A Pilot Study of the Feasibility of Prehospital Delivery of Remote Ischemic Conditioning by Emergency Medical Services in Chest Pain Patients
Phase: NA
Conditions: Chest Pain
Sponsor: University of North Carolina, Chapel Hill

A Pilot Study of the Feasibility of Prehospital Delivery of Remote Ischemic Conditioning by 
Emergency Medical Services in Chest Pain Patients 
(A Study of the Feasibility of Prehospital Remote Ischemic Conditioning) 
 
 
 
NCT number NCT03400579    
Document Date 06/14/2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
CLINICAL RESEARCH PROTOCOL 
A pilot study of the feasibility of prehospital delivery of 
remote ischemic conditioning by emergency medical 
services in chest pain patients
Initial version (date): 
Revised: 
1.0 (July 20, 2017) 
2.0 (August 17 2017) 
2.1 (September 20, 2017) 
2.2 (December 11, 2017)
2.3 (June 14, 2018)
Principal Investigator & 
Regulatory Sponsor: 
Mehul D. Patel, PhD 
Research Assistant Professor 
Department of Emergency Medicine 
University of North Carolina at Chapel Hill 
170 Manning Drive, CB #7594 
Physicians Office Building, 1st Floor 
Chapel Hill, NC 27599-7594 
Email: mehul_patel@med.unc.edu  
Phone: (919) 843-7307 
Co-Investigators: 
Timothy F. Platts-Mills, MD, MSc 
Assistant Professor and Vice Chair of Research 
Department of Emergency Medicine 
University of North Carolina at Chapel Hill 
Joseph M. Grover, MD 
Clinical Assistant Professor 
Department of Emergency Medicine 
University of North Carolina at Chapel Hill 
Medical Director of Orange County Emergency Services 
Joseph S. Rossi, MD, MSCI 
Clinical Associate Professor and Director of Interventional Cardiology 
Division of Cardiology 
University of North Carolina at Chapel Hill 
Funding Sponsors: 
The North Carolina Translational and Clinical Sciences Institute 
University of North Carolina at Chapel Hill 
160 N. Medical Drive, CB #7064 
Brinkhous-Bullitt Building, 2nd Floor 
Chapel Hill, NC 27599-7064 
Department of Emergency Medicine 
University of North Carolina at Chapel Hill 
170 Manning Drive, CB #7594 
Physicians Office Building, 1st Floor 

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Chapel Hill, NC 27599-7594 
Study Product: 
autoRIC® Device 
CellAegis Devices, Inc. 
139 Mulock Avenue, 1st Floor 
Toronto, Ontario M6N 1G9 
Protocol Number: 
N/A 
FDA IDE Number: 
N/A 
UNC IRB Number: 
17-0287 (approval pending) 

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Table of Contents 
STUDY SUMMARY ...................................................................................................................................... 1 
1 
INTRODUCTION .................................................................................................................................. 2 
1.1 
BACKGROUND ................................................................................................................................ 2 
1.2 
INVESTIGATIONAL DEVICE ............................................................................................................... 2 
1.3 
PRECLINICAL DATA ........................................................................................................................ 3 
1.4 
CLINICAL DATA TO DATE................................................................................................................. 3 
1.5 
STUDY RATIONALE ......................................................................................................................... 4 
1.6 
DOSE RATIONALE AND RISK/BENEFITS ............................................................................................ 4 
2 
STUDY OBJECTIVES ......................................................................................................................... 5 
2.1 
PRIMARY OBJECTIVE ...................................................................................................................... 5 
2.2 
SECONDARY OBJECTIVES ............................................................................................................... 5 
3 
STUDY DESIGN ................................................................................................................................... 5 
3.1 
GENERAL DESIGN .......................................................................................................................... 5 
3.2 
PRIMARY OUTCOMES ..................................................................................................................... 6 
3.3 
SECONDARY OUTCOMES ................................................................................................................ 6 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................... 6 
4.1 
INCLUSION CRITERIA ...................................................................................................................... 6 
4.2 
EXCLUSION CRITERIA ..................................................................................................................... 6 
4.3 
SUBJECT RECRUITMENT AND SCREENING ....................................................................................... 7 
4.4 
EARLY WITHDRAWAL OF SUBJECTS................................................................................................. 8 
4.4.1 
When and How to Withdraw Subjects ..................................................................................... 8 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects .......................................................... 8 
5 
STUDY DEVICE ................................................................................................................................... 8 
5.1 
DESCRIPTION ................................................................................................................................. 8 
5.2 
PROCEDURE REGIMEN ................................................................................................................... 8 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ......................................................... 9 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DEVICE ................................................................... 9 
5.5 
SUBJECT COMPLIANCE MONITORING ............................................................................................... 9 
5.6 
PRIOR AND CONCOMITANT THERAPY ............................................................................................... 9 
5.7 
PACKAGING ................................................................................................................................... 9 
5.8 
RECEIVING, STORAGE, DISPENSING AND RETURN ............................................................................ 9 
5.8.1 
Receipt of Devices & Supplies ................................................................................................ 9 
5.8.2 
Storage .................................................................................................................................. 10 
5.8.3 
Dispensing of Study Device .................................................................................................. 10 
5.8.4 
Return or Destruction of Study Device .................................................................................. 10 
6 
STUDY PROCEDURES ..................................................................................................................... 10 
6.1 
AMBULANCE TRANSPORT ............................................................................................................. 10 
6.2 
EMERGENCY DEPARTMENT ........................................................................................................... 11 
6.3 
POST-VISIT .................................................................................................................................. 11 
7 
STATISTICAL PLAN ......................................................................................................................... 11 
7.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 11 
7.2 
STATISTICAL METHODS ................................................................................................................ 12 
7.3 
SUBJECT POPULATION FOR ANALYSIS ........................................................................................... 12 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 12 
8.1 
DEFINITIONS ................................................................................................................................ 12 

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8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 14 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................................. 14 
8.3.1 
Reporting to Study Sponsor .................................................................................................. 14 
8.3.2 
Reporting to IRB .................................................................................................................... 15 
8.4 
UNBLINDING PROCEDURES ........................................................................................................... 15 
8.5 
STOPPING RULES ......................................................................................................................... 15 
8.6 
MEDICAL MONITORING ................................................................................................................. 15 
9 
DATA HANDLING AND RECORD KEEPING ................................................................................... 16 
9.1 
CONFIDENTIALITY ......................................................................................................................... 16 
9.2 
SOURCE DOCUMENTS .................................................................................................................. 16 
9.3 
CASE REPORT FORMS.................................................................................................................. 16 
9.4 
RECORDS RETENTION .................................................................................................................. 16 
10 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 16 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 16 
10.2 
AUDITING AND INSPECTING ........................................................................................................... 17 
11 
ETHICAL CONSIDERATIONS .......................................................................................................... 17 
12 
STUDY FINANCES ............................................................................................................................ 17 
12.1 
FUNDING SOURCE ........................................................................................................................ 17 
12.2 
CONFLICT OF INTEREST ................................................................................................................ 18 
13 
PUBLICATION PLAN ........................................................................................................................ 18 
14 
REFERENCES ................................................................................................................................... 18 
15 
APPENDICES .................................................................................................................................... 21 
APPENDIX A: ORANGE COUNTY EMERGENCY MEDICAL SERVICES 2016 CHEST PAIN PROTOCOL ................. 21 
APPENDIX B: SUGGESTED RECRUITMENT SCRIPTS ..................................................................................... 23 
APPENDIX C: SAMPLE PATIENT INFORMATION SHEET .................................................................................. 24 
APPENDIX D: SAMPLE INFORMED CONSENT FORM ...................................................................................... 25 

