COOL-AMI EU Pivotal Trial: A Multicenter, Prospective, Randomized-Controlled Trial to Assess the Safety and Effectiveness of Cooling As an Adjunctive Therapy to Percutaneous Intervention in Patients With Acute Myocardial Infarction
Phase: NA
Conditions: Acute Myocardial Infarction
Sponsor: ZOLL Circulation, Inc., USA

PROPRIETARY & CONFIDENTIAL 
ZOLLOO 
THE INFORMATION CONTAINED IN THIS DOCUMENT IS CONFIDENTIAL AND PROPRIETARY, AND IS 
THE SOLE PROPERTY OF ZOLL CIRCULATION, INC. ANY DISTRIBUTION OR REPRODUCTION WITHOUT 
WRITTEN CONSENT OF ZOLL IS PROHIBITED. 
EFFECTIVE DATE: * C\· 1f DOCUMENT NUMBER: 
REVISION: 
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EDC-3135 
COOL-AMI EU PIVOTAL TRIAL PROTOCOL 
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EDC-3135 
REVISION: 
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PAGE: 
2  OF 3 
COOL-AMI EU PIVOTAL TRIAL PROTOCOL  
 
PROPRIETARY & CONFIDENTIAL 
 
 
1. PURPOSE 
COOL-AMI EU Pivotal Trial is: A MULTICENTER, PROSPECTIVE, RANDOMIZED 
CONTROLLED TRIAL TO ASSESS THE SAFETY AND EFFECTIVENESS OF 
COOLING AS AN ADJUNCTIVE THERAPY TO PERCUTANEOUS INTERVENTION 
IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION is designed to evaluate 
the safety and efficacy of therapeutic hypothermia, using the ZOLL Proteus IVTM 
System, as an adjunctive therapy for patients presenting with acute myocardial 
infarction and undergoing PCI.  This trial will be conducted by ZOLL Circulation, Inc., 
under Good Clinical Practices in accordance with ISO 14155. 
2. SCOPE 
The scope of the COOL-AMI EU Pivotal Trial is therapeutic hypothermia and will be 
conducted by ZOLL Circulation, Inc., This document provides the ZOLL Circulation, Inc., 
Investigational Plan for the COOL-AMI EU Pivotal Trial, and it details all aspects of the study 
protocol by which the trial will be conducted by ZOLL Circulation, Inc. 
3. REFERENCES 
3.1. None 
4. REQUIREMENTS 
4.1. Clinical trial data shall remain confidential per HIPAA and applicable European Regulations.  
4.2. Clinical trial data shall be maintained in the Clinical Affairs files. 
4.3. Declaration of Helsinki. 
 
5. APPENDICES 
1. Appendix A Rev.6 - For sites that don’t require specific Dual Anti-Platelet Therapy details, 
125 pages 
2. Appendix B Rev.6 – Germany,122 pages 
3. Appendix C Rev.6 - For sites that require specific Dual Anti-Platelet Therapy details,124 
pages 
4. Appendix  D Rev.3 – France,127 pages 
5. Appendix E – Change Log, 2 pages 
 
 
 
 

 
DOCUMENT NUMBER: 
EDC-3135 
REVISION: 
07 
PAGE: 
3  OF 3 
COOL-AMI EU PIVOTAL TRIAL PROTOCOL  
 
 
PROPRIETARY & CONFIDENTIAL 
 
REVISION HISTORY 
Rev. 
Description 
Originator 
Effective Date 
01 
Initial Release into ZOLL Circulation Quality System 
Note: The EDC Cover Page has been updated with the 
statement” ZOLL intends to submit Addendum A to sites that 
we are not certain adhere to DAPT guidelines as a standard 
of care” There are no changes to the contents of the main 
document. 
Candace Elek 
1/09/2017 
02 
Revision of the protocol to include Appendix A, B, and C.  
Appendix A: Main Protocol 
Appendix B: Germany Protocol 
Appendix C: Protocol for sites requiring more specific DAPT 
details. 
Candace Elek 
3/20/17 
03 
Revision of the A, B and C appendices. Changes are identical 
in all appendices 
Appendix A: Main Protocol 
Appendix B: Germany Protocol 
Appendix C: Protocol for sites requiring more specific DAPT 
details. 
Shweta Kalpa 
6/15/2017 
04 
Revision of the A, B and C appendices. Changes are identical 
in all appendices 
Appendix A: Main Protocol 
Appendix B: Germany Protocol 
Appendix C: Protocol for sites requiring more specific DAPT 
details. 
Shweta Kalpa 
07/25/2017 
05 
Added New Appendix D 
Appendix A –unchanged 
Appendix B -unchanged  
Appendix C -unchanged  
Appendix D –Rev 1 
Shweta Kalpa 
10/10/2017 
06 
Appendix A – Rev.4 to Rev.5 
Appendix B – Rev.4 to Rev.5  
Appendix C – Rev.4 to Rev.5  
Appendix D – Rev.1 to Rev.2  
Appendix E - Change Log  
Asmeret 
Kidane 
2/23/2018 
07 
Appendix A – Rev.5 to Rev.6 
Appendix B – Rev.5 to Rev.6  
Appendix C – Rev.5 to Rev.6  
Appendix D – Rev.2 to Rev.3  
Appendix E - Change Log 
Asmeret 
Kidane 
6/19/2018 
 

 
 
 
 
APPENDIX A 
 
 
 
 
 
 
COOL-AMI EU Pivotal Trial Clinical Investigational Plan 
 
For sites that don’t require specific Dual Anti-Platelet 
Therapy details (Rev. 6) 
 
(125 pages) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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COOL-AMI EU Pivotal Trial EDC-3135 Rev 6 
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Clinical Investigation Plan 
 
COOL-AMI EU PIVOTAL TRIAL: A MULTICENTER, PROSPECTIVE, 
RANDOMIZED-CONTROLLED TRIAL TO ASSESS THE SAFETY AND 
EFFECTIVENESS OF COOLING AS AN ADJUNCTIVE THERAPY TO 
PERCUTANEOUS INTERVENTION IN PATIENTS WITH ACUTE 
MYOCARDIAL INFARCTION 
 
 
PROTOCOL NO.: EDC-3135 
 
 
Revision: 6 
 
EFFECTIVE DATE:   JUNE 19, 2018 
 
 
 
 
CONFIDENTIAL & PROPRIETARY 
 
The information in this Protocol is confidential and proprietary and is to be used only in 
connection with matters authorized by ZOLL and no part is to be disclosed to others 
without prior written permission from ZOLL 
 
 
 
 
 
 
 
 

CLINICAL INVESTIGATION PLAN APPROVAL PAGE 
CLINICAL INVESTIGATION PLAN: 
COOL-AMI EU Pivotal Trial: A 
multicenter, prospective, randomized 
controlled Trial to assess the safety and 
effectiveness of cooling as an adjunctive 
therapy to percutaneous intervention in 
patients with acute myocardial infarction 
PROTOCOL No.: 
SPONSOR: 
EDC-3135 
ZOLL Circulation, Inc. 
2000 Ringwood A venue 
San Jose, CA 95131 
SPONSOR 
REPRESENTATIVE: 
ZOLL Medical Deutschland GmbH 
Emil-Hoffmann - StraBe 13 
CLINICAL TRIAL SPONSOR'S 
CONTACT: 
REVISION NUMBER: 
50996 KOln, Germany 
Philippa Hill 
6 
A£p,rgval of Clinical Investigation Plan by Sponsor: 
Date 
COOL-AMI EU Pivotal Trial EDC-3135 Rev 6 
CONFIDENTIAL & PROPRIETARY 
Page 2of125 

Page 3 of 125 
COOL-AMI EU Pivotal Trial EDC-3135 Rev 6 
CONFIDENTIAL & PROPRIETARY  
  
Signature Page 
 
Clinical Investigation Plan  
 
COOL-AMI EU PIVOTAL TRIAL: A MULTICENTER, PROSPECTIVE, RANDOMIZED-
CONTROLLED TRIAL TO ASSESS THE SAFETY AND EFFECTIVENESS OF COOLING AS 
AN ADJUNCTIVE THERAPY TO PERCUTANEOUS INTERVENTION IN PATIENTS WITH 
ACUTE MYOCARDIAL INFARCTION 
PROTOCOL NO.: EDC 3135 
Revision: 6 
Effective Date: JUNE 19, 2018 
 
Signatures of Investigator below constitute their approval of this clinical investigation 
plan (CIP) and provide necessary assurances that they have read the CIP, understand it, 
and will work according to all stipulations of it, and to the ethical principles stated in the 
latest version of the Declaration of Helsinki and the ISO 14155:2011 (Clinical 
Investigation of Medical Devices for Human Subjects – Good Clinical Practice). 
 
 
 
 
Investigator Name (Please Print) 
 
 
 
 
 
 
Investigator Signature 
 
Date 
 
 
 
 
 
 
Institution Name 
 
 
 
 
 
Institution Address 
 
 
 
 
 
ZOLL Circulation, Inc. 
 
 
Sponsor Name 
 
 
 
 
 
2000 Ringwood Avenue, San Jose CA 95131 
Sponsor Address 
 
 
 
 
 
ZOLL Medical Deutschland GmbH 
 
 
Sponsor Representative 
 
 

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Table of Contents 
1 
SYNOPSIS .............................................................................................................. 9 
Inclusion Criteria ...................................................................................................... 10 
Exclusion Criteria ..................................................................................................... 11 
2 
INTRODUCTION ................................................................................................ 15 
3 
BACKGROUND .................................................................................................. 17 
4 
INTENDED USE, SYSTEM OVERVIEW, & DEVICE DESCRIPTION .......... 18 
 
Intended Use / Indication for Use ..................................................................... 18 
 
System Overview .............................................................................................. 18 
 
Device Description ............................................................................................ 19 
4.3.1 Proteus Catheter ................................................................................................ 19 
4.3.2 Proteus Temperature Probe ............................................................................... 19 
4.3.3 Proteus Cassette................................................................................................. 19 
4.3.4 Proteus Console ................................................................................................. 20 
4.3.5 Device Labeling ................................................................................................ 21 
5 
PRIOR INVESTIGATIONS ................................................................................. 21 
 
Pre-Clinical Studies ........................................................................................... 21 
 
