HR) response to exercise is closely correlated with exercise capacity in HFpEF9, 
but it remains unknown whether improving HR responses will translate to improvements in 
exercise tolerance and quality of life in HFpEF. Guideline statements and review articles 
frequently recommend HR reduction, rather than higher heart rates in HFpEF.13 This is based 
on the idea that a slower HR will increase time available for diastolic filling. 
 
There is some evidence to support this approach. In a human invasive study, Westermann 
and colleagues reported that stroke volume dropped in HFpEF during atrial pacing (120 
bpm)- an effect related principally to a 28% reduction in LV end diastolic volume 
(LVEDV).14 However, as pointed out by Kass, this is not an unexpected finding with isolated 
pacing in healthy people and HF patients.15 In a separate acute pacing study, Wachter et al. 
observed less enhancement in LV relaxation velocity (dP/dtmin) coupled with reduced stroke 
volume and end diastolic volumes in HFpEF compared with controls.16 But again, the 
relevance of these observations to exercise physiology is unclear, because pacing was not 
performed during exercise, where venous return is markedly increased. Indeed, in the 
Westermann study, pacing was also associated with a significant reduction in LV filling 
pressures in the HFpEF group (16.1 to 7.7 mmHg, p<0.0001), and it is possible that if venous 
return were enhanced (as with exercise), pacing would have been associated with stable 
filling pressures and stable or even enhanced stroke volume response, which would increase 
cardiac output and improve exercise capacity. 
 
While it is commonly believed that exercise limitation in HFpEF is predominantly caused by 
diastolic dysfunction (ventricular filling abnormality),17 we have recently shown that it is 
rather inadequate cardiac ejection reserve that is the dominant culprit.7 People with HFpEF 
display less increase in cardiac output (CO) for any increase in metabolic demand (oxygen 
consumption, VO2), with no deficit in the increase in preload volume. The abnormality in CO 
reserve is caused by both impaired HR and stroke volume (SV) enhancements during 
exercise.7 If SV were maintained, an increase in HR would improve CO, but based upon the 
studies above, it is possible that gains in HR with pacing could be offset by exacerbation of 
impaired stroke volume reserve from abnormalities in diastolic chamber filling. 
 
Thus while CI is common in HFpEF and is strongly associated with exercise limitation, it 
remains unknown how restoration of normal HR responses with pacing would affect exercise 
capacity—in other words, this remains an unanswered fundamental question for which there 
is currently clinical equipoise. 
 
Permanent pacemaker implantation is approved for the treatment of patients with 
symptomatic chronotropic incompetence (CI).18 However, given the concern for impairing 
diastolic LV filling as suggested by the studies above,14,16 many or most cardiologists are 
reluctant to or do not consider referring HFpEF patients for pacemaker implantation. 

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1.3.2 Anticipated Risks 
 
The main risks associated with this study are from placement of the dual-chamber 
pacemaker, and the possible adverse effect of employing rate-adaptive pacing in patients 
with HFpEF. 
 
Pacemaker implantation is routinely performed and study subjects may be exposed to the 
same risks faced by any patient receiving a pacemaker, which can include: 
• Air embolism 
• Atrial or ventricular arrhythmias 
• Bleeding 
• Cardiac perforation, valve damage, and tamponade 
• Death 
• Failure of the device or leads after placement requiring repeat procedure 
• Hematoma or fluid accumulation 
• Heart block 
• Infection 
• Pneumothorax 
• Venous thrombosis, stroke, pulmonary embolism 
• In placement of the right ventricular lead in a dual-chamber pacemaker system, there 
may be worsening of tricuspid regurgitation. This risk was carefully considered 
against the alternative of use a single-lead (atrial only) pacemaker system. However, 
dual-chamber pacemakers including a ventricular lead are currently standard of care 
and have been shown to be as safe as single-lead systems.19 In another study, 
approximately 2% of patients per year required an additional procedure to place a 
ventricular lead due to development of AV nodal disease.20 The presence of atrial 
fibrillation (AF) also requires the placement of a ventricular lead. A recent study 
showed that up to two thirds of patients with HFpEF will develop AF at some point in 
the natural history of the disease.21 
 
As discussed previously, there may be possible adverse effects of rate-adaptive pacing in 
patients with HFpEF related to increasing the heart rate: 
• Arrhythmias 
• Death 
• Inappropriately high pacing rates due to sensor malfunction 
• Pulmonary edema 
• Worsening heart failure 
 
Possible adverse effects associated with cardiopulmonary exercise (CPX) testing: 
• Arrhythmias 
• Chest pain and difficulty breathing 
• Death 
• Heart attack or stroke 
• Fainting (syncope) or near-fainting 

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Every effort has been made to minimize these potential risks through careful study design, 
patient selection, and close monitoring. The incidence of adverse effects during CPX testing 
in heart failure patients is low (less than 1%) and is generally safe.22–24 Our group is also 
experienced in the conduct of exercise stress tests in patients with HFpEF. 
 