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List of Abbreviations 
AE 
Adverse event 
ALS 
Advanced life support 
CABG 
Coronary artery bypass graft 
CI 
Confidence interval 
CRF 
Case report form 
ECG 
Electrocardiogram 
ED 
Emergency department 
EMS 
Emergency medical services 
FDA 
Food and Drug Administration 
HIPAA 
Health Insurance Portability and Accountability Act 
ID 
Identifier 
IDE 
Investigational device exemption 
IEC 
International Electrotechnical Commission 
IRB 
Institutional Review Board 
LED 
Light-emitting diode 
MI 
Myocardial infarction 
NIH 
National Institutes of Health 
OCES 
Orange County Emergency Services 
PCI 
Percutaneous coronary intervention 
PHI 
Protected health information 
PI 
Principal Investigator 
REDCap 
Research Electronic Data Capture 
RIC 
Remote ischemic conditioning 
RCT 
Randomized controlled trial 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SC 
Study coordinator 
STEMI 
ST-segment elevation myocardial infarction 
TraCS 
Translational and Clinical Sciences 
UNC 
University of North Carolina 

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Study Summary 
Title 
A pilot study of the feasibility of prehospital delivery of remote ischemic 
conditioning by emergency medical services in chest pain patients 
Short Title 
Prehospital RIC Pilot Study 
Protocol Number 
N/A 
Phase 
Pilot 
Methodology 
Open label; Non-randomized; Single-arm 
Study Duration 
12 months 
Study Center(s) 
Single-center 
Objectives 
To assess the feasibility of the delivery of RIC by EMS in the prehospital 
setting by evaluating the following:  
Primary outcome – Duration of RIC administered 
Secondary outcomes – Enrollment rates and protocol efficiency; paramedic 
acceptability of protocol; and patient tolerability of RIC 
Number of Subjects 
50 
Diagnosis and Main 
Inclusion Criteria 
Patients experiencing a recent onset of chest pain or anginal equivalent 
symptoms requiring emergency medical services (suspected ST segment-
elevation myocardial infarction patients will be excluded) 
Study Product, Dose, 
Route, Regimen 
The autoRIC® Device; an upper arm cuff will automatically alternate 5 minutes 
inflated at 200 mm Hg and 5 minutes deflated for a total of 4 cycles (total 40 
minutes) 
Duration of 
administration 
40 minutes (4 cycles at 10 minutes each) 
Reference therapy 
No comparison therapy 
Statistical 
Methodology 
Descriptive statistics (e.g., proportions, medians) will be computed to 
summarize primary and secondary outcomes. Where appropriate, point 
estimates will be presented along with 95% confidence intervals. No inferential 
statistical tests will be performed. Qualitative data will be analyzed using mixed 
methods approaches.  

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1 Introduction 
This document is a protocol for a human research study. This study is to be conducted according to US and 
international standards of Good Clinical Practice (FDA Title 21 part 312 and International Conference on 
Harmonization guidelines), applicable government regulations and Institutional research policies and procedures. 
1.1 Background 
A myocardial infarction (MI), otherwise known as a heart attack, occurs when obstruction of a coronary artery 
causes sudden loss of blood flow to the heart muscle. If blood flow is not restored (reperfusion) within the first few 
hours, the lack of oxygen supply (ischemia) results in irreversible myocardial injury and eventually necrosis of 
heart tissue (infarction). Depending on the extent of tissue damage, or myocardial infarct size, the individual may 
die or suffer long-term disabilities. In the U.S., there are ~750,000 MIs each year and ~117,000 related deaths, 
making it a leading cause of morbidity and mortality.1 Furthermore, the annual health care costs of myocardial 
infarction in the U.S. are projected to exceed $300 billion by 2030.1,2 
Prompt reperfusion with emergency coronary stent placement, or primary percutaneous coronary intervention 
(PCI), substantially reduces myocardial injury and improves clinical outcomes; primary PCI is therefore the 
preferred treatment for many acute MI patients.3 However, reperfusion can paradoxically induce further 
myocardial damage.4 This ischemia-reperfusion injury can account for up to 50% of the final infarct size in 
patients with MI following reperfusion.5 While primary PCI is now the standard of care in the US and other 
developed countries, therapies to protect against ischemia-reperfusion injury remain investigational.5,6  
Remote ischemic conditioning (RIC) is a non-pharmacological and non-invasive therapy for acute MI whereby 
intermittent, brief episodes of benign ischemia and reperfusion are induced by inflating and deflating a standard 
blood pressure cuff on the upper arm or leg.7 This therapy is hypothesized to protect against ischemia-reperfusion 
injury by cellular signaling between the remote site (limb) and the target organ (heart) through humoral or 
neuronal protective signal transfer.8,9 Although the mechanisms of RIC are unclear, it is thought to target several 
mediators of ischemia-reperfusion injury and may therefore be a more effective therapeutic strategy than those 
that target a single pathway.5,10  
1.2 Investigational Device 
The autoRIC® (CellAegis Devices, Inc., Toronto, Ontario) is the only automated device currently available to 
deliver RIC for acute conditions.11,12 With timed inflations and deflations of an arm cuff, it automatically delivers 
four RIC cycles of five minutes of pressure at 200 mm Hg followed by five minutes of no pressure for a total 40-
min treatment period. The autoRIC® has CE Mark certification in Europe and Health Canada approval to 
administer RIC therapy in adult patients with acute MI and 
those undergoing cardiothoracic interventions or surgery; 
the device is however limited to investigational use in the 
U.S. (http://www.cellaegisdevices.com/product.html 
accessed May 9, 2017).  
The autoRIC® system (Figure 1) consists of a 
rechargeable, reusable control unit that clicks into a one-
time use, disposable applicator cuff and inflates and 
deflates the cuff to a preset pressure of 200 mm Hg on a 
timer. The applicator cuffs come in three adult sizes to 
accommodate arm circumferences ranging from 22 to 44 
cm. A stand-alone charger for the control unit uses a 
standard AC adapter and can be wall mounted. The 
autoRIC® is compliant with international safety and 
Figure 1. CellAegis’ autoRIC® Device

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performance standards for medical devices and electrical equipment including particular requirements for 
automated non-invasive sphygmomanometers (IEC 80601‐2‐30:2009). 
1.3 Preclinical Data 
In 1986, Murry et al. first described ischemic conditioning in dogs, in which four 5-min occlusions of the circumflex 
coronary artery separated by 5-min episodes of reperfusion before a sustained occlusion limited myocardial 
infarct size to 25% of that observed in the control group.13 Dickson et al. demonstrated remote ischemic 
conditioning reduces infarct size with the transfer of coronary effluent from a preconditioned donor rabbit heart to 
an acceptor rabbit heart by transfusion.14 In 2002, Kharbanda et al. showed transient lower limb ischemia (four 5-
min cycles) in pigs prior to a myocardial infarction substantially reduced infarct size.15 These researchers also 
demonstrated that the RIC response could be induced in humans non-invasively by simply inflating a standard 
blood pressure cuff around the upper arm to 200 mm Hg of pressure with three cycles of five minutes inflated and 
five minutes deflated. These and other preclinical studies provide convincing evidence of the existence of 
ischemia-reperfusion injury and suggest that ischemic conditioning has significant promise to prevent lethal 
reperfusion injury in humans.5,9 
1.4 Clinical Data to Date 
Prior randomized controlled trials (RCTs) have shown the benefit of RIC in several clinical applications, including 
reducing myocardial and renal injury in patients undergoing coronary artery bypass graft (CABG) surgery, 
abdominal aortic aneurysm surgery, and elective PCI.16-20 However, some clinical studies found null findings with 
RIC in these settings. Possible explanations for these null findings include differences in study design, inclusion 
criteria, and concomitant medications that could mitigate the effects of RIC.21 Recently, two large multi-center 
RCTs, conducted in the United Kingdom and Germany, failed to show a benefit of RIC on clinical outcomes. 
Garratt, et al. suggest one possible reason for the lack of clinical efficacy of RIC in recent large multi-center RCTs 
in patients undergoing elective CABG surgery22,23 is that the anesthetic drug propofol may inhibit signal 
transduction in response to the remote ischemia.24 They, among others, call for further clinical investigations in 
populations that may derive the most benefit from RIC, namely acute ST-segment elevation myocardial infarction 
(STEMI) patients undergoing emergent PCI.24,25 
Existing evidence on clinical efficacy suggests RIC is a promising adjunct to PCI in STEMI patients. Botker et al. 
conducted a randomized trial of RIC administered in the prehospital setting among 333 STEMI patients in 
Denmark, in which they found RIC was feasible to implement in the ambulance and safely improved myocardial 
salvage 30 days after PCI.26 In a subgroup of left anterior descending STEMIs, myocardial salvage further 
increased, and left ventricular function was also significantly improved at 30 days.27 Two smaller randomized 
studies in STEMI patients undergoing primary PCI found RIC had beneficial effects on ST-segment resolution, 
cardiac enzymes, and other intermediate outcomes.28,29In a post hoc analysis of the Danish trial, Sloth et al. found 
the RIC plus PCI group, compared to PCI only, had half the 4-year risk of the primary composite endpoint of 
major adverse cardiovascular events including all-cause mortality (HR=0.49, 95% CI 0.27-0.89).30 A recent meta-
analysis synthesized results from four randomized studies that reported clinical endpoints and found major 
cardiovascular risk was significantly lower in patients receiving RIC + PCI compared PCI only (RR=0.57, 95% CI 
0.40-0.82).31 Patient recruitment is underway for two large, multi-center clinical efficacy trials of RIC, administered 
with the autoRIC® device, in STEMI patients undergoing primary PCI (CONDI2 NCT01857414 and ERIC-PPCI 
NCT02342522). However, even if these European and UK trials establish the efficacy of RIC in these patients, 
further U.S.-based research will be necessary to demonstrate effectiveness and facilitate implementation in U.S. 
emergency cardiac care systems. 