Human Clinical Studies ..................................................................................... 22 
5.2.1 COOL MI Trial ................................................................................................. 22 
5.2.2 COOL MI II Trial .............................................................................................. 29 
5.2.3 COOL RCN Trial .............................................................................................. 32 
5.2.4 ICE- IT Trial...................................................................................................... 35 
5.2.5 RAPID-MI ICE Trial ........................................................................................ 36 
5.2.6 CHILL-MI Trial ................................................................................................ 36 
5.2.7 Induction of Mild Systemic Hypothermia With Endovascular Cooling During 
Primary Percutaneous Coronary Intervention for Acute Myocardial Infarction .......... 37 
5.2.8 VELOCITY Trial .............................................................................................. 37 
5.2.9 EU AMI Case Series ......................................................................................... 39 
5.2.10 COOL-AMI EU PILOT Trial ........................................................................... 40 
 
Summary and Clinical Trial Rationale .............................................................. 41 
6 
CLINICAL TRIAL PLAN .................................................................................... 42 

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Trial Objective................................................................................................... 42 
 
Trial Endpoints .................................................................................................. 42 
6.2.1 Primary Effectiveness Endpoint ........................................................................ 42 
6.2.2 Primary Safety Endpoint ................................................................................... 42 
6.2.3 Additional Assessments: Demographics and Other Parameters ....................... 42 
 
Trial Design ....................................................................................................... 43 
 
Patient Population ............................................................................................. 43 
 
Selection Criteria ............................................................................................... 43 
 
Inclusion Criteria ............................................................................................... 44 
 
Exclusion Criteria .............................................................................................. 44 
 
Clinical Trial Procedures ................................................................................... 45 
6.8.1 Patient Screening ............................................................................................... 45 
6.8.2 Informed Consent .............................................................................................. 46 
6.8.3 Roll-In Enrollment ............................................................................................ 47 
6.8.4 Approval to Randomize in the Trial .................................................................. 48 
6.8.5 Randomization .................................................................................................. 48 
6.8.6 Acute Care and Emergency Room Triage......................................................... 49 
6.8.7 Standardized Care Prior to the Cooling Procedure ........................................... 49 
6.8.8 Documentation Procedures ............................................................................... 50 
6.8.9 Study Flow and Procedures ............................................................................... 51 
6.8.10  Pre-Cooling Assessment Procedures ................................................................ 55 
6.8.11 Initiation, Maintenance, and Reversal of Cooling with Proteus IVTM System 
Procedures / Evaluations and Data Collection for Subjects Enrolled in the Test Arm 56 
6.8.12 Test Arm: Temperature Management Protocol and Data Collection Time 
Points 56 
6.8.13 Trial Schedule for Test Arm Subjects ............................................................... 63 
6.8.14 Trial Schedule for Control Arm Subjects .......................................................... 64 
6.8.15 Control Arm Protocol and Data Collection Time Points .................................. 65 
6.8.16 Follow-up at 4-6 days and at 30 days following the PCI Procedure ................. 65 
6.8.17 Follow-up at 12 months following PCI ............................................................. 66 
6.8.18 Use of other Cooling Methods .......................................................................... 66 

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6.8.19 Transferring Subject during Cooling................................................................. 66 
6.8.20 Patient Withdrawal and Discontinuation........................................................... 66 
6.8.21 Patient Lost to Follow-up .................................................................................. 67 
6.8.22 Early Termination of a Clinical Investigation ................................................... 67 
6.8.23 Amendments and Protocol Deviations .............................................................. 68 
6.8.24 Trial Exit ........................................................................................................... 69 
6.8.25 Subject Confidentiality ...................................................................................... 69 
6.8.26 Device Accountability ....................................................................................... 70 
6.8.27 Return of Materials upon Trial Termination ..................................................... 70 
6.8.28 Trial Closure ...................................................................................................... 71 
 
Cardiac Magnetic Resonance (cMR) imaging Core Laboratory ....................... 71 
7 
ADVERSE EVENTS & DEVICE DEFICIENCIES ............................................ 71 
 
Definitions ......................................................................................................... 71 
7.1.1 Adverse Event (AE) .......................................................................................... 71 
7.1.2 Serious Adverse Event (SAE) ........................................................................... 72 
7.1.3 Device Deficiency (DD).................................................................................... 72 
7.1.4 Adverse Device Effect (ADE)........................................................................... 72 
7.1.5 Serious Adverse Device Effect (SADE) ........................................................... 72 
7.1.6 Unanticipated Serious Adverse Device Effect (USADE) ................................. 73 
 
Adverse Event Reporting .................................................................................. 73 
7.2.1 Adverse Event Reporting from Site to Sponsor and MEC................................ 73 
7.2.2 Serious Adverse Event Reporting to Sponsor and MEC................................... 73 
7.2.3 UADE/USADE Reporting to Sponsor and MEC .............................................. 74 
7.2.4 Sponsor Reporting to NCAs (National Competent Authority) when European 
Sites Participate in the Trial ......................................................................................... 74 
 
Device Relationship .......................................................................................... 75 
8 
MONITORING BY DATA MONITORING COMMITTEE .............................. 77 
9 
ADJUDICATION OF EVENTS........................................................................... 77 
10 
RECOMMENDATION FOR DAPT AND STENTS........................................... 78 
11 
RISK ANALYSIS ................................................................................................. 79 
 
Risk Assessment Process .................................................................................. 79 

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Expected Clinical Observations ........................................................................ 80 
 
Potential Clinical Risks ..................................................................................... 80 
11.3.1 Potential Adverse Events associated with the Proteus Catheter and Cooling 
System: ......................................................................................................................... 81 
11.3.2 Potential Adverse Events associated with the cooling procedure include but are 
not limited to the following: ......................................................................................... 81 
11.3.3 Risks Associated with Anti-shivering Medications .......................................... 82 
 
Additional investigations due to the trial .......................................................... 83 
11.4.1 Delay in PCI through the use of hypothermia therapy ...................................... 83 
11.4.2 Implementation of PCI in patients undergoing hypothermia (patient-related 
risks)    .......................................................................................................................... 84 
11.4.3 Implementation of PCI with concurrent use of endovascular hypothermia. ..... 84 
11.4.4 The concurrent medication. ............................................................................... 84 
11.4.5 The supply of 4°C cooled saline solution ......................................................... 84 
11.4.6 Other procedures within the clinical trial .......................................................... 84 
 
Potential Clinical Benefits ................................................................................. 85 
 
Methods to Minimize Risk ................................................................................ 85 
 
Risk – Benefit Assessment ................................................................................ 86 
12 
RECORDS AND REPORTS ................................................................................ 87 
 
Investigator Records .......................................................................................... 87 
 
Investigator Responsibilities ............................................................................. 88 
 
Sponsor Records ................................................................................................ 90 
 
Sponsor Reports ................................................................................................ 91 
13 
MONITORING AND AUDITING PROCEDURES............................................ 92 
 
Clinical Trial Sponsor and Monitors ................................................................. 92 
 
Monitoring Methods .......................................................................................... 93 
 
Monitoring Visits .............................................................................................. 93 
 
Pre-trial Qualification Visit ............................................................................... 94 
 
Initiation Visit ................................................................................................... 94 
 
On-Site Interim Monitoring Visits .................................................................... 95 
 
Audits ................................................................................................................ 95 
 
Final Monitoring Review .................................................................................. 95 

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14 
DATA MANAGEMENT PROCEDURES........................................................... 95 
 
Case Report Forms ............................................................................................ 96 
 
Source Documentation ...................................................................................... 96 
 
Transmission of Data ........................................................................................ 97 
 
Data Queries ...................................................................................................... 97 
15 
STATISTICAL ANALYSIS PLAN ..................................................................... 97 
 
Data Analysis .................................................................................................... 98 
 
Statistical Methods .......................................................................................... 100 
 
Sample Size Justification ................................................................................ 101 
16 
PUBLICATION .................................................................................................. 105 
17 
INTELLECTUAL PROPERTY ......................................................................... 105 
18 
STATEMENT OF COMPLIANCE .................................................................... 105 
ATTACHMENT I – REFERENCES ......................................................................... 106 
ATTACHMENT II – ANTI-SHIVERING PROTOCOL ........................................ 110 
ATTACHMENT III – BEDSIDE SHIVERING ASSESSMENT SCALE (BSAS) 112 
ATTACHMENT IV – SPECIFIC NEW-ONSET ADVERSE EVENT 
DEFINITIONS ............................................................................................................. 113 
ATTACHMENT V – ADVERSE EVENT DEFINITIONS ..................................... 116 
ATTACHMENT VI – INVESTIGATOR LIST ........................................................ 122 
ATTACHMENT VII – LIST OF ABBREVIATIONS ............................................. 123 
 
 
 

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1 
SYNOPSIS 
Clinical Trial 
Title 
COOL-AMI EU PIVOTAL TRIAL: A MULTICENTER, 
PROSPECTIVE, RANDOMIZED-CONTROLLED TRIAL TO 
ASSESS THE SAFETY AND EFFECTIVENESS OF COOLING 
AS AN ADJUNCTIVE THERAPY TO PERCUTANEOUS 
INTERVENTION IN PATIENTS WITH ACUTE 
MYOCARDIAL INFARCTION 
Clinical Trial 
Sponsor 
ZOLL® Circulation, Inc. 
Clinical Trial 
Sponsor’s 
Contact 
Philippa Hill 
Senior Director, Clinical Affairs 
ZOLL Circulation, Inc. 
2000 Ringwood Ave. 
San Jose, CA 95131 
Main:    +1 (408) 541-2140 
Fax:  +1 (408) 541-1030 
PHill@zoll.com@zoll.com 
Trial Number 
EDC-3135 
Investigational 
Device 
Proteus™ Intravascular Temperature Management (IVTM) 
System 
Trial Objective The objective of this trial is to evaluate the safety and effectiveness of 
therapeutic hypothermia, using the ZOLL Proteus IVTM System, as 
an adjunctive therapy for patients presenting with acute anterior 
myocardial infarction (AMI) and undergoing percutaneous coronary 
intervention (PCI) in comparison with patients with acute anterior 
myocardial infarction and undergoing PCI only. 
 
Trial Design 
A multicenter, prospective, interventional, randomized-controlled trial. 
Randomization will be in a 1:1 ratio, Test Arm (PCI + Cooling) or 
Control Arm (PCI alone) in up to 500 randomized subjects (250 
subjects in each arm). 
 