1.3.3 Potential Benefits 
 
We are studying a group of highly symptomatic patients with HFpEF. Pacing 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 HFpEF with 
chronotropic incompetence may also benefit from the results of this study. If pacing is found 
to significantly improve symptoms in HFpEF, without excessive risk, it may become 
common practice for this population. 
 
2 Study Objectives 
 
This investigation constitutes a pivotal study to assess the effectiveness of rate adaptive 
pacing (RAP) in subjects with chronotropic incompetence and heart failure with a preserved 
ejection fraction in a double blind, crossover study design, examining effects on exercise 
capacity, symptoms, chronic daily activity tolerance, quality of life and neurohormone levels. 
 
We anticipate it will take 20 weeks per patient to complete this study. During this time there 
will be 6 study visits to Mayo Clinic. 
 
2.1 Objective 1 
 
To determine the effects of rate adaptive atrial pacing on exercise capacity in HFpEF. 
People with HFpEF and chronotropic incompetence (CI) will undergo permanent pacemaker 
implantation, and exercise capacity will be assessed by expired gas analysis with pacing on 
or off in a crossover design. 
• Our primary hypothesis is that rate-adaptive atrial pacing will improve exercise 
capacity in HFpEF with CI. 
• Our secondary hypotheses are that pacing will reduce symptoms of dyspnea and 
fatigue during exercise and improve ventilatory efficiency. 
 
 
2.2 Objective 2 
To identify the effects of rate adaptive atrial pacing on daily activity tolerance in HFpEF. 
Activity tolerance will be as assessed by accelerometers contained within the implanted 
pacemaker device during the pacing-on and off periods. Six minute walk test will be 
performed with pacing on versus off. 
• Our primary hypothesis is that daily activity (minutes active per day assessed by 
accelerometry) will be greater during the pacing-on period as compared with pacing 
off. 

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• Our secondary hypothesis is that 6 minute walk distance will be greater with pacing 
on compared with pacing off. 
 
2.3 Objective 3 
To determine the effects of rate adaptive atrial pacing on quality of life and biomarkers in 
HFpEF. People with HFpEF will complete quality of life questionnaires with blood testing 
with pacing on/off. 
• Our primary hypothesis is that quality of life will be improved with pacing on as 
compared with pacing off. 
• Our secondary hypothesis is that NT-proBNP levels will be lower with pacing on 
versus off. 
 
3 Study Design 
3.1 
General Design 
 
This will be a pivotal study of rate adaptive pacing in patients with HFpEF and CI. It will be 
a randomized, prospective, double blind, cross-over study. Each participant will have 6 study 
visits over 20 weeks. After the study, the permanent pacemaker will remain implanted, and 
the patients will follow-up for standard clinical care with their cardiologist. 
 
We plan to enroll 50 subjects with HFpEF and CI meeting entry criteria to allow for 
complete endpoint data in 30. 
 
 
Study schematic: 
 
 
Group 1 
Group 1 
Group 2 
Group 2 

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3.2 
Primary Study Endpoints 
Assessment of exercise performance and symptoms (Objective 1) 
Volumes of oxygen consumed (VO2), 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/VCO2 slope) 
will be measured using a low resistance, open-circuit automated metabolic system (Medical 
Graphics) integrated with a mass spectrometer (Perkin Elmer, model 1100) as previously 
utilized by our group.7–9,25 Subjective effort and dyspnea during exercise will be graded by 
the Borg perceived effort and dyspnea scales.26 Exercise physiology staff supervising the test 
(and determining when peak exercise has been achieved) will be blinded to the 
electrocardiogram to limit potential for bias. Respiratory exchange ratio (RER) will be 
determined as the ratio of VCO2/VO2. VO2 at anaerobic threshold (VAT) will be determined 
using the V-slope method. Peak VO2 will be determined as the final 30 second average at 
peak exercise. 
 
Assessment of Daily Activity Tolerance (Objective 2) 
While peak exercise capacity is a valid, clinically relevant intermediate endpoint in HF trials, 
it provides relatively little insight into changes in activities of daily living, which are of more 
concern to the individual patient. The pacemaker devices used in this trial contain 
accelerometers that provide highly quantitative data (such as hours active each day) and have 
been used to characterize activity and to assess the impact of interventions on activity levels 
in patients with other chronic diseases such as COPD, obesity and arthritis. 
 