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1.5 Study Rationale 
Emergency medical services (EMS) play a key role in regional systems of STEMI care in the U.S. With proper 
training and patient care protocols, paramedics can perform and interpret 12-lead electrocardiogram (ECG) for 
STEMI in the field and directly transport suspected STEMI patients to a PCI-capable hospital, which has been 
shown to reduce delays to treatment and improve outcomes.32-34 Based on the findings from the Danish trial, EMS 
is a promising setting for field administration of RIC in acute MI patients prior to hospital arrival. There are 
however important differences in the provision of EMS between European countries like Denmark and the U.S. 
While EMS care in European countries is often provided by emergency physicians and have a culture of treating 
patients at the scene, ambulances in the U.S. are staffed with paramedics who are trained to prioritize timely 
transport to the hospital.35-37 Additional U.S.-based research of RIC is needed to elucidate the influence of these 
personnel and system factors and inform design decisions for future U.S.-based clinical studies that build on the 
completed trial from Denmark and the other European trials currently underway.  
A recent feasibility study of administering RIC in patients with STEMI during U.S. air medical transports showed 
84% of patients had at least three cycles of RIC completed.38 In this multi-state region, the air medical crew was 
typically a paramedic and nurse team, which made timed, manual cuff inflations and deflations feasible. However, 
the vast majority of acute MI patients in the U.S. are transported by ground ambulance, not by air, with care 
provided by a single paramedic. An automated device, such as the autoRIC®, could prevent delays or 
interruptions in care and eliminate the need for dedicated personnel or ongoing provider attention.7,11,12 Further 
study of EMS use of an automated device is needed to inform the design and optimize methods for a future U.S.-
based trial of the clinical efficacy of RIC administered during ground ambulance transport. 
1.6 Dose Rationale and Risk/Benefits 
In previously published clinical studies, one cycle of RIC has typically been five minutes of upper arm ischemia, 
induced by inflating a cuff to 200 mm Hg, followed by five minutes of reperfusion by deflating the cuff. Each 10-
min cycle is repeated four times. This dosing regimen was followed in recently completed clinical trials,22,23 and is 
being used in the ongoing CONDI2 (NCT01857414) and ERIC-PPCI (NCT02342522) trials. Our study protocol 
will therefore administer RIC in accordance with these studies using the autoRIC® device, which automates the 
process. 
Based on previous studies, RIC is a safe procedure with minimal risk to subjects across various settings and 
patient populations. From the Danish trial in which RIC was administered in STEMI patients in the ambulance 
prior to hospital arrival, Botker et al. reported no local adverse effects, such as pain or thrombophlebitis.26 In two 
large RCTs in patients undergoing CABG surgery, one observed no adverse events related to RIC;23 the other 
found 5% of the RIC intervention group experienced skin petechiae or arm weakness or altered sensation 
although none had long-term effects.22 In a U.S. study of RIC during air medical transport of STEMI patients,  only 
2% of patients stopped RIC due to discomfort.38 
Published studies of the autoRIC® device support the safety of this specific device for administering RIC. Two 
previous studies used this specific automated device to investigate the effect of RIC on coagulation, platelet 
function, and fibrinolysis in small samples of healthy male volunteers39 and patients with chronic heart failure.40 
Neither study reported any complications or adverse events related to RIC or the device itself. However, neither 
study directly evaluated risks to subjects or studied the device in an emergency care setting.  
Given the benign nature of the RIC procedure, no serious adverse events are expected as a result of the device. 
However, the device may result in non-serious adverse events, such as minor arm discomfort, temporary 
discoloration of the arm or hand, and minor skin bruising or abrasions on the upper arm. These anticipated risks 
are not expected to have long term consequences and are reasonable in relation to the knowledge gained on the 
feasibility of RIC and optimal methods for a full-scale clinical trial to help establish long-term benefits. 

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2 Study Objectives 
The overall purpose of this pilot study is to assess the feasibility of the delivery of RIC by EMS in the prehospital 
setting. To this end, we will conduct a single-arm study of the standard RIC procedure (i.e., up to four cycles of 
alternating 5-min inflation and 5-min deflation) administered by Orange County (North Carolina) Emergency 
Services in 50 patients experiencing chest pain or other symptom consistent with cardiac etiology. The 
investigational autoRIC® device will be initiated by paramedics during ambulance transport, and automated RIC 
cycles will continue through emergency department (ED) arrival and stay. This pilot study will address the 
following objectives: 
2.1 Primary Objective 
Examine the duration of RIC administered in patients having the procedure initiated in the prehospital setting 
Hypothesis: Four cycles of RIC will be completed in at least 80% of patients having the procedure initiated. 
2.2 Secondary Objectives 
The following secondary objectives will inform the design and optimize methods for a future clinical trial: 
1.
Evaluate patient enrollment and study protocol efficiency, i.e. patient eligibility and participation rates,
times to screen, recruit and start the autoRIC® device
2.
Assess acceptability of the study protocol by paramedics
3.
Determine patient tolerability of the RIC procedure and describe related risks and discomforts
3 Study Design 
3.1 General Design 
This single-arm, open-label pilot study will enroll 50 patients experiencing chest pain or anginal equivalent 
symptom requiring a 9-1-1 response to incident scene and ground ambulance transport by Orange County 
Emergency Services (OCES), the primary EMS provider in the county. Eligible patients will be >18 years of age  
and be transported to the University of North Carolina (UNC) Medical Center, an accredited chest pain center. For 
this pilot study, patients suspected of STEMI based on the prehospital ECG and thus requiring urgent intervention 
in the cardiac catheterization lab will be excluded.1 Detailed subject selection criteria are described in Section 4.  
The following diagram (Figure 2) illustrates the overall flow of patient enrollment and major procedural steps 
during ambulance transport and ED stay. 
Figure 2. Diagram of Patient Enrollment and Study Procedures 
1 Although high risk STEMI patients hold the most promise for therapeutic benefit, the aims of this study surrounding feasibility 
of prehospital RIC can be addressed with a low risk population. By using chest pain patients not suspected of STEMI, we will 
simulate the prehospital setting expected for an efficacy trial of RIC while allowing adequate time to interview patients in the ED. 