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Roll-In Subjects: To enhance each site’s ability to successfully 
integrate steps of the protocol and for training purposes prior to 
randomizing subjects in the trial, each site may enroll up to 4 Roll-In 
subjects in a non-randomized fashion. Roll-In subjects will be treated 
and followed in the same manner as subjects in the Test Arm of the 
protocol (PCI + Cooling). Up to a total of 280 Roll-In subjects (up to 4  
per site) may be enrolled. Due to limited cMR data available in 
patients with inferior MI who received an adequate dose of cooling 
prior to revascularization, Inferior MI subjects will be allowed to be 
included as Roll-Ins to further evaluate inferior MI infarct size by 
cMR imaging. Evaluation of infarct size will be performed by cMR 
imaging at 4-6 days. 
Primary 
Effectiveness 
Endpoint  
Relative reduction of 20% in mean anterior myocardial infarct size as 
determined by Cardiac Magnetic Resonance (cMR) imaging at 4-6 
days post infarct in the Test Arm (cooling + PCI) relative to the 
Control Arm (PCI only). 
Primary Safety 
Endpoint 
Per-patient rate of composite Major Adverse Cardiac Events (MACE) 
in randomized subjects, defined as Cardiac Death (CD), All 
Myocardial Infarction (All MI) and Clinically-Indicated Target Lesion 
Revascularization (CI-TLR) at 30 day follow-up; non-inferiority to the 
control. 
Investigational 
Sites 
Up to 70 clinical sites in Europe 
Inclusion & 
Exclusion 
Criteria 
Patients shall be screened to the following inclusion and exclusion 
criteria. Subjects are qualified for participation only if all Inclusion 
Criteria have been met and all Exclusion Criteria have been confirmed 
not present. 
 
Inclusion Criteria 
All Inclusion Criteria must be answered YES for subject to satisfy 
Inclusion Criteria: 
 
1. The patient is ≥ 18 years of age. 
2. The patient must have symptoms consistent with AMI (i.e. chest 
pain, arm pain, etc.) and unresponsive to nitroglycerin, with 
symptoms beginning greater than 30 minutes but less than 
4.5hours prior to presentation at hospital. 

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3. Qualifying Infarct location: 
a. Roll-In subjects:  Evidence of Acute Anterior or Inferior 
MI with ST-segment elevation of  ≥ 0.2 mV in two or more 
anterior or inferior contiguous precordial leads (V1 –V4). 
b. Randomized subjects:  Evidence of Acute Anterior MI 
only with ST-segment elevation of  ≥ 0.2 mV in two or 
more anterior contiguous precordial leads (V1 –V4). 
4. The patient is eligible for PCI. 
5. The patient is willing to provide written informed consent to 
participate in this clinical trial. 
 
Exclusion Criteria 
All Exclusion Criteria must be answered NO for subject to satisfy 
Exclusion Criteria: 
The patient has had a previous myocardial infarction. 
1. The patient has had a previous Myocardial Infarction. 
2. The patient is experiencing cardiogenic shock, systolic blood 
pressure [SBP] <100 mmHg, HR>100 bpm and arterial oxygen 
saturation (pulse oximetry) <92% without additional oxygen.   
3. The patient is presenting with resuscitated cardiac arrest, atrial 
fibrillation, or Killip risk stratification class II through IV. 
4. The patient has an aortic dissection or requires an immediate 
surgical or procedural intervention other than PCI. 
5. The patient has known history of Congestive Heart Failure (CHF), 
hepatic failure, end-stage kidney disease or severe renal failure 
(clearance < 30ml/min/1.73m²).  
6. The patient is febrile (temperature > 37.5 °C) or has experienced 
an infection with fever in the last 5 days. 
7. The patient has a known previous CABG. 
8. The patient has a known recent stroke within 90 days of admission.  
9. Cardio-pulmonary decompensation that has occurred en route to 
the hospital or, in the opinion of the physician, that is imminent or 
likely to occur following presentation to the clinical site. 
10. Contraindications to hypothermia, such as patients with known 
hematologic dyscrasias which affect thrombosis (e.g., 
cryoglobulinemia, sickle cell disease, serum cold agglutinins) or 
vasospastic disorders (such as Raynaud’s or thromboangitis 
obliterans). 
11. Any contraindication to cardiac MRI, or any implant in the upper 
body which may cause artifacts on cardiac MRI imaging. 

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12. The patient has a known hypersensitivity or contraindication to 
aspirin, heparin, or sensitivity to contrast media, which cannot be 
adequately pre-medicated. 
13. The patient has a known history of bleeding diathesis, 
coagulopathy, cryoglobulinemia, sickle cell anemia, or will refuse 
blood transfusions. 
14. The patient has a height of <1.5 meters (4 feet 11 inches). 
15. The patient has a known hypersensitivity or contraindication to 
buspirone hydrochloride or Pethidine (Meperidine) and/or has 
been treated with a monoamine oxidase inhibitor in the past 14 
days. 
16. Patient has a known history of severe hepatic or renal impairment, 
untreated hypothyroidism, Addison’s disease, benign prostatic 
hypertrophy, or urethral stricture that in the opinion of the 
physician would be incompatible with Pethidine administration. 
17. The patient has an Inferior Vena Cava filter in place (IVC). 
18. The patient has a pre-MI life expectancy of <1 year due to 
underlying medical conditions or pre-existing co-morbidities. 
19. The patient has a known, unresolved history of drug use or alcohol 
dependency, or lacks the ability to comprehend or follow 
instructions. 
20. The patient is currently enrolled in another investigational drug or 
device trial. 
21. The patient is apprehensive about or unwilling to undergo the 
required MRI imaging at follow-up, has a documented or 
suspected diagnosis of claustrophobia, or has Gadolinium allergy, 
or is in permanent Atrial Fibrillation. 
22. The patient has received thrombolytic therapy en route to the 
hospital. 
23. The patient shows clinical evidence of spontaneous reperfusion as 
observed symptomatically and/ or from baseline ECG findings 
(partial or complete ST resolution in baseline ECG prior to 
informed consent and randomization). 
24. The patient is a vulnerable subject, for instance, a person in 
detention (i.e., prisoner or ward of the state). 
25. The patient is a female who is known to be pregnant. 
Clinical Trial 
Population 
Adult male and female patients presenting with an acute myocardial 
infarction. To qualify, patients must have symptoms consistent with 
AMI (i.e. chest pain, arm pain, etc.) unresponsive to nitroglycerin, 

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with symptom onset greater than 30 minutes but less than 4.5 hours 
prior to presentation at hospital and be eligible for PCI. 
 
Randomized subjects must have evidence of Acute Anterior MI only 
with ST-segment elevation of ≥ 0.2 mV in two or more anterior 
contiguous precordial leads (V1 –V4)will be included. 
 
Roll-In subjects with evidence of Acute Anterior or Inferior MI with 
ST-segment elevation of ≥ 0.2 mV in two or more anterior or inferior 
contiguous precordial leads (V1 –V4) will be included. 
Intervention 
Intravascular permissive hypothermia as an adjunct to PCI.  Cooling 
will be initiated prior to PCI with infusion of up to 1 L of cold saline 
(4°C) (according to the guideline) and with the Proteus Console set at 
32.0 degrees Celsius.  Total cooling time will be 3 hours (± 15 
minutes) and will be followed with active rewarming with the Proteus 
IVTM System to attain normothermia [36 °C (96.8°F)]. 
Length of 
Follow Up 
12 months 
Enrollment 
Initiation of enrollment: January 2017 
Completion of Enrollment: June 2019 
Follow up completed: June 2020 
Summary of 
Statistical 
Analysis 
Primary efficacy endpoint of infarct size measured as percentage of 
total LV mass by cMR, the null hypothesis of equal infarct size 
between two arms will be tested with t-test for the study population. 
For the safety endpoint, comparison of per patient MACE rate for non-
inferiority will be made with Fisher’s exact Test. 
Planned 
Interim 
Analyses 
Two interim analyses are planned to be performed at approximately 
50% and 75% of randomization, once subjects have completed 4-6 day 
cMR follow-up. At the interim stage, the trial will be stopped to reject 
the null hypothesis of no difference or continue enrollment. 
Analysis Sets 
The Intention-to-Treat (ITT) population will be used for primary 
statistical analyses and summaries for all analyses except for Safety 
endpoints. The ITT population includes subjects who have signed an 
informed consent and have been randomized to the Test Arm or the 
Control Arm of the trial. ITT subjects will be evaluated according to 
the group to which they were randomized. 

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The Per-Protocol (PP) population includes those subjects who met 
inclusion and exclusion criteria, were randomized to either the Test 
Arm or Control Arm, received the treatment to which they were 
randomized, and complied substantially with the treatment timeline 
and steps of this protocol without major protocol violations. 
The Safety Analysis Set will be used to evaluate safety endpoints. 
These will be all subjects included in the study as defined by the ITT 
analysis set and Roll-In subjects. For the safety analysis subjects will 
be followed for all Adverse Events 30 days post procedure. 
Additionally, all subjects will be followed through 12 months post 
procedure for the incidence of Serious Adverse Events (SAEs), Death 
and Heart Failure (as assessed by NYHA and Kansas City 
Cardiomyopathy Questionnaire (KCCQ),). 
Trial 
Oversight 
Each participating site will dedicate one Principal Investigator to 
oversee the execution of the clinical trial in accordance with the 
protocol. 

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2 
 INTRODUCTION 
Clinical investigations have shown that induction of hypothermia before reperfusion of 
acute coronary occlusion reduces infarct size.  A pilot study from Lund University 
demonstrated that the induction of mild hypothermia (<35°C) in ST Elevation Myocardial 
Infarction (STEMI) patients prior to performing Percutaneous Coronary Intervention 
(PCI) can save (preserve) 38% more cardiac tissue compared with the PCI alone.1 
Hypothermia has proven to be one of the most potent and consistent adjunctive therapies 
for infarct size reduction in numerous preclinical studies, when administered prior to 
reperfusion.  This is unlike the well accepted approach for therapeutic hypothermia for 
cardiac arrest, where cooling is applied after reperfusion. The mechanisms leading to 
protection are multifactorial.  However, unlike the consistent findings in preclinical 
studies, clinical trials (COOL -MI, ICE-IT, CHILL-MI) have failed to show a decrease in 
infarct size.  The major reason is likely due to the difficulty in achieving adequate cooling 
prior to reperfusion.  As shown in Table 1 below, none of the clinical trials to date has 
reached target temperature prior to reperfusion, as has been done in all of the animal 
studies. 
Table 1: Major Cooling Trials in STEMI. 
Major Cooling Trials in STEMI 
Trial 
Sample 
Size 
Target 
Temp 
(°C) 
Actual 
Temp at 
Reperfusion 
(°C) 
Temp Miss 
(°C) 
Cooling Time 
before 
Reperfusion 
(min) 
COOL -MI 168 – 
Hyp 
157 – 
Control 
33.0 
35.0 
2.0 
18 
ICE-IT 
105 – 
Hyp 
99 – 
Control 
33.0 
35 
2.0 
16 
CHILL-MI 61 – 
Hyp 
59 – 
Control 
33.0 
34.7 
1.7 
13 
 
The target temperature for each trial was 33.0 °C.  The actual temperature at the time of 
reperfusion was 1.7-2.0 °C higher than target.  This is a miss in temperature “dose” of 
around 50% [normal temperature is 37.0 °C, target temperature was 33.0 °C, (37.0 – 35.0) 
/ (37.0 – 33.0) = 50%].     