Quality of life and biomarker assessment (Objective 3) 
Quality of life will be assessed using the Kansas City Cardiomyopathy Questionnaire 
(KCCQ).27 NT-proBNP levels will also be obtained at multiple time points. 
 
3.3 
Primary Safety Endpoints 
 
Data will be collected to determine: 
• Overall survival 
• Hospitalizations for any cause, and for heart failure in particular 
• Symptoms of worsening heart failure 
• Incidence of all serious adverse events including unanticipated adverse device effects 
• Incidence of all device failures and malfunctions 
 
4 Subject Selection, Enrollment and Withdrawal 
 
Patients with HFpEF and chronotropic incompetence will be the target population of this 
trial. We plan to recruit 50 subjects for this study to allow for complete endpoint data in 30. 

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4.1 
Inclusion Criteria 
 
1. Age >18 years and able to provide informed consent to enroll in the trial, or consent 
through a legal guardian or power of attorney. 
2. Previous clinical diagnosis of HF with current NYHA Class II–III symptoms 
3. At least one of the following: 
• Hospitalization for decompensated HF 
• Acute treatment for HF with an intravenous diuretic or hemofiltration 
• Chronic treatment with a diuretic for control of HF symptoms + left atrial 
enlargement or elevated E/e’ ratio (≥14 average, ≥15 septal) on echocardiography 
• Resting PCWP  ≥15 mm Hg or LV end-diastolic pressure >18 mmHg at 
catheterization for dyspnea, and/or exercise PCWP/LV end-diastolic pressure  
≥25 mmHg 
• Elevated NT-proBNP level (≥300 pg/ml) 
4. Left ventricular EF ≥40% within 12 months with clinical stability 
5. Stable cardiac medical therapy for ≥30 days 
6. Sinus rhythm 
7. Chronotropic incompetence on recent (within 6 months) clinical exercise test, defined as 
heart rate reserve (HRR) <0.80 or <0.62 if on beta blockers 
• HRR = [observed peak HR – observed rest HR]/[predicted peak HR – observed 
rest HR] 
• Predicted peak HR will be calculated using the formula (220-age) 
8. Meet both screening criteria on clinically-performed CPX within 12 months 
• 
4.2 
Discernable ventilatory anaerobic threshold on previous CPX study.Exclusion 
Criteria 
 
1. Inability to exercise, or non-cardiac condition that precludes exercise testing 
2. Any contraindication to a pacemaker system 
3. Non-cardiac condition limiting life expectancy to less than one year 
4. Significant left sided structural valve disease (>mild stenosis, >moderate regurgitation) 
5. Hypertrophic obstructive cardiomyopathy 
6. Infiltrative or inflammatory myocardial disease (amyloid, sarcoid) 
7. Pericardial disease 
8. Non-group 2 pulmonary arterial hypertension 
9. Chronic stable exertional angina 
10. Acute coronary syndrome or revascularization within 60 days 
11. Other clinically important causes of dyspnea 
12. Atrial fibrillation 
13. PR interval >210 msec 
14. Resting heart rate (HR) > 100 bpm 
15. A history of reduced ejection fraction (EF<40%) 
16. Advanced chronic kidney disease (GFR < 20 ml/min/1.73m2 by modified MDRD 
equation) 

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17. Women of child bearing potential without negative pregnancy test and effective 
contraception 
18. Severe anemia (Hemoglobin <10 g/dL) 
19. Severe hepatic disease 
20. Complex congenital heart disease 
21. Listed for cardiac transplantation 
22. Other class I indications for pacing 
 
4.3 
Subject Recruitment, Enrollment and Screening 
 
Based on previous trials at Mayo Clinic, patients with HFpEF are generally highly motivated 
to enroll in trials testing novel therapies as there is no established effective treatment for 
HFpEF. We have an established list of patients with HFpEF who have shown chronotropic 
incompetence on previous exercise testing and have expressed interest in enrolling in new 
trials. 
 
Additional patients can be referred from the heart failure clinic. Standard clinical practice 
will be followed to diagnose and screen patients for possible eligibility for this trial. Patients 
who meet all of the entry criteria and agree to participate must give written informed consent 
approved by the investigator’s Institutional Review Board (IRB). 
 
Heart failure symptoms such as fatigue and dyspnea on exertion, pulmonary edema, pitting 
edema will be classified according to the New York Heart Association (NYHA). Those with 
Class II (symptoms with strenuous activity) or Class III (symptoms with mild activity) heart 
failure symptoms are eligible for the study. 
 