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3.2 Primary Outcomes 
To assess the feasibility of delivering RIC in the prehospital setting, the primary endpoint will be the completion of 
4 cycles of RIC without interruption using the autoRIC® device. We will also examine total time (in minutes) and 
number of cycles that RIC was administered. 
3.3 Secondary Outcomes 
Secondary Objective #1: Patient enrollment and protocol efficiency 
a)
Eligibility and participation rates and corresponding reasons for ineligibility and refusal
b)
Timing of study procedures
i)
Time to onset of transport from initial arrival on scene
ii)
Time to start screening from onset of transport
iii)
Time to screen, whether eligible or not
iv) Time to recruit, whether enrolled or not
v)
Time to start the autoRIC® device once consent is obtained
Secondary Objective #2: Paramedic acceptability 
a)
Paramedics’ feedback on the delivery of RIC and other study procedures
Secondary Objective #3: Patient tolerability 
a)
Documentation of anticipated adverse events including RIC discontinuation due to discomfort
b)
Patients’ experiences while undergoing the RIC procedure
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
Eligible patients will meet the following criteria: 
1.
Requiring 9-1-1 response to scene2
2.
At least 18 years of age
3.
Experiencing non-traumatic chest pain or anginal equivalent3 symptom, as defined in OCES “Chest Pain:
Cardiac and STEMI” patient care protocol (see Appendix A)
4.
Not meeting EMS criteria for a suspected STEMI based on prehospital ECG4
5.
Systolic blood pressure (SBP) between 100-180 mm Hg
6.
Designated for ambulance transport to UNC Medical Center (Chapel Hill, NC)
7.
Capable of providing informed consent
4.2 Exclusion Criteria 
The following exclusions will be made in the prehospital setting and confirmed prior to recruitment: 
1.
Unconscious or otherwise in critical condition
2.
Lacking capacity to consent to the study5
3.
Non-English speaking
2 Does not include non-9-1-1 responses such as interfacility transfers and non-urgent medical transports 
3 Includes pain in other location suggesting cardiac etiology such as arm, shoulder, neck, or jaw; dyspnea; diaphoresis; 
nausea/vomiting; or dizziness 
4 Defined as 1 mm or greater ST segment elevation in at least 2 contiguous leads or otherwise prompting a prehospital STEMI 
alert or activation of the cardiac catheterization laboratory 
5 As judged by study paramedic and study coordinator 

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4.
Pre-existing condition precluding blood pressure check or use of the autoRIC® at the discretion of the
provider or listed here:
a.
Paresis of upper limb
b.
Pre-existing traumatic injury to arm
c.
Presence of an arteriovenous shunt for dialysis
d.
Prior mastectomy
e.
Existing peripheral inserted central catheter line
f.
Arm edema or other indication of upper extremity thrombosis
5.
Serial ECG evidence of evolving STEMI
4.3 Subject Recruitment and Screening 
Two full-time OCES ground ambulance units that provide advanced life support (ALS) services to the southern 
part of Orange County and typically transport to UNC Medical Center will be used for this study. Paramedics 
assigned to these units will be responsible for assessing and screening patients during the enrollment period from 
6am-6pm, Monday-Friday. So that arrival to the UNC ED is not delayed, screening and recruitment will not begin 
until the patient is en route to the hospital and given usual care, at the discretion of the paramedic. Paramedics 
will assess the patients’ capacity to consent for the study following their usual approach to assessing patients’ 
capacity to make medical decisions, e.g. accept or refuse treatment.  
In a two-stage screening and recruitment process 
(Figure 3), the study paramedic will first assess and 
determine whether the patient meets all eligibility 
criteria. If the patient is not eligible, the paramedic will 
document the primary reason(s) on a screener form. If 
the patient is eligible, the paramedic, using a 
suggested script (see Appendix B), will offer the 
patient an opportunity to learn more about the study by 
telephone call with a study coordinator (SC). If the 
patient agrees, the paramedic will hand the patient a 
study information sheet (see Appendix C) and will call 
the SC or back-up key study personnel using a 
dedicated cellular telephone. In the second screening 
stage, the SC will confirm with the paramedic that the 
patient is eligible. Then the patient will be handed the 
telephone. The SC, following a script (see Appendix 
B), will provide basic information about the purpose of 
the study, RIC procedure, and risks and benefits of 
participating and will answer any questions that patient 
may have. To assess consent capacity, the SC will ask 
the patient to describe the RIC procedure and whether 
study participation will have any effect on medical care 
received. A patient with capacity to consent will be 
invited to participate. If the patient responds in the 
affirmative, this will be considered verbal consent, and 
the SC will instruct the paramedics to apply and start 
the autoRIC® device. This telephonic method to obtain 
consent in the field is based on a strategy developed 
and tested in prior prehospital trials by Saver et al.41,42
Figure 3. Flow chart of recruitment and enrollment 

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When the patient and paramedic crew arrive to the ED, providers in the ED will first provide standard care. The 
SC will collect study forms and other documentation from the paramedic. Once initial care (e.g., provider 
assessment, repeat ECG, lab draws) is completed and the patient is placed under observation for further work-up, 
the SC will approach the patient, with approval from the treating physician, to complete the full informed consent 
process and describe additional data collection including medical record review and abstraction and collection 
and storage of blood samples for future testing. The SC will assess comprehension based on the patient’s ability 
to restate key study objectives and procedures and anticipated risks and benefits. If the patient consents, both SC 
and patient will sign two copies of the informed consent form (see Appendix D), one for study documentation and 
the other for the patient. If the patient refuses, RIC will be stopped and data collected up to that point will be de-
identified and retained to address primary and secondary study objectives.  
4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Subjects may withdraw from the study at any point without consequence to their future care. If consent is 
withdrawn while RIC cycles are being administered, regardless of reason, the autoRIC® device will be stopped 
and removed from the patient. There are no anticipated risks to patients from abrupt termination of the RIC 
procedure. Care providers (i.e. paramedics or ED physicians) may terminate RIC if the patient becomes severely 
hypotensive (SBP < 90 mm Hg), experiences an unsafe drop or rise in blood pressure, or for other safety reasons 
at the discretion of the provider. Discontinuation of RIC prematurely will be documented as a primary endpoint. 
Specific reason(s) for discontinuation whether related to patient tolerability or safety will be documented to 
address secondary objectives and will be recorded for adverse event reporting.  
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Study objectives do not require subject follow-up past EMS response, ambulance transport, and ED stay. 
Withdrawn subjects will be asked for primary reason(s) for terminating participation in the study.   
5 Study Device 
5.1 Description 
The autoRIC® is a device system that automatically delivers cycles of RIC. Once placed on the upper arm, the 
programmed device is initiated by pressing a single start button with each cycle consisting of a 5-min period of a 
cuff inflated to 200 mm Hg followed by a 5-min period of the cuff deflated. The system is programmed to operate 
a total length of 35 minutes since the final 5-min period of deflation is technically no action or intervention. 
Additional details of the investigational device are provided in Section 1.2.  
5.2 Procedure Regimen 
The autoRIC® is programmed to deliver four cycles of RIC with each cycle consisting of a 5-min period of a cuff 
inflated to 200 mm Hg followed by a 5-min period of the cuff deflated for a total procedure time of 40 minutes. At 
any time, RIC can be terminated by pressing the stop button or physically removing the cuff-device system from 
the arm.  
For this study population, RIC is not considered a treatment since no clinical benefit is expected in patients not 
undergoing reperfusion, as in STEMI patients receiving PCI, or otherwise at risk for ischemia-reperfusion injury. 
Therefore, rather than testing a treatment effect, the autoRIC® in this study is being evaluated for feasibility of 
prehospital delivery and operational efficiency.  