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Post hoc analysis of these trials showed that patients with anterior MI that were cooled to 
less than 35°C at the time of PCI showed a significant reduction in infarct size, supporting 
the idea of a dose response (See Figure 1).  Recent preclinical results (Stanford-ZOLL 
data) have shown that temperature at reperfusion of 32 °C is superior to 35 °C for reducing 
infarct size, confirming a dose response.  Future clinical trials will require more powerful 
cooling devices, and more consistency in implementing 18 minutes of cooling before 
reperfusion across all study sites in order to evaluate the actual effectiveness of therapeutic 
hypothermia as a protection strategy. 
 
 
Figure 1: Temperature at reperfusion for the Major Therapeutic Hypothermia in 
AMI Clinical trials. 
 
The Proteus device has a confirmed faster cooling rate.  With a duration of cooling of 18 
minutes prior to reperfusion, as occurred in the COOL -MI trial, the expected temperature 
at reperfusion is 33.3°C with the Proteus device.  This is significantly better than the 35°C 
achieved in COOL -MI and ICE-IT, and 34.7°C achieved in CHILL-MI. The relative 
effectiveness of the Proteus device for cooling, compared to the performance of the prior 
studies is shown in Figure 1 above. The addition of a bolus infusion of 4°C cold saline is 
expected to further enhance the temperature achieved at reperfusion with the Proteus 
System.  

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This Investigational Plan was developed in accordance with the requirements set forth in 
the Good Clinical Practices (E6)2, ISO 14155:2011 Clinical investigation of medical 
devices for human subjects3 - Good clinical practice, the Declaration of Helsinki, and the 
local regulatory requirements an adjunctive therapy to PCI. 
3 
BACKGROUND 
Coronary heart disease complicated by acute myocardial infarction (AMI) remains a 
leading cause of death and disability worldwide.  AMI most commonly occurs when a 
coronary artery becomes occluded by thrombus following the rupture of an atherosclerotic 
plaque. Factors that may affect the size of the subsequent infarction include duration of 
ischemia, size of ischemic territory, collateral blood flow, and myocardial metabolic rate. 
Long-term sequelae of AMI include ventricular remodeling, loss of ventricular function, 
congestive heart failure, dysrhythmias, and sudden death. 
Although major gains have been made in improving the outcome of patients suffering 
AMI, and early myocardial reperfusion with the use of thrombolytic therapy or primary 
percutaneous coronary intervention (PCI) are effective, morbidity and mortality remain 
substantial.  This may be because restoration of blood flow to the ischemic myocardium 
can itself induce injury through myocardial “ischemia reperfusion injury” (IRI), which 
can be defined as that portion of the ischemia-reperfusion continuum which is preventable 
by treatment initiated after restoration of blood flow.4 It has been proposed that 50% of 
the final infarct size may be a function of IRI. 4 
Ischemia reperfusion injury is protean in its components, likely including free radical and 
reactive oxygen species, disordered vasculature, inflammatory injury, programmed cell 
death, and pathologic remodeling among others.5   Unfortunately, the cascading nature of 
these events challenge and, in the end, may defeat the single molecular target 
pharmacologic model.  The long list of failed IRI pharmacologic agents includes 
antioxidants, calcium channel blockers, anti-inflammatory drugs, sodium hydrogen 
exchange inhibitors, among others, has led some to question the importance of reperfusion 
injury in the myocardium.6 Large infarctions still occur despite timely reperfusion, due to 
reperfusion injury.  Numerous treatments have been studied to reduce reperfusion injury, 
with little success to date. 7-9 
Therapeutic hypothermia (TH) has been studied for many years as a potential therapy 
for ischemia and reperfusion.10 -16 The past few years have seen development of a broad 
literature reporting both laboratory and clinical trials of mild post-reperfusion TH in the 
treatment of disease entities as diverse as acute cardiac arrest, stroke, and myocardial 
infarction, among others.  Unlike single pharmacologic agents, TH has the potential to 
modify and ameliorate multiple pathways of injury. 

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4 
INTENDED USE, SYSTEM OVERVIEW, & DEVICE DESCRIPTION 
 
Intended Use / Indication for Use 
The ZOLL® Proteus™ Intravascular Temperature Management (IVTM) System is 
indicated for use in adult subjects with acute myocardial infarction to induce and maintain 
hypothermia prior to percutaneous coronary intervention as an adjunctive therapy to 
reduce anterior infarct size.  The Proteus IVTM System is to be used only as part of the 
clinical investigation. 
 
System Overview 
The Proteus Intravascular Temperature Management (IVTM) System consists of four 
primary components: a single-use heat exchange catheter; heat exchange cassette; a 
temperature probe and a reusable microprocessor-driven console.  The system is designed 
to achieve and maintain patient temperatures within the range of 32 - 37°C. Its 
performance profile includes: 
1. Rapid patient cooling and warming 
2. Precise achievement and maintenance of a desired patient target temperature 
3. Quick and simple deployment: See the catheterization lab, critical care unit, 
emergency department, and other hospital settings 
Reference the Investigator Brochure for additional information on the Proteus 
IVTM System. 
The Proteus IVTM System couples a heat exchange catheter with a dual microprocessor-
driven controller to manage patient temperature. The Proteus IVTM System is designed 
to rapidly cool and warm patients, achieve and precisely maintain a target patient 
temperature and to be quickly and easily deployed. 
Cool or warm sterile saline is continuously circulated through the catheter, thereby cooling 
or warming the blood as it flows over the catheter without perfusion of fluids into the 
body. The saline is transported from the catheter to the cassette (mounted in the console) 
via extension lines. The cassette has an integral heat exchange element and a pump that 
couples with the console to cool or warm the saline being pumped through the closed 
circuit comprised of the cassette and catheter. The Proteus IVTM Console continuously 
monitors the patient temperature and controls the catheter temperature to cool, warm or 
maintain the target temperature. 

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Device Description 
4.3.1 Proteus Catheter 
The Proteus Catheter (Figure 2) is a single-use, heparin coated, endovascular heat 
exchange catheter consisting of a triple lobed, helically wound balloon mounted on the 
distal portion of a multi-lumen shaft.  The catheter is designed for placement in the Inferior 
Vena Cava via the femoral vein using a 12Fr or a 14Fr hemostatic introducer sheath.  The 
catheter has a fluid supply lumen, a fluid return lumen, a guidewire port at the proximal 
end of the catheter connecting to a guidewire lumen that accommodates guidewires with 
diameters up to 0.038”.  The expanded balloon portion of the catheter has an expanded 
diameter of 17 mm and a length of 26 cm during system operation.  The catheter has a 
radiopaque marker mounted at the distal and proximal end of the balloon portion of the 
catheter.  The distal end of the catheter has a non-traumatic soft tip.  The fluid supply and 
fluid return lumens of the catheter are connected to the cassette via extension lines 
approximately 2 meters in length, which provide the closed heat transfer fluid circuit.  The 
0.038”, 145-cm. stainless steel guidewire included in the package has a soft atraumatic 
tip. 
Figure 2 Diagram of  Proteus Catheter 
 
4.3.2 Proteus Temperature Probe 
The Proteus System measures a patient’s core body temperature using a heparin-coated 
endovascular dual output probe (X-Probe) advanced through the guidewire lumen of the 
Proteus Catheter after the catheter is placed. 
4.3.3 Proteus Cassette 
The single-use Proteus Cassette consists of a heat exchange element, a pump, a pump 
coupling to interface with the motor drive in the console and fluid lines to interface with 
the heat transfer fluid circulated by the console.  The cassette is designed to be removed 
from the portable control console allowing the catheter to remain in the patient to 

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facilitate moving the patient to another location where temperature management can 
continue using the same or another control console. 
4.3.4 Proteus Console 
The Proteus Console (Figure 3) consists of solid-state thermoelectric modules, a motor 
drive, dual fluid level detection systems and dual microprocessors.  A dilute 
polypropylene glycol/water mixture (process fluid) circulates within the console to 
provide heat exchange with the saline heat transfer fluid loop in the cassette.  This 
technology along with microprocessor proportional control of both the saline and the 
patient temperature enable the following features: 
• Designated patient temperature between 32-37°C is maintained within ± 0.3°C 
continuous calculation and display, in all ambient lighting conditions, of patient 
actual temperature, target temperature, and rate of cooling/warming 
• Redundant safety system to shut down and warn user of patient overheat or 
overcool, saline leakage, sensor failure, and electrical or mechanical malfunction 
• Control console automatically performs a hardware and software diagnostic check 
of all functional and safety systems upon startup 
• Maximum cooling and heating rates vary from patient to patient depending on the 
patient’s cardiac output, size and weight, room temperature and humidity, and the 
successful implementation of the anti-shivering medication regimen, type and 
amount anesthesia, combined use with blankets or active heating/cooling 
apparatus, body cavity exposure to the environment during surgery and other 
factors. 
 
Figure 3:  Proteus Console 
                                  
 

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Figure 4:  Proteus Catheter and Interconnection between Catheter, Temperature 
Probe (X-Probe), Cassette and Console. 
 
 
 
4.3.5 Device Labeling 
Written Instructions for Use, Operation Manual, Quick Reference Guide, and Service 
Manual for the Proteus IVTM System will be packaged with product shipped to the 
investigational sites.  The Proteus IVTM System is to be used only as part of the clinical 
investigation.  (See Proteus IVTM System Labeling) 
5 
PRIOR INVESTIGATIONS 
 
Pre-Clinical Studies 
Hypothermia has been shown to reduce metabolic demand and provide ischemic 
protection.  Recent studies across numerous different animal models have demonstrated a 
strong direct relationship between myocardial temperature and infarct size.11,12,14- 18  Mild 
to moderate degrees of hypothermia (32-35°C) have resulted in significant reductions in 
infarct size when applied either before or after the onset of coronary occlusion in animal 
studies.   