4.4 
Early Withdrawal of Subjects 
 
4.4.1 When and How to Withdraw Subjects 
 
A patient may be withdrawn from the study at any time, before or after implantation of the 
pacemaker, and prior to that subject completing all of the study related procedures. Because 
of the invasive nature of this study, investigators will do everything 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 
• Disease progression 
• Subject decides to withdraw from the study (withdrawal of consent) 
 
Depending on the time a patient withdraws, investigators may choose to replace that subject 
with a newly enrolled subject in order to maintain sample size. 
 
In the event of sudden study termination (trial is stopped before completion), patients will be 
requested to follow-up with their regular cardiologist or at the pacemaker clinic to decide on 
pacemaker settings. 

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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 classified as Follow-up Only. They will 
continue to be seen at visits according to the study protocol, but not necessarily performing 
tests. The patient will be monitored to capture adverse events, hospitalizations, or medical 
procedures performed in the term of their expected participation. Implanted pacemakers will 
be programmed at the discretion of their regular cardiologist. 
 
5 Study Device 
 
The device to be implanted is a dual-chamber cardiac pacemaker manufactured by 
Medtronic, model Azure XT DR MRI™ with MRI safe leads Medtronic CapSureFix MRI™ 
model number 5086. They will be provided by Medtronic, Inc. and stored in original 
marketed packaging until use. 
 
5.1 
Description 
 
Permanent pacemaker implantation is approved for treatment of symptomatic sinus node 
dysfunction with chronotropic incompetence (Class I indication).18 
 
We will use the following devices/components: 
• Pacemaker pulse generator: Medtronic Azure XT DR MRI™ model W1DR01 
• Leads: Medtronic CapSureFix MRI™ model number 5086 
 
All components and devices used in this trial are market-approved and not investigational 
devices. They will be provided by the manufacturer, Medtronic, and will be the same devices 
used clinically. Therefore standard clinical practice will be followed for their implantation, 
programming, and monitoring. Implantation will be performed by a cardiac 
electrophysiologist. 
 
A pacemaker system is comprised of a pulse generator which contains the battery, electronics 
and software, and leads which connect it to the heart. The pulse generator is typically 
inserted underneath the skin of the left upper chest through an incision. The implanting 
physician will determine the exact location at the time of implant. The pulse generator is 
connected to a right atrial lead, and a right ventricular lead. These leads are usually inserted 
into the left subclavian vein and anchored by screwing the tips into the myocardium. The 
position after placement is confirmed by X-ray. 
 
The pacemaker is able to monitor the electrical activity of the atria and ventricles 
independently to determine the rhythm and heart rate. The pulse generator also contains an 
accelerometer that records patient motion. If activity is sensed on the real time accelerometry 
data, the pacemaker will increase the rate of pacing. The pattern of rate increase and return to 
baseline will be programmed to achieve a 30 bpm increase in rate with vigorous walking. 

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This model of pacemaker employs a dual-slope rate response curve that allows two stages of 
increase for activities of daily living, and active exercise. 
 
Each device (pulse generator and leads) has a manufacturer assigned serial number that will 
be documented in the patient chart as per routine clinical practice. 
 
5.2 
Method for Assigning Subjects to Treatment Groups 
 
Patients will be randomized into two groups using randomization software after the screening 
visit. One group will start with pacing on, while the other starts with pacing off. They will 
cross over to the opposite setting midway in the study after the wash out period as outlined in 
the schematic in section 3.1. Patients and investigators will remain blinded to the 
programmed status, but the assignment will be kept locked away by the study coordinator if 
it becomes necessary. 
 
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. 
The device should be implanted within 30 days of signing of the informed consent. All 
implant procedures should be conducted in accordance with the Medtronic physicians 
manual for the Azure pacemaker system. 
 
The atrial lead will preferably be placed in the high right atrium or atrial septum. The 
ventricular lead will preferably be placed in the right ventricular apex. The pulse generator is 
preferably placed in the left pectoral pocket. The implanting physician will perform standard 
of care testing during the implantation procedure to determine acceptable pacing and sensing 
thresholds, and later placement will be confirmed on X-ray. 
 
Immediately following completion of the implant, the pacemaker should be set to inactive or 
minimal pacing modes such as VVI or AAI (50 ppm). Prior to discharge, the pacemaker will 
be programmed to AAIR mode with a lower rate limit of 50 and the accelerometer set to 
passive. It will remain in this minimal pacing mode for the next 4 weeks to allow post-op 
recovery, and collection of baseline sensor and activity data. The Cardiac Compass feature 
should be enabled to collect data during this period. 
 