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5.3 Method for Assigning Subjects to Treatment Groups 
Since this is a single-arm, pilot study, all subjects will receive the study device. There will be no assignment or 
randomization of treatment groups.  
5.4 Preparation and Administration of Study Device 
The autoRIC® device will be stored in a locked cabinet at the EMS station while not in use for the study. At the 
start of each 6AM-6PM enrollment period, the paramedic will ensure the device is fully charged. The charging 
cradle will be set up in the ambulance unit, and, after each use, the device will be returned to charging cradle. If 
necessary, up to 3 consecutive patients can be treated on a full charge, but every effort will be made to keep the 
device fully charged.  
The autoRIC® will be administered according to the operator’s manual. Briefly, once the paramedic determines 
the appropriate cuff size, the applicator cuff, with control unit, is placed directly on the upper arm without any 
clothing, tubing, or other foreign object between the cuff and patient. If IV access has been established in an arm 
as part of providing usual care, the device will be applied to the opposite arm. Blood pressure measurements, for 
usual care, will be made in the arm with the IV in place.  
Once the device is in place and the paramedic presses the “Start” button, s/he will confirm all LEDs illuminate to 
ensure the device is working properly. After the fourth and final cuff inflation, the device can be removed from the 
patient for the final 5-min deflation period. The applicator cuffs are single-use, and therefore, they will be disposed 
according to OCES and UNC’s medical waste policy.  
The paramedic will retrieve the device after each use. If the ambulance unit is back in service prior to the 
completion of four cycles, the device will be returned to the ambulance by the SC or other key study personnel. 
5.5 Subject Compliance Monitoring 
Device start and stop times will be recorded by paramedic or SC, as appropriate. If the autoRIC® is prematurely 
terminated for any reason, the number of cycles completed and progress of the current cycle will also be recorded 
as indicated by LED lights on the device. This information will be captured as the primary study endpoint. 
5.6 Prior and Concomitant Therapy 
Medications administered by the paramedic will be collected. It is expected these will primarily consist of aspirin 
and nitroglycerin for management of chest pain.  
5.7 Packaging 
The autoRIC® devices will be shipped with their standard packaging and product labeling. 
5.8 Receiving, Storage, Dispensing and Return 
5.8.1 Receipt of Devices & Supplies 
The required number of autoRIC® devices (three total – two for study use and one for training and back-up) will 
be shipped from the supplier CellAegis Devices, Inc. (Toronto, Canada) to the study PI. Upon receipt of the study 
devices and supplies, an inventory will be performed, and a device receipt log filled out and signed by the person 
accepting the shipment. Designated study staff will count and verify that the shipment contains all the items noted 
in the shipment inventory.   

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5.8.2 Storage 
According to technical specifications, the autoRIC® can be transported and stored in an ambient temperature 
range of -4 °F to 122 °F and a relative humidity range of 0% to 85%. When not in use, devices will be stored in 
locked cabinets.   
5.8.3 Dispensing of Study Device 
Devices will be dispensed to study paramedics by the PI. In a device accountability log, the PI and SC will keep 
track of each device and document each use including the size of the single-use applicator cuff. Using this log, 
the study PI and SC will monitor the remaining supply of each cuff size and will re-order as needed.  
5.8.4 Return or Destruction of Study Device 
At the completion of the study, the autoRIC® devices will be stored in a locked cabinet at the study site. If no 
future studies are planned, the devices will be shipped back to the supplier CellAegis Devices, Inc.   
6 Study Procedures 
This study requires a single visit. Table 1 illustrates the flow of study procedures throughout the study visit and 
additional data collection following the visit. All study procedures involving direct patient interaction will occur in 
the ambulance and ED. Prior to the onset of subject enrollment, study paramedics will undergo training on the 
study protocol and standard operating procedures.  
6.1 Ambulance Transport 
During ambulance transport, the study paramedic will record information on a paper Case Report Form (CRF). 
The CRF will be pre-populated with a unique subject identifier (ID). The paramedic will document general 
information, including incident date-time, patient name and contact information, and will also complete the 
screener. As previously described, eligible patients interested in learning more about the study will be connected 
to the SC by telephone. After verbal consent is obtained over the telephone, the paramedic will prepare the 
autoRIC® device (e.g. check battery, determine appropriate cuff size). The device will be placed on the patient 
and started according to the operator’s manual. Along the way, the paramedic will record the time of RIC initiation 
and other key time points needed to compute secondary endpoints. While RIC is being administered, the 
paramedic will note observations and feedback on the recruitment process, operating the device, patient safety or 
adverse events, and any delays incurred due to RIC or other study procedures. If RIC is terminated prematurely, 
the paramedic will document the primary reason(s).  
Table 1. Flow of Study Procedures and Data Collection 
Study Procedures 
Study Visit 
Post-
Visit 
Ambulance Transport 
Emergency Department 
Standard care (paramedic and ED staff) 
X 
X 
Screening 
X 
Initial verbal consent by telephone 
X 
RIC intervention* 
X        
        
Safety and adverse event reporting 
X 
X 
Full written informed consent 
X 
Blood collection, preparation, and storage 
X 
Patient interview 
X 
Additional Data Collection 

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Medical record review 
X 
Cardiac monitor report retrieval 
X 
Blood analysis (post-hoc) 
X 
*may overlap with other study procedures
6.2 Emergency Department 
The SC will meet the paramedic team and patient in the ED. At this point, the paramedic will hand over the CRF 
to the SC and transfer study responsibilities, including safety and adverse event reporting. After initial ED care 
and while the patient is under observation and awaiting further work-up, the SC will complete the full informed 
consent process. This process may occur while the RIC procedure is still in progress. Although the study 
intervention is already started, the subject will have the opportunity to decline participation in the patient interview; 
access to medical records and other clinical data; and collection and storage of blood specimens for future 
testing. The SC will assess comprehension of consent by asking the subject to describe the purpose of the study, 
foreseeable risks and benefits of study participation, the possibility of unanticipated risks, and other elements of 
informed consent. No additional study procedures will occur until the consent process is complete and both 
patient and SC sign necessary consent forms.  
After consent is obtained, a blood sample of 15 mL will be collected by Department of Emergency Medicine 
clinical research staff using existing venous access. When possible, this sample will be obtained with other blood 
draws taken as part of usual care. Blood for plasma will be collected using an EDTA tube (e.g., BD Vacutainer® 
plastic blood collection tube). Tubes will be labeled with the date and time of collection and the unique subject ID 
but no other identifiers. Specimens will be prepared according to standard procedures for separating plasma and 
will be stored in a -80 °C freezer located in a locked area in the department’s research laboratory. No blood 
testing or analyses will be done under this protocol. In future studies, these samples may be used to investigate 
biomarkers and molecular pathways involved in the mechanism(s) of RIC.   
Using an interview guide, the SC will elicit patient feedback on undergoing the RIC procedure (e.g., “what did it 
feel like?”, “how would you describe to someone else?”). The SC will note subject responses in the CRF.  
6.3 Post-Visit 
There will not be any post-ED visits required of the subject. All additional study data collected following the study 
visit will be obtained by the SC or other study personnel via retrospective chart review and will not require subject 
interaction. Subjects will however be contacted after 48 hours, either by telephone or in-person depending on 
location, to assess for adverse events related to study participation. 
Following the study visit, the SC will enter data from the CRF into a secure, web-based database (Research 
Electronic Data Capture, REDCap). Additional relevant clinical data from the subject’s medical record (e.g. 
medical history, diagnoses, and lab results) and the EMS patient care report will also be abstracted and entered 
into the database. Furthermore, automatic reports from the EMS agency’s LIFEPAK® 12 cardiac monitor will be 
retrieved and saved for potential additional analyses of vital signs and ECG patterns. Frozen plasma specimens 
may be thawed and tested in future research exploring mechanisms of RIC.   
7 Statistical Plan 
7.1 Sample Size Determination 
Since the primary objective of this pilot study is to assess feasibility and optimize methods, no formal statistical 
hypothesis testing will be performed. A 5-month enrollment period is appropriate given limited time and resources, 