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In other studies, in 1996, Duncker et al, and in 1998 Miki et al, both demonstrated a dose 
response relationship between myocardial temperature and infarct size using a laboratory 
model of AMI.11,12Subsequently, Dae et al in collaboration with Radiant Inc. 
demonstrated that therapeutic hypothermia can be induced safely and rapidly in animal 
models using intravascular cooling.13 They then showed that hypothermic therapy initiated 
late during ischemia and continuing for several hours after reperfusion significantly 
improved reflow and reduced macroscopic zones of no-reflow and necrosis in this 
model.15  The study showed:  
• A striking reduction of myocardial infarct size.  The cooled group had an infarct 
of 9 ± 6% of the area at risk vs. 45 ± 8% of the area at risk for controls 
• Preservation of myocardial perfusion and viability in the cooled group as 
demonstrated by radionuclide imaging 
• No evidence of apoptosis in salvaged myocardium in the cooling arm.  Well-
preserved cardiac output during the cooling process. 
Of particular relevance, Gotberg et al reported in 2008 that hypothermia achieved before 
reperfusion decreased infarct size, while hypothermia initiated at the time of reperfusion 
prevented microvascular obstruction, but did not decrease myocardial infarct size. 16 
 
 
Human Clinical Studies   
5.2.1 COOL MI Trial  
The COOL MI Trial19 was conducted from September 2001 through April 2003. A total 
of 421 patients were enrolled (199 Control, 193 Intervention, 29 Roll-In) at 27 
investigational sites in the US, Germany and Australia.  The primary analysis population 
included 357 patients (180 Control, 177 Intervention) who received the assigned 
treatment.  The COOL MI Trial evaluated the safety and effectiveness of cooling as an 
adjunctive therapy to percutaneous coronary intervention (PCI) in patients with acute 
myocardial infarction.  Table 2 below displays enrollment characteristics. 
 
 
 
 
Table 2: COOL MI Trial Enrollment Characteristics 

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Control  
(N=180) 
Intervention 
(N=177) 
p-value 
Anterior Myocardial 
Infarction 
77 (44%) 
74 (42%) 
0.77 
Inferior Myocardial 
Infarction 
99 (56%) 
103 (58%) 
0.77 
Failed thrombolytic therapy 
prior to enrollment 
23 (12.8%) 
18 (10.3%) 
0.67 
Time in minutes – median (interquartile range) 
From symptom onset to 
hospital presentation 
123 (69 – 201) 
114 (60 – 190) 
0.08 
From hospital presentation to 
PCI 
88 (61 – 114) 
104 (80 – 134) 
<0.0001 
 
5.2.1.1 
Procedural and Angiographic Results COOL MI Trial 
The Trial demonstrated that endovascular cooling using the Radiant Medical’s (now 
ZOLL’s) Reprieve System TM in the setting of myocardial infarction was safe, well 
tolerated, and readily integrated into the existing treatment pathway.  While the primary 
effectiveness endpoint of the study was not achieved, the data provided a strong signal 
indicating that when patients were sufficiently cooled prior to reperfusion, myocardial 
damage was reduced.19 
The Control and Intervention groups were well matched in terms of culprit vessels, 
percutaneous coronary intervention (PCI) procedures and treatment success.  As expected, 
cooling did not affect the angiographic success of PCI procedures.  Of the 357 patients 
who underwent primary PCI, the majority were treated with stent implantation and a 
platelet glycoprotein receptor inhibitor.  Approximately 20% of study subjects were 
determined to have Thrombolysis in Myocardial Infarction (TIMI 3) flow prior to PCI.  
TIMI Grade Flow is a scoring system from 0-3 referring to levels of coronary blood flow 
assessed during percutaneous coronary angioplasty: 
• TIMI 0 flow (no perfusion) refers to the absence of any antegrade flow beyond a 
coronary occlusion. 
• TIMI 1 flow (penetration without perfusion) is faint antegrade coronary flow 
beyond the occlusion, with incomplete filling of the distal coronary bed. 
• TIMI 2 flow (partial reperfusion) is delayed or sluggish antegrade flow with 
complete filling of the distal territory. 
• TIMI 3 flow (complete perfusion) is normal flow which fills the distal coronary 
bed completely 

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After PCI, TIMI 3 flow was achieved in approximately 92% of patients. Only about 30% 
of patients had TIMI myocardial perfusion grade 3; however the percentage was similar 
in both treatment groups and is consistent with literature reports of myocardial perfusion. 
Procedural and angiographic data are presented in Table 3 below. 
Table 3: COOL MI Trial - Procedural and Angiographic Data 
 
*Thrombolysis in Myocardial Infarction 
5.2.1.2 
COOL MI Trial Results 
Of the 177 Intervention patients, 11 (6.2%) patients had the Reprieve Catheter placed in 
the emergency room (ER), one (0.6%) patient had the catheter placed in the cath lab 
holding area, and 165 (93.2%) patients had the catheter placed in the cath lab.  Overall, 
patients in the Intervention group received a median of 17 minutes (interquartile range 
(IQR): 10-27) of cooling prior to PCI.  During that time, patient temperature was 
decreased from a median of 36.2°C (IQR: 35.8-36.5) at the initiation of cooling to 35.1°C 
 
Control  
(N=180) 
Intervention 
(N=177) 
p-value 
Infarct related artery, Stent implantation, Glycoprotein & Stenosis Diameter 
Left anterior descending coronary 
artery 
70 (39%) 
69 (39%) 
0.91 
Circumflex artery 
13 (7%) 
14 (8%) 
0.87 
Right coronary artery 
77 (43%) 
74 (42%) 
0.93 
Stent implanted 
153 (92%) 
157 (94%) 
0.59 
Glycoprotein IIb/IIIa receptor inhibitor 140 (78%) 
142 (80%) 
0.74 
Initial diameter stenosis  
(mean ± std dev) 
92 ± 14% 
92 ± 12% 
0.93 
Initial TIMI flow 
Grade 0/1 
126 (71%) 
122 (69%) 
0.77 
Grade 2 
14 (8%) 
21 (12%) 
0.28 
Grade 3 
38 (21%) 
34 (19%) 
0.74 
Final diameter stenosis 
7 ± 9% 
8 ± 10% 
1.00 
Final TIMI* flow 
Grade 0/1 
2 (1%) 
5 (3%) 
0.33 
Grade 2 
7 (4%) 
12 (7%) 
0.31 
Grade 3 
170 (95%) 
160 (90%) 
0.11 
Final myocardial perfusion grade 
 
 
 
Grade 0/1 
63 (43%) 
76 (53%) 
0.11 
Grade 2 
35 (24%) 
26 (18%) 
0.27 
Grade 3 
49 (33%) 
41 (29%) 
0.54 

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(IQR: 34.5-35.6) at the time of PCI (Figure 1).  The median of the minimum temperature 
reached by each patient was 33.1°C (IQR: 33.0-33.4), which was achieved in 75 minutes 
(IQR: 50-108).  Target patient temperature was set at a 33°C for 3 hours post-PCI.  Patients 
were then re-warmed at 1°C/hr until Investigator-determined normothermia was reached 
[median=36.5 (IQR: 36.2-36.8]).  Figure 5 below shows patient temperature over time 
with cooling and time to PCI.  The goal to reach target temperature of 33°C at PCI was 
not achieved in the trial, due to the inadequate cooling power of the Reprieve System.  As 
noted above, target temperature of 33°C was reached after 75 minutes of cooling, long 
after PCI had occurred. 
Figure 5: Median Temperature and Elapsed Times for Intervention Patients 
 
5.2.1.3 
COOL MI Trial Tolerability of Cooling 
Shivering was managed according to the shivering suppression guidelines recommended 
for this study by Dr. Daniel Sessler, Chairman of the Department of Anesthesiology at the 
University of Louisville.  The recommended baseline combination of Pethidine, buspirone 
and skin warming using a forced-air blanket could be supplemented incrementally in the 
event of shivering or patient discomfort, by additional Pethidine, or by slightly increasing 
the target temperature.  If these steps were unsuccessful, patients could be actively 
rewarmed to normothermia. 
This protocol proved to be quite effective at maintaining patient comfort.  Intervention 
patients received an average of 56 mg of oral buspirone and an average of 267 mg of 
intravenous Pethidine over the course of the cooling procedure.  Of 177 patients in the 
treatment group, only one patient (0.6%) required premature warming due to intolerability 
of cooling.  Nine patients (5.1%) required a slight increase in target temperature (0.2°C – 
0.5°C) to maintain patient comfort.  Ninety-eight patients (55.7%) required supplementary 
1        2        3        4        5        6        7        8        9        10
Elapsed Time (hours)
37
36
35
34
33
Onset 
to 
Door
115 min
Door 
to 
PCI
104 min
Start Temp
= 36.2°C
Median Minimum Temp = 33.1°C
Time to Minimum Temp = 75 min
Temperature ºC
Temp at PCI = 35.1 °C
Cooling Prior to PCI = 17 min
1        2        3        4        5        6        7        8        9        10
Elapsed Time (hours)
37
36
35
34
33
Onset 
to 
Door
115 min
Door 
to 
PCI
104 min
Start Temp
= 36.2°C
Median Minimum Temp = 33.1°C
Time to Minimum Temp = 75 min
Temperature ºC
Temp at PCI = 35.1 °C
Cooling Prior to PCI = 17 min

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dosing of Pethidine, but 60 of these 98 patients (61.2%) had not received the 
recommended loading dose of the anti-shivering drugs. 
COOL MI Trial Safety Results: The primary safety endpoint of the COOL MI study was 
the incidence, through 30 days, of Major Adverse Cardiac Events (MACE), defined as the 
composite of death, recurrent myocardial infarction of the target vessel and the need for 
urgent revascularization of the target vessel.  As shown in Table 4 below, there was no 
statistical difference in the incidence of MACE in the Intervention group as compared to 
the Control group.  All MACE were adjudicated by an independent Clinical Events 
Committee and none were attributed to cooling or use of the Reprieve System. Table 4 
below demonstrates the results of the study with regard to the incidence of Major Adverse 
Cardiac Events. 
Table 4: COOL MI Trial Incidence of MACE 
 
These MACE rates observed in COOL MI compare favorably with those reported for 
similar patients in recent AMI trials, such as ADMIRAL, CADILLAC, DANAMI and 
RAPID MI-ICE (Table 5). 
 