5.4 
Subject Compliance Monitoring 
 
Once a patient has been randomized and implanted, every effort will be made by the study 
team to maintain contact with the patient and adhere to scheduled protocol visits and testing 
procedures over the 20 week participation period. During this time, the study team will keep 
in contact with the patient to arrange for study visits, and to monitor for adverse events, 
hospitalizations and overall survival. 

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If the patient declines to participate further in the study, or changes location, or cannot be 
contacted or located despite our best efforts, they will be classified as “Lost to Follow Up” 
and survival will be censored at the last time the patient was known to be alive. 
 
5.5 
Prior and Concomitant Therapy 
 
We will collect information on current medications at the baseline visit, including all cardiac 
medications. In particular, beta-blockers and dosages. There will not be restrictions on 
medications that can be used during the study. 
 
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 Medtronic in their original packaging. Labeling includes the 
device model and serial number. 
 
5.7 
Blinding of Study 
 
This will be a double-blind study. Patients will be blinded to their randomization assignment 
and to the pacemaker programming or settings. This will be explained to the patient, and 
study personnel should not disclose this information to the patient except in the event of a 
medical emergency. To the fullest extent possible, personnel involved in cardiopulmonary 
exercise testing should be blinded to the status during the test. Pacer spikes on 
electrocardiograms should be disabled. 
 
5.8 
Receiving, Storage, Distribution and Return 
 
5.8.1 Receipt of Investigational Devices 
 
The pacemaker pulse generator and leads will be obtained from the manufacturer Medtronic. 
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 
 
Pacemakers and leads 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 

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Pacemaker and leads will be distributed to the implanting physicians and their team before 
the procedure. The specific serial numbers will be recorded in the patient’s chart. 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 
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: Screening to determine eligibility + Baseline visit 
• The consent form should be reviewed and signed before proceeding with screening 
• Patient history will be reviewed for complete medical history, physical examination, 
EKG, cardiopulmonary exercise testing, a pregnancy test if applicable, review of 
current medications and NT-proBNP results. 
• Prior to implantation, consult with an electrophysiologist to determine eligibility and 
rule out contraindications to pacing or exclusion criteria (such as preexisting AV 
nodal disease). 
 
6.2 
Visit 2: Pacemaker Implantation 
• If patient is eligible, they will undergo implantation with a Medtronic Azure XT DR 
MRI™ dual-chamber permanent pacemaker with MRI compatible atrial and 
ventricular leads. Placement will be verified on X-ray and the device will be tested to 
ensure it is functioning correctly. 
• Following placement, there will be a 4 week recovery period with the pacemaker off. 
6.3 
Visit 3: Randomization 
• During this visit patients will take their baseline Kansas City Cardiomyopathy 
Questionnaire (KCCQ), NT-proBNP, and a limited echocardiogram. 
• In pacemaker clinic the device function will be verified and patients will undergo a 
hall walk or treadmill walk to titrate rate responsiveness to achieve about 30 bpm 
greater HR with pacing during vigorous walking. 
• At this visit, half the participants (group 1) will have their pacemakers turned on, 
while the other half (group 2) will have them off until the next follow-up 4 weeks 
later. 
 
6.4 
Visit 4: Follow-up 1 
• At this visit there will be an exercise stress test, a six-minute walk test, a repeat 
KCCQ, and NT-proBNP. 

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• Pacemaker function will be checked and both groups will have their pacemakers 
turned off for 4 weeks for a wash out period. 
 
6.5 
Visit 5: Follow-up 2 
• At this visit a repeat KCCQ and NT-proBNP will be obtained. 
• Pacemaker function will be checked, and then subjects will be switched to the 
opposite setting. If pacemaker was off at the randomization visit, it will be turned on. 
If pacemaker was on at the randomization visit, it will remain off. 
 
6.6 
Visit 6: Follow-up 3 
• Pacemaker function will be checked. They will undergo an exercise test, a six-minute 
walk test, a KCCQ, and NT-proBNP. 
• After the final visit, all patients will have their pacemakers turned on and will follow- 
up for standard clinical care with their cardiologist. 
 