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and will be sufficient to enroll the target of 50 patients. This sample size would produce a 95% (confidence 
interval) CI half width of 0.11 given the frequency of RIC completion is 0.80 (primary hypothesis). Sample sizes 
larger than 50 provide only marginal gains in precision (Figure 4).  
Figure 4. Statistical precision in the primary endpoint by sample size 
7.2 Statistical Methods 
Summary statistics (e.g., proportions, medians) will be used to characterize the study sample with respect to 
patient demographic and clinical characteristics and process factors related to the RIC procedure. The primary 
outcome measure, as previously discussed, will be the frequency (i.e., proportion) of all subjects receiving RIC 
who completed 4 cycles. The primary hypothesis will be evaluated by comparing the proportion and its 95% CI to 
the predetermined benchmark of 0.80. Since this is a pilot study to collect feasibility data, no inferential statistical 
tests will be performed. Descriptive analyses will compare patient characteristics (demographics, medical history, 
clinical factors) and process measures (timing of study procedures) between RIC completers and non-completers. 
Qualitative data from paramedic feedback and patient interviews will be analyzed for general themes regarding 
key aspects of study methodology. Themes will be derived from qualitative text and related to quantitative 
demographic and clinical characteristics in a mixed methods analysis using the software MAXQDA (VERBI 
GmbH, Berlin, Germany). A full analysis plan will be developed in consultation with UNC mixed methods research 
experts.  
7.3 Subject Population for Analysis 
For both primary and secondary objectives, any subject consented and enrolled to receive RIC will be analyzed. 
8 Safety and Adverse Events 
8.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria: 
•
Unexpected in nature, severity, or frequency  (i.e. not described in study-related documents such as the
IRB-approved protocol or consent form) 

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•
Related or possibly related to participation in the research (i.e. possibly related means there is a
reasonable possibility that the incident experience, or outcome may have been caused by the procedures
involved in the research,
•
Serious (as defined below)  “Serious” is different than “severe” as reported in the CTC criteria that
applies a grade to the AE.
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity during 
the course of the study visit. Intercurrent illnesses or injuries should be regarded as adverse events. Abnormal 
results of diagnostic procedures are considered to be adverse events if the abnormality: 
•
results in study withdrawal
•
is associated with a serious adverse event
•
is associated with clinical signs or symptoms
•
leads to additional treatment or to further diagnostic tests
•
is considered by the investigator to be of clinical significance
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is: 
•
fatal
•
life-threatening
•
requires or prolongs hospital stay
•
results in persistent or significant disability or incapacity
•
any of the following important medical events: acute STEMI, severe hypertension (SBP > 200 mm Hg),
significant heart block requiring emergency cardiac pacing, cardiogenic shock, cardiac arrest
Important medical events are those that may not be immediately life threatening, but are clearly of major clinical 
significance in this patient population. They may jeopardize the subject, and may require intervention to prevent 
one of the other serious outcomes noted above.   
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious adverse 
events.  
Adverse Event Reporting Period 
The study period during which adverse events must be reported will start at the time of verbal consent, include the 
40-min RIC procedure, and conclude when the SC completes study procedures in the ED. A subject follow-up 
contact will be made at 48 hours to assess for adverse events. If a subject expresses RIC-related health concerns 
at any time, s/he will be connected to a study physician for a telephone assessment and triage which will include 
a determination of whether re-evaluation in the ED is needed.  
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.   
Abnormal Laboratory Values 
All lab tests conducted during the study visit will be part of the usual care in the ED and not the study procedures. 
Therefore, any abnormal values will not be reported as AEs. Blood collected for future research may be tested at 
a later date, and any abnormal values will also not be reportable.  

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Hospitalization or Prolonged Hospitalization 
The majority of subjects, due to their cardiac condition, will be hospitalized. This will not be reported as an SAE. 
However, a hospitalization or prolonged stay related to participation in the study will be reportable.  
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.  Information on all adverse events should be recorded immediately in the 
source document, and also in the appropriate adverse event module of the case report form (CRF). All clearly 
related signs, symptoms, and abnormal diagnostic procedures results should recorded in the source document, 
though should be grouped under one diagnosis. 
All adverse events occurring during the study period must be recorded. The clinical course of each event should 
be followed until resolution, stabilization, or until it has been determined that the study treatment or participation is 
not the 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 
possibly related to the study treatment or study participation should be recorded and reported immediately. 
8.3 Reporting of Serious Adverse Events and Unanticipated Problems 
Investigators and the protocol sponsor must conform to the adverse event reporting timelines, formats and 
requirements of the various entities to which they are responsible, but at a minimum those events that must be 
reported are those that are: 
•
related to study participation,
•
unexpected, and
•
serious or involve risks to subjects or others
(see definitions in Section 8.1).
If the report is supplied as a narrative, the minimum necessary information to be provided at the time of the initial 
report includes: 
•
Study Identifier
•
Subject number
•
A description of the event
•
Date of onset
•
Current status
•
Whether study treatment was discontinued
•
The reason why the event is classified as serious
•
Investigator assessment of the association
between the event and study treatment
8.3.1 Reporting to Study Sponsor 
Any study-related unanticipated problem posing risk of harm to subjects or others and any serious adverse event 
(see Section 8.1) must be reported to the study sponsor-investigator. i.e. PI, by telephone within 24 hours of the 
event. To report such events, a Serious Adverse Event (SAE) form must be completed by the SC, study 
paramedic, or other study staff and provided to the study PI within 24 hours. The PI will keep a copy of this SAE 
form on file at the study site. Report serious adverse events by phone and facsimile to: 
Mehul D. Patel, PhD          Phone: (919) 843-7307          Fax: (919) 966-3049 
Within the following 48 hours, the PI must provide further information on the serious adverse event or the 
unanticipated problem in the form of a written narrative. This should include a copy of the completed Serious 
Adverse Event form, and any other diagnostic information that will assist the understanding of the event.  
Significant new information on ongoing serious adverse events should be provided promptly to the study PI. 

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8.3.2 Reporting to IRB 
For reportable deaths, the initial submission to the UNC IRB may be made by contacting the IRB Director or 
Associate Director. The SAE Form is required as a follow up to the initial submission. 
Other Reportable events: 
For this clinical study, the following events are also reportable to the UNC IRB: 
•
Any unanticipated problems involving risk to subjects or others (See Section 8.1)
•
Any adverse event that would cause the sponsor to modify the investigators brochure, protocol or informed
consent form, or would prompt other action by the IRB to assure protection of human subjects.
•
Information that indicates a change to the risks or potential benefits of the research, in terms of severity or
frequency. For example:
–
An interim analysis indicates that participants have a lower rate of response to treatment than initially
expected.
–
Safety monitoring indicates that a particular side effect is more severe, or more frequent than initially
expected.
•
Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic used in a
research protocol.
•
Breach of confidentiality
•
Change to the protocol taken without prior IRB review to eliminate apparent immediate hazard to a
research participant.
•
Complaint of a participant when the complaint indicates unexpected risks or the complaint cannot be
resolved by the research team.
•
Protocol violation (meaning an accidental or unintentional deviation from the IRB approved protocol) that in
the opinion of the investigator placed one or more participants at increased risk, or affects the rights or
welfare of subjects.
8.4 Unblinding Procedures 
This is an open-label study, so no unblinding procedures will be necessary. 
8.5 Stopping Rules 
This study does not present potential for serious risk to the health, safety, and welfare of subjects, so no stopping 
rules will be necessary.  
8.6 Medical Monitoring 
It is the responsibility of the PI to oversee the safety of the study at his site. 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 Study Monitoring, Auditing, and 
Inspecting). Medical monitoring will include a regular assessment of the number and type of serious and non-
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 (i.e. that the subject is alive) at the end of their scheduled study period. 
9.2 Source Documents 
Source data is 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. 
9.3 Case Report Forms 
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 ERASE OR WHITE OUT ERRORS.  For clarification of illegible or 
uncertain entries, print the clarification above the item, then initial and date it. 
9.4 Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after the completion of 
the study. These documents should be retained for a longer period if required by an agreement with the study 
sponsor or IRB.  In such an instance, it is the responsibility of the investigator to inform the study team as to when 
these documents no longer need to be retained.  
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
The study PI will ensure that adequate data and safety monitoring information is collected and reviewed according 
to the study monitoring plan. The focus of monitoring will be adverse event review and reporting, data security 