Table 5 Incidence of MACE for Comparable Patients in Recent AMI Trials  
Trial 
Death 
Reinfarction 
Revascularization 
COOL MI (Treatment Group) 
(n=177) 
3.4% 
0.6% 
2.3% 
ADMIRAL (n=149)17 
3.4% 
1.3% 
4.7% 
CADILLAC (n=524)18 
2.7% 
0.8% 
1.6% 
DANAMI-2 (n=790)19 
6.6% 
1.6% 
NA 
RAPID MI-ICE (n=20)1 
0% 
0% 
0% 
5.2.1.4 
COOL MI Trial Adverse Events Related to Cooling 
Potential adverse events related to cooling (e.g., arrhythmia or hemodynamic 
complications) and to placement and/or use of the Reprieve Catheter (e.g., vascular or 
thrombogenic complications) were also evaluated as a secondary endpoint.  The incidence 
Events through 30 days 
Control  
(N=180) 
Intervention 
(N=177) 
p-value 
MACE 
7 (3.9%) 
11 (6.2%) 
0.45 
 
Death 
4 (2.2%) 
6 (3.4%) 
0.71 
 
Recurrent MI 
3 (1.7%) 
1 (0.6%) 
0.63 
 
Urgent Revascularization 
0 (0%) 
4 (2.3%) 
0.12 

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of these types of events is presented.  It is important to note that these complications are 
also risks of myocardial infarction and coronary intervention themselves. Table 6 below 
reports the incidence of non-MACE complications. 
Table 6: Incidence of Other Complications 
Events through 30 days 
Control  
(N=180) 
Intervention 
(N=177) 
p-value 
Bradyarrhythmia 
41 (22.8%) 
46 (26.0%) 
0.56 
Ventricular Tachycardia/Fibrillation 
36 (20.0%) 
31 (17.5%) 
0.64 
Cardiogenic Shock 
11 (6.1%) 
22 (12.4%) 
0.06 
Pulmonary Edema 
3 (1.7%) 
6 (3.4%) 
0.49 
Vascular Complications  
      Retroperitoneal bleed 
      Hematoma >6cm 
      Pseudoaneurysm 
      AV fistula 
15 (8.3%) 
2 (1.1%) 
12 (6.7%) 
1 (0.6%) 
1 (0.6%) 
15 (8.5%) 
1 (0.6%) 
13 (7.3%) 
3 (1.7%) 
0 (0%) 
0.90 
0.95 
0.99 
0.63 
0.95 
Bleeding Requiring Transfusion  
14 (7.8%) 
20 (11.3%) 
0.34 
Deep Venous Thrombosis 
0 
3 (1.7%) 
0.24 
Pulmonary Embolism 
3 (1.7%) 
0 
0.24 
Stroke 
1 (0.6%) 
0 
0.95 
Arrhythmias are a known risk of moderate to severe hypothermia.  In the COOL MI trial, 
with its mild hypothermia target temperature, arrhythmias were not more common and 
appeared to be primarily related to ischemia and/or the coronary intervention.  
Cardiogenic shock requiring treatment with an intra-aortic balloon pump trended toward 
a higher incidence in the hypothermic group.  However, the majority of shock cases 
appeared to be more related to complicated MIs and/or complex interventions than to 
cooling.  Other potential contributory factors (e.g., age, weight, Pethidine dose) were 
compared between shock and stable patients; however, no causal relationships were 
apparent.  The majority of the vascular complications reported in the Intervention group 
were related to the arterial access site for the PCI procedure rather than the venous access 
site for the cooling catheter.  Three cases of deep venous thrombosis (DVT) were reported 
in the Intervention group. 
5.2.1.5 
COOL MI Trial Effectiveness Results 
The primary effectiveness endpoint in the COOL MI study was infarct size, measured 
using SPECT imaging at 30 days.  Overall, there was no observed difference in infarct 
size (%LV) between study groups (Table 7).  The secondary effectiveness endpoints of 
LV ejection fraction, CK-MB release, and ST-segment resolution, likewise did not 
demonstrate a difference between the Intervention and Control groups. 

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Table 7: COOL MI Results 
 
Control  
Intervention 
p-value 
% LV Infarct Size  (N) 
     mean ± std dev 
     median 
157 
13.8 ± 15.1 
10 
168 
14.1 ± 14.3 
10 
0.83 
LV Ejection Fraction  (N) 
     mean ± std dev 
     median 
104 
55.2 ± 11.4 
54 
115 
53.0 ± 12.0 
53 
0.17 
Peak CK-MB  (N) 
     mean ± std dev 
     median 
167 
42.8 ± 48.1 
33.9 
168 
49.1 ± 50.7 
33.6 
0.25 
ST-segment resolution - 90 min. post-PCI 
(N) 
      < 30% 
      30 - 69% 
      ≥ 70% 
90 
11.1% 
27.8% 
53.3% 
82 
20.7% 
35.4% 
39.0% 
 
0.13 
0.36 
0.09 
ST-segment resolution - 180 min. post-PCI 
(N) 
      < 30% 
      30 - 69% 
      ≥ 70% 
79 
10.1% 
20.3% 
60.8% 
80 
16.3% 
27.5% 
51.3% 
 
0.36 
0.38 
0.30 
 
In addition, no statistically significant differences were demonstrated when the 
Intervention and Control patients were compared based on the following stratifications:  
infarct location, time from onset of symptoms to PCI, prior MI, or TIMI flow prior to PCI.  
However, subsequent analysis revealed a strong relationship between final infarct size and 
patient temperature at the time of reperfusion. 
The mean temperature at the time of reperfusion, or more specifically, at the time of first 
balloon inflation, was 35.1°C.  As shown in Figure 6, in the population of patients with 
anterior myocardial infarction, those patients who had a temperature <35°C at the time of 
reperfusion had a statistically significant reduction in final infarct size as compared to 
both the control group (9.3% vs. 18.2%, p=0.05) and those with a temperature ≥35°C 
(9.3% vs. 21.9%, p=0.01). 

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5: Mean Infarct Sizes (%LV) of Patients with Anterior Infarctions 
  
 
 
 
 
 
 
 
 
 
This effect has a strong basis in physiology and was consistent across other clinical 
measures, i.e., there was a trend toward decreased CK-MB release and increased LV 
Ejection Fraction in the cooled patients.  This effect is not attributable to differences in 
baseline clinical or angiographic variables.  In fact, those patients with a temperature 
<35°C were more likely to have occlusion of the proximal versus mid left anterior 
descending coronary artery and a longer time to reperfusion.  These factors would be 
expected to increase infarct size in this group, but the observed reduction in infarct size 
appears to be the result of cooling. 
5.2.2 COOL MI II Trial  
Because of the encouraging results in patients with anterior AMI’s in whom hypothermia 
had been achieved at the time of PCI, COOL MI II was initiated.  Additionally, COOL 
MI II Trial was intended to verify the feasibility of initiating cooling earlier in the 
treatment pathway (e.g., in the emergency department).  Only a fraction of the anticipated 
sample size were enrolled before the trial was ended early because the sponsor became 
financially insolvent after only41 patients were enrolled. The study data were submitted 
by the sites to a Data Management CRO.  As a result, the final report is not currently 
available because the data was not released to ZOLL by the Data Management CRO upon 
ZOLL acquisition of Radiant Medical.   
In COOL MI II, all cooling was initiated in the Cath Lab even though the focus was on 
earlier cooling.  Since earlier initiation of cooling was not accomplished, reaching the goal 
of a core temperature of 35° C before PCI was dependent on the more powerful GTO 
System.  This was accomplished in 26 of the 27 patients without the intentional delay of 
PCI.  Pivotal data for 23 patients were available and the mean time to reach 35°C was 6.1 
17.9 
9.3 
21.9 
18.2 
0 
10 
20 
30 
All Treatment < 35°C 
≥ 35°C Control 
%LV 
p=0.92 
p=0.05 
p=0.30 
(n=61) 
(n=16) 
(n=38) 
(n=59) 
Subject groups: 
i)   All Intervention patients 
regardless of temperature at PCI 
ii)  Intervention patients cooled 
to      < 35°C at PCI 
iii) Intervention patients > 35°C 
at PCI 
iv) Control patients 
Subject groups: 
i)   All Intervention patients 
regardless of temperature at PCI 
ii)  Intervention patients cooled 
to      < 35°C at PCI 
iii) Intervention patients > 35°C 
at PCI 
iv) Control patients 
Figure 6: Mean Infarct Sizes (%LV) of Patients with Anterior Infarction 

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minutes (± 3.0), 34°C was 14.5 minutes (± 7.9) and 33°C was 31.3 minutes (± 29.9).  Data 
showed 15 of the patients were cooled to 32°C; the mean time was 36.1 minutes (± 14.0).  
Efforts to initiate cooling as early as possible resulted in a median of 39 minutes of cooling 
time prior to PCI, a significant improvement over the median of 18 minutes of cooling 
time achieved in the previous study.  In addition, the median door-to-balloon time was 
106 minutes for these COOL MI II patients, compared to a median of 104 minutes for 
Test patients in the previous study, indicating that PCI was not delayed by the introduction 
of cooling.  By focusing on cooling earlier in the treatment pathway, additional cooling 
time can be achieved without significant adverse impact on time to reperfusion. 
5.2.2.1 
COOL MI II Trial Adverse Events 
As with COOL MI, the primary safety endpoint of the COOL MI II study was the 
incidence, through 30 days, of MACE. Shown below are the adverse events in the COOL 
MI II trial in the intent to treat (ITT) population.  Table 8 combines the Feasibility and 
Pilot hypothermia groups for a total of 41 patients (12 Feasibility and 29 Pivotal). 

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Table 8:  Incidence of MACE and Other Complications 
Events through 30 Days 
Normothermia 
Hypothermia 
Enrollment 
10 
41 
UADE 
0 
0 
Cardiac 
  
  
     Death 
0 
1 (2.4%) 
     Repeat MI 
0 
1 (2.4%) 
     Repeat PCI 
1 (10%) 
3 (7.3%) 
     CABG 
0 
2 (4.9%) 
     Hypotension / Shock 
1 (10%) 
6 (14.6%) 
     CHF 
0 
2 (4.9%) 
     Pericardial Effusion 
0 
1 (2.4%) 
     Pericarditis 
0 
1 (2.4%) 
     HTN 
0 
1 (2.4%) 
Arrhythmias  
  
  
     Ventricular Fibrillation 
0 
4 (9.8%) 
     Vent. Tachycardia 
1 (10%) 
7 (17.1%) 
     Frequent PACs 
1 (10%) 
0 
     SVT 
0 
1 (2.4%) 
     Atrial Fibrillation 
0 
11 (26.8%) 
Vascular Events 
  
  
     Bleeding requiring transfusion 
0 
3 (7.3%) 
     Thrombocytopenia 
0 
2 (4.9%) 
     Anemia 
0 
2 (4.9%) 
     Hematoma > 6cm 
0 
2 (4.9%) 
     DVT   
0 
1 (2.4%) 
     Local Tissue Trauma 
0 
1 (2.4%) 
     Epistaxis 
1 (10%) 
0 
     Hemoptysis 
0 
1 (2.4%) 
     Stroke 
0 
0 
Respiratory Events 
  