Schedule of Events Summary 
 
Study Activity 
Baseline 
Screening 
2 
Implant 
3 
Randomize 
4 
F/U 1 
5 
F/U 2 
6 
F/U 3 
Approximate weeks from 
baseline 
0 
4 
8 
12 
16 
20 
Consent 
X 
Review EMR for 
Inclusion/Exclusion Criteria 
X 
Review Medications 
X 
Electrophysiology Consult 
X 
NT-proBNP 
X 
X 
X 
X 
Exercise Test 
X 
X 
Pacemaker Implantation 
X 
Chest X-Ray 
X 
6 Minute Walk Test 
X 
X 
Echocardiogram 
X 
Kansas City Questionnaire 
X 
X 
X 
X 
Hall Walk 
X 
Device Programming 
X 
X 
X 
X 
Device Interrogation Save to Disk 
X 
X 
X 
X 
X 
Record Adverse Events 
X 
X 
X 
X 
X 
 
7 Statistical Plan 
7.1 
Sample Size Determination 
 
A power analysis was done in planning for this trial. Based on previous work, we have 
observed that the standard deviation of the change in ventilator anaerobic threshold (VAT) 
between two CPX tests in subjects receiving placebo in the RELAX trial was 1.14 
ml/kg/min. Assuming this degree of variability, a sample size of 30 subjects will provide 
90% power to detect a change in VAT of 0.70 ml/kg/min or greater with pacing, assuming a 
two-sided significance level of 0.05 in a crossover study design. This detectable difference 
corresponds to approximately 10% of the baseline mean VAT observed in RELAX. Peak 

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HR in the RELAX trial was 109±24 bpm, on average 39 bpm below expected peak HR based 
upon the average age of the population. We expect based upon our algorithm for pacemaker 
programming (based upon observed vigorous hall walk) that HR at anaerobic threshold will 
be ~30 bpm greater than resting HR. 
 
7.2 
Statistical Methods 
Descriptive Statistics 
Univariate descriptive statistics and frequency distributions will be calculated, as appropriate 
for all variables. Baseline values for demographic, clinical, and outcome variables (primary 
and secondary) will be tabulated for the treatment groups. These analyses will help identify 
potential confounding variables to be used as covariates in sensitivity analyses. 
 
Handling of Missing Data 
 
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. 
 
Multiplicity 
 
No correction will be made for multiple comparisons as we are evaluating a relatively small 
number of variables. 
 
Objective 1: Determine effects of rate adaptive pacing on exercise capacity 
Primary Hypothesis: 
VO2 at anaerobic threshold (VAT) within 4 weeks of pacing on is significantly greater than 
with pacing off. 
 
Comparisons will be made for subjects with pacing set to on versus pacing off. Because these 
are paired data, statistical comparisons will be made using paired t-tests and McNemar Chi- 
square test. 
 
Secondary Hypothesis: 
Other measures of exercise capacity, including treadmill exercise time, peak VO2, and 
VE/VCO2 slope, will be improved with pacing on as compared to pacing off. Self-reported 
symptoms of breathlessness and fatigue during CPX (Borg scores) are lower with pacing on 
versus off. 
 
Objective 2: Identify effects of rate adaptive pacing on daily activity tolerance 
Primary Hypothesis: 
Daily activity assessed by average daily minutes active during the 28 day period of pacing-on 
is greater than with pacing off. 

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Secondary Hypothesis: 
The six minute walk test distance is greater with pacing on vs pacing off. 
 
Objective 3: Determine effects of rate adaptive pacing on quality of life and biomarkers 
Primary Hypothesis: 
KCCQ scores are higher after 4 weeks of pacing on versus pacing off (indicating improving 
quality of life) 
 
Secondary Hypothesis: 
NT-proBNP levels are lower after 4 weeks of pacing on versus pacing off. 
 
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 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) 

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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). 
 
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. 
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as 
an adverse event in the following circumstances: 
 
• 
Hospitalization for diagnostic or elective procedures for a preexisting condition. 
Surgery will not be reported as an outcome of an adverse event if the purpose of the 
surgery was elective or diagnostic and the outcome was uneventful 
 
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, 

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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, AND 
• 
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 
event is "unanticipated" when it occurs at an increased frequency or at an increased 
severity than expected, AND 
• 
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 at the final visit (Visit 6). As 
this is approved therapy for chronotropic incompetence, no further monitoring 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). 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. 

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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. 
 
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. 

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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 
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 and personnel in this study, except 
in the event of an emergency where it may become apparent which group the patient is in by 
witnessing pacer spikes on EKG or telemetry, or by needing to disable the pacer or change 
programming modes. 
 
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 pacing, or the presence of the 
pacemaker or leads. 
 
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. 

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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. 
 
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. 
 
An electronic system may be used as the primary means of recording clinical and laboratory 
data related to the study. Such a system will be compliant with the FDA electronic records 
and signatures regulations. 
 
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 and 
it may be an electronic form. All data requested on the CRF must be recorded. All missing 

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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 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. 
 
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 –“Access to and Retention of 
Research Data Policy” 
 
whichever is longer. 