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and subject privacy and confidentiality, and study procedure quality control and data completeness and accuracy. 
The PI will hold weekly meetings with study staff to review and verify these steps. 
The PI will allocate adequate time for such monitoring activities. The study investigators and other key personnel 
will meet biweekly during the enrollment period to review and discuss data and safety monitoring information. In 
the event of monitoring by the UNC Quality Assurance Office, the PI will also ensure access to all the above 
noted study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and 
adequate space to conduct the monitoring visit. 
10.2 Auditing and Inspecting 
The sponsor-investigator will permit study-related monitoring, audits, and inspections by the IRB, government 
regulatory bodies, and University compliance and quality assurance groups of all study related documents (e.g. 
source documents, regulatory documents, data collection instruments, study data etc.). The investigator will 
ensure the capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.). 
Participation as an investigator in this study implies acceptance of potential inspection by government regulatory 
authorities and applicable University compliance and quality assurance offices. 
11 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical Practice (FDA Title 21 
part 312 and International Conference on Harmonization guidelines), applicable government regulations and 
Institutional research policies and procedures. 
This protocol and any amendments will be submitted to a properly constituted independent Institutional Review 
Board (IRB), in agreement with local legal prescriptions, for formal approval of the study conduct.  The decision of 
the IRB concerning the conduct of the study will be made in writing to the investigator and a copy of this decision 
will be provided to the sponsor 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. See Appendix C for a copy of the 
Subject Informed Consent Form. This consent form will be submitted with the protocol for review and approval by 
the EC/IRB for the study. A separate form for stored specimens with identifiers will be provided to consent 
subjects to the collection and storage of blood samples for future research.  
Under Investigational Device Exemptions (IDE) regulations (21 CFR 812), the sponsor-investigator Dr. Patel has 
determined this medical device study to be a nonsignificant risk and will present this determination to the UNC 
IRB. Given the minimal risk of the study intervention and limited time to start the procedure prior to ED arrival, the 
subject must provide verbal consent prior to undergoing RIC. The full written consent of a subject, using the IRB-
approved consent form, must be obtained before the subject undergoes remaining study procedures. The consent 
form must be signed by the subject and the investigator-designated research professional obtaining the consent.  
12 Study Finances 
12.1 Funding Source 
The study is jointly financed through Dr. Patel’s junior faculty development award from the UNC Office of the 
Provost, internal funds from the UNC Department of Emergency Medicine, and a pilot award from the NC TraCS 

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Institute (funded through a CTSA grant from NIH’s National Center for Advancing Translational Sciences). 
Additional funding support has been requested in a pilot grant application to the Falck Foundation (Aarhus, 
Denmark). These funds will be used to purchase devices and other supplies and cover other study expenses. 
CellAegis Devices, Inc. provides discounted prices on autoRIC® devices and cuffs to researchers. Otherwise, no 
industry funding is supporting this study. 
12.2 Conflict of Interest 
Any investigator 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 prior to participation in this study. All University of North Carolina investigators 
will follow the University conflict of interest policy. Any potential conflicts of interests will disclosed in the UNC 
certification process.  
13 Publication Plan 
The sponsor-investigator Dr. Patel holds primary responsibility for the publication of the results of the study. 
Findings from the study will be shared in invited seminars, conference presentations, and peer-reviewed 
publications. In compliance with current NIH policy, this pilot study will also be registered at ClinicalTrials.gov no 
later than 21 days after enrolling the first subject. Furthermore, summary results will be submitted no later than 
one year after the primary completion date, i.e., the date that the final subject received the study procedure.  
14 References 
1.
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the American Heart Association. Circulation. 2016;133(4):e38-e360.
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factors. JAMA. 2013;310(6):591-606.
3.
O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation
myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association
Task Force on Practice Guidelines. Journal of the American College of Cardiology. 2013;61(4):e78-140.
4.
Verma S, Fedak PW, Weisel RD, et al. Fundamentals of reperfusion injury for the clinical cardiologist.
Circulation. 2002;105(20):2332-6.
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Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. New England Journal of Medicine.
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6.
Ibáñez B, Heusch G, Ovize M, Van de Werf F. Evolving therapies for myocardial ischemia/reperfusion injury.
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Frumkin K, Bloom AS. Ischemic Conditioning: Implications for Emergency Medicine. Annals of emergency
medicine. 2016;68(3):268-74.
8.
Bell R, Yellon D. Surgery: Remote ischaemic conditioning–approaching prime time?. Nature Reviews
Cardiology. 2013;10(11):619-21.
9.
Heusch G, Bøtker HE, Przyklenk K, et al. Remote ischemic conditioning. Journal of the American College of
Cardiology. 2015;65(2):177-95.
10. Hausenloy DJ, Yellon DM. Remote ischemic preconditioning: underlying mechanisms and clinical application.
Cardiovascular Res. 2008. 79(3):377-86.
11. Belaoussoff V, Ganske R, Redington A. Remote Ischemic Conditioning: The Commercial Market? CellAegis
Perspective. Journal of Cardiovascular Pharmacology and Therapeutics. 2017 Jan 1:1074248417707051.
12. Garratt KN, Leschinsky B. Remote Ischemic Conditioning: The Commercial Market: LifeCuff Perspective.
Journal of Cardiovascular Pharmacology and Therapeutics. 2017 Jun 20:1074248417715003.

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13. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic
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14. Dickson EW, Lorbar M, Porcaro WA, et al. Rabbit heart can be “preconditioned” via transfer of coronary
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15 Appendices  
Appendix A: Orange County Emergency Medical Services 2016 Chest Pain Protocol 
<Front> 

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<Back> 

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Appendix B: Suggested Recruitment Scripts 
Paramedic Script: 
It looks like you may qualify for a pilot study evaluating a technique called remote 
ischemic conditioning, or “RIC” for short. If you would like more information about 
the study, I will call the study coordinator/investigator who will explain the study 
and go through this information sheet with you. While you are on the phone, I will 
be providing usual care. Is it okay with you if I call the study coordinator so they 
can tell you more about the study? 
Telephone Script: 
Hello, my name is __________. I’m a study coordinator/investigator in the UNC 
emergency department. Thank you very much for wanting to learn more about our 
study. I understand you are having ________ symptoms. Is that correct? 
You are eligible to participate in a pilot study to help understand a technique 
known as remote ischemic conditioning, or RIC for short. RIC is a simple, non-
invasive procedure where a cuff placed on your upper arm is automatically inflated 
and deflated using a special medical device. You may not benefit from this 
procedure, but your participation will help us learn more about RIC, and this 
valuable knowledge will be used in future studies of the benefits of RIC. Previous 
studies of RIC have shown no serious adverse events or safety risks. The inflation 
of the cuff however may be uncomfortable. Your participation is voluntary, and 
regardless of your decision, you will continue to receive the usual care. Also, if you 
decide to participate, you’re free to withdraw for any reason at any time. Thank 
you for considering. Do you have any questions on the study that I may be able to 
answer at this time? 
Can you describe the procedure that you will receive if you agree to participate in 
this study? 
Will you receive medical care from the paramedic if you don’t agree to participate? 
Do you wish to participate in our study? 
Thank you again for your time. Please hand the phone back to the paramedic. 