  
     Pulmonary Edema 
0 
8 (19.5%) 
     Pulmonary Embolism 
0 
0 
     Hypoxia 
0 
1 (2.4%) 
     Respiratory Failure 
0 
1 (2.4%) 
     Plural Effusion 
0 
3 (7.3%) 
     Increased Pulmonary HTN 
1 (10%) 
0 
     Pneumonia 
1 (10%) 
0 

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Renal 
  
  
     Renal requiring Treatment 
1 (10%) 
2 (4.9%) 
     Hemodialysis 
0 
0 
     UTI 
0 
2 (4.9%) 
     Hematuria 
1 (10%) 
0 
Other 
  
  
     Nausea / Vomiting 
1 (10%) 
15 (36.6%) 
     Systemic Infection 
0 
3 (7.3%) 
     Fever 
0 
3 (7.3%) 
     Muscular Pain 
1 (10%) 
3 (7.3%) 
     Rhabdomyolysis 
1 (10%) 
0 
     Mental Status Changes 
0 
2 (4.9%) 
     Hypokalemia 
0 
1 (2.4%) 
     Vaginal Infection 
0 
1 (2.4%) 
 
5.2.3 COOL RCN Trial 
The COOL RCN (Radio-Contrast nephropathy) trial was undertaken to evaluate whether 
endovascular cooling provides more effective protection for patients at high risk of 
experiencing RCN.  The trial was designed as an international, multicenter, 1:1 
randomized controlled trial of up to 400 subjects at up to 35 investigational sites.  Subjects 
with a calculated Creatinine clearance of 20 – 50 mL/min and scheduled for a diagnostic 
or interventional catheterization procedure were enrolled. The trial utilized Radiant 
Medical’s Reprieve System. The study was commenced in March 2006 and was 
terminated after enrolling only 136 subjects due to the financial insolvency of Radiant 
Medical. 
Table 9: COOL RCN Trial: Adverse Events Incidence of Complications In-
Hospital  
  
Normothermia  Hypothermia 
P Value 
Enrollment 
70 
58 
  
Nausea/Vomiting 
6 / 70 (8.6%) 
26 / 58 
(44.8%) 
<0.01 
Bradycardia 
2 / 70 (2.9%) 
7 / 58 (12.1%) 0.04 
Bleeding Requiring 
Transfusion 
7 / 70 (10.0%) 
1 / 58 (1.7%) 
0.05 
Atrial Fibrillation 
2 / 70 (2.9%) 
3 / 58 (5.2%) 
0.5 
CABG 
4 / 70 (5.7%) 
1 / 58 (1.7%) 
0.25 
Pulmonary Edema 
4 / 70 (5.7%) 
1 / 58 (1.7%) 
0.25 

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Normothermia  Hypothermia 
P Value 
Renal Complication 
2 / 70 (2.9%) 
3 / 58 (5.2%) 
0.5 
     Acute Renal Failure 
2 / 70 (2.9%) 
2 / 58 (3.4%) 
0.85 
     Elevated Serum Creatinine 
0 / 70 (0%) 
1 / 58 (1.7%) 
-- 
     Hemodialysis 
2 / 70 (2.9%) 
0 / 58 (0%) 
-- 
     Urinary Tract Infection 
3 / 70 (0.4%) 
1 / 58 (1.7%) 
0.41 
Hypotension/Shock 
1 / 70 (1.4%) 
3 / 58 (5.2%) 
0.22 
Hematoma >6cm 
0 / 70 (0%) 
3 / 58 (5.2%) 
-- 
SVT 
0 / 70 (0%) 
2 / 58 (3.4%) 
-- 
MI 
0 / 70 (0%) 
1 / 58 (1.7%) 
-- 
Ventricular Tachycardia 
1 / 70 (1.4%) 
1 / 58 (1.7%) 
0.89 
Death 
0 / 70 (0%) 
1 / 58 (1.7%) 
-- 
Repeat PCI 
1 / 70 (1.4%) 
1 / 58 (1.7%) 
0.89 
Stroke 
0 / 70 (0%) 
1 / 58 (1.7%) 
-- 
 
Table 10: COOL RCN Trial: Incidence of Complications to 30 Days  
  
Normothermia 
Hypothermia 
P Value 
Enrollment 
70 
58 
  
Renal 
7 
2 
0.15 
     Acute Renal Failure 
5 
1 
0.15 
     Renal Stent 
2 
0 
-- 
     Kidney Infection 
0 
1 
-- 
Cardiac 
8 
14 
0.1 
     MI 
1 
1 
0.89 
     CABG 
2 
3 
0.5 
     PCI 
1 
3 
0.22 
 
 

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Normothermia 
Hypothermia 
P Value 
     PCI or CABG 
3 
6 
0.18 
     Death - Cardiac 
1 
2 
0.45 
     Shock 
0 
3 
-- 
     CHF 
2 
1 
0.67 
     Angina 
1 
0 
-- 
     Hypertension 
0 
1 
-- 
Arrhythmia 
3 
3 
0.81 
     Atrial Fibrillation 
2 
1 
0.67 
     Bradycardia 
0 
2 
-- 
     SVT 
1 
0 
-- 
     Ventricular Fibrillation 
0 
0 
-- 
Non-Cardiac 
3 
3 
0.81 
     Stroke 
1 
0 
-- 
     Bleed/Transfusion 
2 
3 
0.5 
     Dialysis  
0 
0 
-- 
Vascular Complications Requiring  Surgery  
0 
0 
-- 
Rehospitalization 
13 
13 
0.59 
Other 
9 
12 
0.23 
     Anasarca 
1 
  
-- 
     Fatigue 
1 
  
-- 
     Ischemic Bowel 
1 
1 
0.89 
     Hypoglycemia 
1 
  
-- 
     Lesion Excision 
1 
  
-- 
     Anemia 
1 
  
-- 
     Hiatal Hernia 
1 
1 
0.89 
     Pulmonary Edema 
1 
  
-- 
     Knee Injury 
1 
  
-- 
     Rash 
  
1 
-- 
     Debridement of Sternal Wound 
  
1 
-- 
     Leg Weakness 
  
1 
-- 
     Nausea/Vomiting 
  
2 
-- 
     Dehydration 
  
1 
-- 
     Acute Respiratory Failure 
  
1 
-- 
     Metabolic Acidosis 
  
1 
-- 
     Back Pain 
  
1 
-- 
     Systemic Infection 
  
1 
-- 

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5.2.3.1 
Unanticipated Adverse Events 
(i) 
COOL MI Trial – Unanticipated Adverse Events 
There was one Unanticipated Adverse Device Effect (UADE) in the COOL MI Trial; A 
patient experienced nasopharyngeal trauma and bleeding potentially caused by the 
nasoesophageal temperature probe used as part of the Reprieve System. This resulted in a 
modification to the Informed Consent Form to explain the risk of nasal trauma and/or 
bleeding due to the nasoesophageal probe.  
(ii) 
COOL MI II Trial – Unanticipated Adverse Events 
There were no UADE’s in the COOL MI II Trial. 
(iii) 
COOL RCN Trial – Unanticipated Adverse Events 
There was one UADE in the COOL-RCN Trial.  A 73 year old male with chronic renal 
insufficiency and a history of aortobifemoral bypass scheduled for cardiac catheterization.  
The patient was randomized to the Hypothermia arm. The Reprieve catheter was placed 
via the left femoral vein.  The angiogram and stenting procedures were performed via 
right radial arterial access.  After approximately 1 hour of cooling, the patient complained 
that his feet were itching and it was noted that the patient’s left foot and leg were cyanotic 
up to mid-thigh, with no left DP pulse, and  the right foot was slightly discolored.  He was 
subsequently rewarmed at the maximum rate for approximately 40 minutes.  It was 
observed that the cyanosis lightened as the patient rewarmed and was apparently resolved 
with no further sequelae after discontinuation of treatment with the Reprieve catheter, 
indicating that cooling with the device contributed to the reduced peripheral circulation.  
The already compromised peripheral vascular circulation is suspected to have been 
exacerbated by hypothermia induced vasoconstriction. It is known that hypothermia 
induces superficial vasoconstriction, but this degree of cyanosis had not been observed 
with previous use of the device.  Additionally, after the patient had received Pethidine and 
versed as part of the anti-shivering protocol, his respiration became depressed, requiring 
assisted ventilation, Romazicon and Narcan. It is possible that this transient hypoxic event 
may have also contributed to the cyanosis. 
 
Lower extremity cyanosis in the presence of peripheral vascular insufficiency had 
not been identified in the protocol or informed consent document as a potential risk of 
mild hypothermia or use of the Reprieve catheter. The resolution of the cyanosis upon 
rewarming and removal of the catheter indicated that these may have contributed to the 
event. The risk section of the protocol and informed consent were subsequently revised.  
5.2.4 ICE- IT Trial 
The Intravascular Cooling Adjunctive to Percutaneous Coronary Intervention for Acute 
Myocardial Infarction Trial (ICE-IT) 23randomized 228 patients presenting with an acute 

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MI within 6 hours of symptom onset to endovascular cooling concomitant with PCI versus 
routine PCI. The primary endpoint of infarct size at 30 days as measured by SPECT 
imaging was similar between the 2 groups (10% for the hypothermia group versus 13% 
for the control group, p = 0.14). Like the COOL MI trial, ICE-IT was also an overall 
negative trial. But while TH did not demonstrate any significant decrease in infarct size 
overall, a trend towards benefit was again observed on post-hoc analysis of the subgroup 
with anterior infarction who were sufficiently cooled to a temperature of < 35°C at the 
time of revascularization (infarct size of 12.9% of the left ventricle in the TH population 
compared to 22.7% in the control group, p = 0.09).23 
5.2.5 RAPID-MI ICE Trial 
Recently, Lund University presented a preliminary report of their RAPID-MI ICE Trial.1 
This trial enrolled 20 patients presenting with acute myocardial infarction, and 10 patients 
each were randomized to TH by intravascular cooling or a control group.  Cooling was 
accomplished with a combination of 2L of cold saline infusion and the Phillips InnerCool 
catheter-based cooling system.  The endpoint was infarct size normalized to myocardium 
at risk assessed by cardiac magnetic resonance using T2 weighted imaging and late 
gadolinium enhancement.  Although the sample size is relatively small, the trial produced 
a number of potentially important results: 
• Core body temperature less than for 35°C was achievable before reperfusion without 
significant delay in the door to balloon time. 
• Infarct size normalized to myocardium at risk was reduced by a remarkable 38% in 
patients receiving hypothermia. 
• There were also significant decreases in peak and cumulative Troponin I or T in the 
hypothermia group. 
5.2.6 CHILL-MI Trial 
Lund University recently reported the results of the CHILL-MI trial37, which was a multi-
center study of 120 patients with STEMI (< 6 hours) planned to undergo PCI who were 
randomized to hypothermia induced by rapid infusion of 600 – 2000 ml of cold saline and 
endovascular cooling, or standard of care.  Hypothermia was initiated before PCI and 
continued for 1 hour after reperfusion.  The primary endpoint was infarct size as a 
percentage of the myocardium at risk (IS/MaR), assessed by cardiac MRI at 4±2 days.  
The goal to reach target temperature of 33°C at reperfusion was also not achieved in the 
CHILL-MI trial, due to the inadequate cooling power of the cooling device.  Patients 
randomized to cooling achieved a core body temperature at reperfusion of 34.7°C with a 
9 minute longer door-to-balloon time.  Hypothermia induced by cold saline infusion and 
endovascular cooling was feasible and safe, however, there was no significant difference 
in IS/MaR between the groups.  Exploratory analysis of early anterior infarctions (0-4 hrs) 
showed a significant reduction in IS/AAR of 33% (p<0.05).  Further, the incidence of 