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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. 
 
This study will be monitored on a routine basis during the conduct of the trial. The Mayo 
Clinic Office of Research Regulatory Support will provide clinical monitoring for the trial as 
a service for the sponsor-investigator. Clinical trial monitoring requires review of the study 
data generated throughout the duration of the study to 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. 
 
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. 

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12 Study Finances 
12.1 Funding Source 
This study is being financed primarily by research grants and sweep funds of the Mayo 
investigators. Secondary funding will be provided by Medtronic, Inc. 
 
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. 
 
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 Medtronic 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 Medtronic. 
Publication of the results will not include Confidential Information of Medtronic without the 
permission of Medtronic. In addition, Medtronic 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 Medtronic 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. 
 
14 References 
 
1. 
Roger VL, Go AS, Lloyd-Jones DM, et al. Heart Disease and Stroke Statistics—2012 
Update A Report From the American Heart Association. Circulation. 2012;125(1):e2– 
e220. doi:10.1161/CIR.0b013e31823ac046. 
 
2. 
Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in 
Prevalence and Outcome of Heart Failure with Preserved Ejection Fraction. N Engl J 
Med. 2006;355(3):251–259. doi:10.1056/NEJMoa052256. 
 
3. 
Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, 
diagnosis, 
and 
treatment. 
Eur 
Heart 
J. 
2011;32(6):670–679. 
doi:10.1093/eurheartj/ehq426. 

Rate-adaptive Atrial Pacing In Diastolic Heart Failure (RAPID-HF) 
 
Page 30 of 32 
Mayo Clinic and Medtronic, Inc. 
CONFIDENTIAL 
 
 
4. 
Maurer MS. Heart Failure With a Normal Ejection Fraction (HFNEF): Embracing 
Complexity. J Card Fail. 2009;15(7):561–564. doi:10.1016/j.cardfail.2009.04.004. 
 
5. 
Haykowsky MJ, Brubaker PH, John JM, Stewart KP, Morgan TM, Kitzman DW. 
Determinants of Exercise Intolerance in Elderly Heart Failure Patients With Preserved 
Ejection 
Fraction. 
J 
Am 
Coll 
Cardiol. 
2011;58(3):265–274. 
doi:10.1016/j.jacc.2011.02.055. 
 
6. 
Bhella PS, Prasad A, Heinicke K, et al. Abnormal haemodynamic response to exercise 
in heart failure with preserved ejection fraction. Eur J Heart Fail. 2011;13(12):1296– 
1304. doi:10.1093/eurjhf/hfr133. 
 
7. 
Abudiab MM, Redfield MM, Melenovsky V, et al. Cardiac output response to exercise 
in relation to metabolic demand in heart failure with preserved ejection fraction. Eur J 
Heart Fail. 2013;15(7):776–785. doi:10.1093/eurjhf/hft026. 
 
8. 
Borlaug BA, Melenovsky V, Russell SD, et al. Impaired Chronotropic and Vasodilator 
Reserves Limit Exercise Capacity in Patients With Heart Failure and a Preserved Ejection
 
Fraction. 
Circulation. 
2006;114(20):2138–2147. 
doi:10.1161/CIRCULATIONAHA.106.632745. 
 
9. 
Borlaug BA, Olson TP, Lam CSP, et al. Global Cardiovascular Reserve Dysfunction in 
Heart Failure With Preserved Ejection Fraction. J Am Coll Cardiol. 2010;56(11):845– 
854. doi:10.1016/j.jacc.2010.03.077. 
 
10. Brubaker PH, Joo K-C, Stewart KP, Fray B, Moore B, Kitzman DW. Chronotropic 
incompetence and its contribution to exercise intolerance in older heart failure patients. 
J Cardiopulm Rehabil Prev. 2006;26(2):86–89. 
 
11. Phan TT, Shivu GN, Abozguia K, et al. Impaired Heart Rate Recovery and Chronotropic 
Incompetence in Patients With Heart Failure With Preserved Ejection Fraction. Circ
 
Heart 
Fail. 
2009;3(1):29–34. 
doi:10.1161/CIRCHEARTFAILURE.109.877720. 
 
12. Redfield MM, Chen HH, Borlaug BA, et al. Effect of phosphodiesterase-5 inhibition on 
exercise capacity and clinical status in heart failure with preserved ejection fraction: A 
randomized 
clinical 
trial. 
JAMA. 
2013;309(12):1268–1277. 
doi:10.1001/jama.2013.2024. 
 