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Appendix C: Sample Patient Information Sheet 

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Appendix D: Sample Informed Consent Form 
CONSENT FORM AND AUTHORIZATION FOR DISCLOSURE OF PROTECTED HEALTH 
INFORMATION 
Mehul Patel, Ph.D. in the Department of Emergency Medicine at the University of North Carolina at 
Chapel Hill is engaged in research to better understand a procedure known as remote ischemic 
conditioning (RIC) in patients transported by ambulance. This investigational study is known as:  
A pilot study of the feasibility of prehospital delivery of remote ischemic conditioning by 
emergency medical services in chest pain patients 
You have been invited to participate in a research study. Before you decide, it is important for 
you to understand why the study is being done, what it will involve, and what are the potential 
risks or benefits to you. The following information is being provided so you can decide with 
confidence whether or not to participate in this study. Please read this information carefully 
and ask as many questions as you like before deciding whether you want to take part. 
STUDY DESCRIPTION: 
The purpose of this research study is to better understand a technique known as remote ischemic 
conditioning, or RIC for short. RIC is a simple, non-invasive procedure where a cuff placed on the upper 
arm is inflated to temporarily cut off blood flow in the arm and then deflated to restore blood flow. This 
process is typically repeated up to four cycles. This study uses an investigational medical device called 
the autoRIC® (CellAegis Devices, Inc., Toronto, Canada) to automatically administer the RIC cycles.   
There is evidence to suggest that RIC can benefit patients having a major heart attack. However, larger, 
better designed clinical trials are needed to establish the therapeutic benefits of RIC. Although you are 
not the type of patient that is expected to benefit from RIC, your participation will help us learn more 
about it. 
This pilot study, rather than testing the benefits of RIC, is evaluating the feasibility of starting RIC in the 
ambulance and continuing the procedure for all four cycles in patients such as yourself. Approximately 
50 patients will participate in this study. Valuable knowledge gained from these participants will 
significantly strengthen future clinical studies.  
STUDY PROCEDURES: 
Should you decide to participate in the remainder of the study, you will be interviewed during your stay 
in the Emergency Department (ED). The interview will consist of open-ended questions regarding the 
RIC procedure and general aspects of the study. This interview will require about 10-15 minutes of your 
time and will not interfere with your medical care while in the ED. You may refuse to answer any 
questions. 

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Clinical research staff will also collect a blood sample (approximately one tablespoon) from you for 
future testing. When possible, this blood sample will be obtained with other blood draws taken as part of 
usual care. In the future studies, this sample may be used to look for proteins, enzymes, or other 
molecules associated with RIC so that we may learn more about how it works. For the time being, your 
blood sample will be stored indefinitely in a lab freezer within a locked space. Your frozen specimen 
will be coded and will not identify you. You will not be given any information about the results of the 
any future blood testing. The results would not be useful to you or your doctors. Additional description 
of the collection and storage of a blood sample for future testing will be provided in a separate form. 
You will be given the opportunity to consent to or refuse this piece separately.  
Your participation in the study is limited to the ambulance transport and ED stay. However, members of 
the research team may access and examine your medical records for relevant clinical information about 
you. Your data will be stripped of any personally identifying information and will be kept confidential 
throughout the course of the study. There are no follow-up visits required of you though a research team 
member will attempt to contact you after 48 hours, either by telephone or in-person if you are still in the 
hospital, to ask about how you are doing.  
FORESEEABLE RISKS AND DISCOMFORTS: 
RIC is a safe procedure. It has been carried out in thousands of patients in previous studies with no 
reports of serious adverse events or safety risks. However, some patients have reported minor pain and 
discomfort due to the inflation of the cuff. Also, in rare cases, there may be some small red spots on the 
skin caused by the inflated cuff bursting blood vessels in the skin. This is known as skin petechiae and 
may last for a few days. Skin petechiae does not cause permanent harm or damage.  
With any research study, there is the risk that health information about you could be disclosed. The 
research team have worked to minimize this risk to confidentiality in several important ways: 
1. Information collected about you for this study will never be reported using identifying
information, such as your name. Information will only be reported anonymously, and about the
whole group of patients in the study.
2. The information that we collect about you will be labeled with an identification number only,
rather than your name. All paper forms and other information about you will be stored in locked
file cabinets with specially made keys in the research office. Any forms that link your name to
your study number will be stored in a separate locked cabinet from the information collected
about you.
3. Information stored on computer will be kept on servers at the Department of Emergency
Medicine at the University of North Carolina, Chapel Hill. Access to the data will be password
protected and the servers themselves are behind a firewall and kept in a locked office.
4. Paper forms and electronic data will only be accessible by key members of the research team and
will not be shared outside the team.

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BENEFITS OF RESEARCH: 
You are not expected to receive any personal benefit for being a part of this pilot study. Your 
participation will help us learn more about how RIC is administered in the ambulance and ED. This is 
important information that will help us to test the clinical benefit of RIC in future studies. 
ALTERNATIVE MEDICAL TREATMENTS: 
You do not have to participate in the study to receive care for your current condition. Appropriate 
medical treatments will be provided to you regardless of your decision to participate.  
DISCLOSURE AND CONFIDENTIALITY OF RECORDS: 
As mentioned above, several important measures will be taken to maintain the confidentiality of your 
medical records. However, this information may be disclosed and used by the following or their 
representatives: 
•
Study investigators
•
UNC Hospital
•
UNC IRB
•
US FDA
•
NIH
•
Other government agencies when required by law
Disclosure or use of your records could be, for example, to assure compliance with the study protocol or 
to provide protection to you as a study participant. There is no expiration date for the use of your records 
from the study. Any information disclosed to the parties identified above may be re-disclosed by them; 
however, such re-disclosure is not under the protection of this Consent and Authorization.  
COMPENSATION IN CASE OF INJURY: 
Should inadvertent injury or damage result from your participation in this study, there are no designated 
funds provided for subsequent medical care or compensation by either the research study or UNC 
Hospital. However, you do not waive any legal rights by signing this consent form. 
VOLUNTARY PARTICIPATION AND WITHDRAWAL: 
Your participation is voluntary, and you may discontinue participation at any time. Refusal to participate 
or withdrawal will involve no penalty or loss of benefits to which you are otherwise entitled, including 
medical care at UNC Hospital. However, if you do not agree to sign this Consent and Authorization 
form, you will not be permitted to participate in this study.  
If you decide to withdraw from the study, you must provide a written statement of your choice to 
withdraw. However, where the study has relied on your consent and authorization up to that point, your 
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The study investigators may remove you from this study without your consent for any appropriate 
reason, which will be explained to you.  
STUDY SPONSOR AND FUNDING: 
This is an investigator-sponsored study, which means the principal and co-investigators have planned 
the entire study and are responsible for all aspects of it. The study is jointly funded by the UNC 
Department of Emergency Medicine and the North Carolina Translational and Clinical Sciences (NC 
TraCS) Institute. No industry funding is supporting this study.  
CONTACT INFORMATION: 
You may contact the Principal Investigator, Dr. Mehul Patel, at mehul_patel@med.unc.edu or (919) 
843-7307 to answer any questions you might have about your study participation or in case you think 
you may have any research related injuries.  
If you have any questions or concerns about your rights as a research subject, you may contact, 
anonymously if you wish the UNC Office of Human Research Ethics at IRB_Subjects@unc.edu or 
(919) 966-3113.  

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STATEMENT OF VOLUNTARY PARTICIPATION: 
I have read the above, have asked questions and have received answers about this study to my 
satisfaction. I understand what I have read and willingly give my consent to participate in “A pilot study 
of the feasibility of prehospital delivery of remote ischemic conditioning by emergency medical 
services in chest pain patients.” I understand that I will receive a signed copy of this document. I 
further authorize the use or disclosure of my health and personal information contained in records as 
described above.  
______________________________________________________ 
Signature of Research Participant 
____________________ 
Date 
______________________________________________________ 
Printed Name of Research Participant 
______________________________________________________ 
Signature of Research Team Member Obtaining Consent 
____________________ 
Date 
______________________________________________________ 
Printed Name of Research Team Member Obtaining Consent