13. Heart Failure Society of America. HFSA 2010 Comprehensive Heart Failure Practice 
Guideline. J Card Fail. 2010;16(6):e1–e2. doi:10.1016/j.cardfail.2010.04.004. 
 
14. Westermann D, Kasner M, Steendijk P, et al. Role of Left Ventricular Stiffness in Heart 
Failure With Normal Ejection Fraction. Circulation. 2008;117(16):2051–2060. 
doi:10.1161/CIRCULATIONAHA.107.716886. 

Rate-adaptive Atrial Pacing In Diastolic Heart Failure (RAPID-HF) 
 
Page 31 of 32 
Mayo Clinic and Medtronic, Inc. 
CONFIDENTIAL 
 
 
15. Kass DA. Letter by Kass Regarding Article, “Role of Left Ventricular Stiffness in Heart 
Failure 
With 
Normal 
Ejection 
Fraction.” 
Circulation. 
2009;119(1):e4–e4. 
doi:10.1161/CIRCULATIONAHA.108.788729. 
 
16. Wachter R, Schmidt-Schweda S, Westermann D, et al. Blunted frequency-dependent 
upregulation of cardiac output is related to impaired relaxation in diastolic heart failure. 
Eur Heart J. 2009;30(24):3027–3036. doi:10.1093/eurheartj/ehp341. 
 
17. Paulus WJ. Culprit Mechanism(s) for Exercise Intolerance in Heart Failure With Normal 
Ejection 
Fraction. 
J 
Am 
Coll 
Cardiol. 
2010;56(11):864–866. 
doi:10.1016/j.jacc.2010.04.041. 
 
18. Tracy CM, Epstein AE, Darbar D, et al. 2012 ACCF/AHA/HRS Focused Update 
Incorporated Into the ACCF/AHA/HRS 2008 Guidelines for Device-Based Therapy of 
Cardiac Rhythm Abnormalities: A Report of the American College of Cardiology 
Foundation/American Heart Association Task Force on Practice Guidelines and the Heart 
Rhythm Society. J Am Coll Cardiol. 2013;61(3):e6–e75. doi:10.1016/j.jacc.2012.11.007. 
 
19. Nielsen JC, Thomsen PEB, Hojberg S, et al. A comparison of single-lead atrial pacing 
with dual-chamber pacing in sick sinus syndrome. Eur Heart J. 2011;32(6):686–696. 
doi:10.1093/eurheartj/ehr022. 
 
20. Kristensen L, Nielsen JC, Pedersen AK, Mortensen PT, Andersen HR. AV block and 
changes in pacing mode during long-term follow-up of 399 consecutive patients with sick 
sinus syndrome treated with an AAI/AAIR pacemaker. Pacing Clin Electrophysiol 
PACE. 2001;24(3):358–365. 
 
21. Zakeri R, Chamberlain AM, Roger VL, Redfield MM. Temporal Relationship and 
Prognostic Significance of Atrial Fibrillation in Heart Failure Patients With Preserved 
Ejection Fraction A Community-Based Study. Circulation. 2013;128(10):1085–1093. 
doi:10.1161/CIRCULATIONAHA.113.001475. 
 
22. O’Neill JO, Young JB, Pothier CE, Lauer MS. Severe frequent ventricular ectopy after 
exercise as a predictor of death in patients with heart failure. J Am Coll Cardiol. 
2004;44(4):820–826. doi:10.1016/j.jacc.2004.02.063. 
 
23. Tristani FE, Hughes CV, Archibald DG, Sheldahl LM, Cohn JN, Fletcher R. Safety of 
graded symptom-limited exercise testing in patients with congestive heart failure. 
Circulation. 1987;76(6 Pt 2):VI54–58. 
 
24. Jónsdóttir S, Andersen KK, Sigurðsson AF, Sigurðsson SB. The effect of physical 
training 
in 
chronic 
heart 
failure. 
Eur 
J 
Heart 
Fail. 
2006;8(1):97–101. 
doi:10.1016/j.ejheart.2005.05.002. 
 
25. Johnson BD, Beck KC, Proctor DN, Miller J, Dietz NM, Joyner MJ. Cardiac output 
during exercise by the open circuit acetylene washin method: comparison with direct 
Fick. J Appl Physiol. 2000;88(5):1650–1658. 

Rate-adaptive Atrial Pacing In Diastolic Heart Failure (RAPID-HF) 
 
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Mayo Clinic and Medtronic, Inc. 
CONFIDENTIAL 
 
 
26. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 
1982;14(5):377–381. 
 
27. Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of the 
Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart 
failure. J Am Coll Cardiol. 2000;35(5):1245–1255. doi:10.1016/S0735-1097(00)00531- 
3.