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heart failure was lower with hypothermia at 45 days (3% vs 14%, p<0.05).  This trial, as 
the others cited above, shows potential efficacy of cooling in patients with anterior 
STEMI, supporting further research for confirmation. 
5.2.7 Induction of Mild Systemic Hypothermia With Endovascular 
Cooling During Primary Percutaneous Coronary Intervention for 
Acute Myocardial Infarction 
 
This multi-center study included 42 patients with acute myocardial infarction (AMI) 
(onset less than 6hrs) and evaluated the safety and feasibility of endovascular cooling 
during primary PCI for AMI. 39 Subjects were randomized to PCI with or without 
endovascular cooling (target core temperature 33°C). Cooling was maintained for 3 h after 
reperfusion. Skin warming, oral buspirone, and intravenous meperidine were used to 
reduce the shivering threshold. The primary end point was major adverse cardiac events 
at 30 days. Infarct size at 30 days was measured using SPECT imaging. All patients 
successfully cooled did achieved a core temperature below 34°C (mean target temp 33.2 
± 0.9°C). MACE events occurred in 0% vs. 10% (p = NS) of treated versus control 
patients. The median infarct size was not significantly smaller in patients who received 
cooling compared with the control group (2% vs. 8% of the left ventricle, p = 0.80). 
5.2.8 VELOCITY Trial 
The VELOCITY trial38 randomized 54 STEMI patients at 7 centers in the United States 
and Canada to emergent PCI with (n = 28) or without (n = 26) hypothermia induced by 
the Velomedix Automated Peritoneal Lavage System (Velomedix; Menlo Park, CA) 
between January 2013 and January 2014. Baseline characteristics were similar between 
the 2 groups, and 46.3% of all infarcts were anterior. 
Hypothermia (core temperature at or below 34.9°C) was achieved in 96.3% of patients 
and PCI was performed in all but 1 patient in each treatment group. Median door-to-
balloon time was shorter in the control vs hypothermia group (47 vs 62 minutes; P = 
.007). Among the 46 PCI patients who underwent MRI 3 to 5 days post procedure, the 
median myocardial infarct size was similar in the control vs hypothermia group (16.1% 
vs 17.2% of LV mass; P = .54). 
VELOCITY Investigators observed that prolonged door-to-balloon time in the 
hypothermia group may have attenuated the effect of hypothermia on infarct size though 
it is unlikely to have been totally responsible for absence of effect as DTB times were 
short in both groups and within the range wherein further reductions in mortality may not 
be realized. 

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At 30-day follow-up, no patients in the control group had a primary composite safety 
endpoint event, compared with 6 (21.4%) of the patients who underwent hypothermia 
(P = .01). Further details in Section 5.2.8.1. 
In conclusion, the VELOCITY study found that controlled systemic hypothermia through 
automated peritoneal lavage may be safely and rapidly established in patients with 
evolving STEMI undergoing primary PCI at the expense of a modest increase in door-to-
balloon time. In the VELOCITY randomized trial, peritoneal hypothermia was associated 
with an increased rate of adverse events (including stent thrombosis) without reducing 
infarct size. Adequately powered randomized trials (likely limited to patients with anterior 
MI) are needed to assess the effect of rapidly induced hypothermia on myocardial salvage 
and clinical outcomes after primary PCI. 
5.2.8.1 VELOCITY Trial Adverse Events at 30 Days 
At 30-day follow-up, no patients in the control group had a primary composite safety 
endpoint event (death, reinfarction, ischemia-driven TLR, major bleeding, sepsis, 
pneumonia, peritonitis, severe arrhythmias, or renal failure), compared with 6 (21.4%) 
of the patients who underwent hypothermia (P = .01). Four patients (14.3%) experienced 
MACE (cardiac death, reinfarction, or ischemia-driven TVR), and 3 (11.0%)—all in the 
hypothermia arm—developed definite stent thrombosis. 

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Table 11: VELOCITY Trial Clinical Event Rates Within 30 Days 
 
5.2.9 EU AMI Case Series 
ZOLL is currently enrolling patients in the COOL-AMI EU Case Series Trials to assess 
the ability to integrate hypothermia into the current pathway for patients receiving PCI for 
ST elevation MI.  To date, 308 patients have been enrolled at 36 sites in the EU.  Both 
anterior and non-anterior STEMI patients have been enrolled, and cooling is performed 
using the ZOLL Thermogard XP (TGXP) System or Proteus IVTM system.  A series of 
six standards has been developed and monitored to enable consistency in the execution of 
the protocol.  The standards include delivery of the antishivering regimen correctly, 
delivery of 1 L of iced saline before PCI, and at least 18 minutes of cooling delivered prior 
to wire crossing the lesion.  Feedback in the form of a report card (Figure 7) is provided 
to the site after each case as indicated in the following diagram: 
Figure 7:  Report Card Standards 
 

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These six standards are consistently achieved at all sites.  The 18 minute duration of 
cooling matches the average duration of cooling in the previous EU COOL AMI trial.  
The ability to deliver 18 minutes of cooling prior to PCI is consistently achieved in the 
recent EU Case Series, where the door to balloon (DTB) times, at all sites, were less than 
60 minutes (ranging from 38 minutes to 58 minutes).  This is far less than the maximum 
door to balloon time of 90 minutes recommended by the current guidelines for PCI, 2011 
ACCF/AHA/SCAI PCI Guideline24,50). The experience of one of the sites has been 
published26, and notes that the average DTB time for the first 11 patients enrolled in the 
trial was 38 minutes, compared to a mean DTB time of 37 minutes for all patients 
presenting with STEMI without cooling.  In view of the validation that implementation of 
hypothermia in the treatment pathway for PCI of STEMI patients is feasible, ZOLL has 
also conducted the COOL-AMI EU PILOT Trial, following the same standards of 
implementation, with cooling done by the more powerful Proteus device.  The goal is to 
maximize the dose of cooling prior to PCI. 
5.2.10 COOL-AMI EU PILOT Trial 
ZOLL has completed enrollment in the COOL-AMI EU PILOT Trial that evaluated the 
retention of subjects after integrating therapeutic hypothermia using the ZOLL Proteus 
IVTM System into existing STEMI treatment protocols for subjects who presented with 
acute anterior myocardial infarction.  50 subjects were randomized at 16 sites in the EU. 
22 patients (88%; 95% confidence interval [CI]: 69-97%) in the hypothermia group and 
23 patients (92%; 95% CI: 74-99) in the control group completed cardiac magnetic 
resonance imaging at four to six days and 30-day follow-up. A series of three standards 
were monitored to enable consistency in the execution of the protocol.  The standards 
included delivery of the antishivering regimen correctly, delivery of up to 1 L of iced 
saline, and 18 minutes of cooling delivered prior to wire crossing the lesion. Patients with 

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anterior STEMI were rapidly and safely cooled. Intravascular temperature at coronary 
guidewire crossing after 20.5 minutes of endovascular cooling decreased to 33.6°C 
(range 31.9-35.5°C), which is ≥1.1°C lower than in previous cooling studies. There 
was a 17-minute (95% CI: 4.6-29.8 min) cooling-related delay to reperfusion. In the “per 
protocol” analysis, median infarct size/left ventricular mass was 16.7% in the hypothermia 
group versus 23.8% in the control group (absolute reduction 7.1%, relative reduction 30%; 
p=0.31) and median left ventricular ejection fraction (LVEF) was 42% in the hypothermia 
group and 40% in the control group (absolute reduction 2.4%, relative reduction 6%; 
p=0.36). There were no statistically significant differences between the groups, in adverse 
events or serious adverse events.49 
 
Summary and Clinical Trial Rationale 
Previous clinical trials in patients experiencing acute myocardial infarction (AMI) have 
demonstrated that therapeutic hypothermia is safe, well tolerated and showed reductions 
in infarct size.19  Additionally, recent preclinical results (Stanford-ZOLL data) have shown 
that temperature at reperfusion of 32 °C is superior to 35 °C for reducing infarct size, 
confirming a dose response. Future clinical trials will require more powerful cooling 
devices, and more consistency in implementing 18 minutes of cooling before reperfusion 
across all study sites in order anterior infarctions. It is therefore the objective of the 
COOL-AMI EU PIVOTAL Trial to evaluate the actual effectiveness of therapeutic 
hypothermia as a protection strategy. 
Further clinical trials are needed to evaluate more powerful cooling devices, along with a 
refined therapeutic hypothermia protocol (target temperature of 32°C + 18 minutes of 
cooling prior to PCI). It will also be important to understand whether adequate cooling to 
32°C + 18 minutes of cooling prior to PCI can be implemented into existing STEMI 
treatment protocols with no significant delay in door-to-balloon times. This trial aims to 
address the need for a powered clinical evaluation assessing the safety and effectiveness 
of the Proteus IVTM for this refined therapeutic hypothermia protocol as an adjunct 
therapy for AMI patients undergoing PCI. Among these refinements are: 1) A larger dose 
of cooling was achieved with the Proteus System (temp at PCI was 33.6°C as opposed to 
35°C for COOL MI), 2) Delivery of at least 18 minutes of cooling prior to PCI was 
possible (mean 20 minutes in the EU Pilot Study), 3) the anti-shivering protocol was 
refined and worked successfully, and 4) the use of report cards for every case to track : a) 
anti-shivering protocol impementation, b) infusion of 1 liter of cold saline prior to PCI, c) 
18 minutes of cooling prior to PCI, d) door to balloon time less than 90 minutes, e) total 
ischemic time less than 6 hours, and f) proper administration of dual antiplatelet therapy 
(DAPT) are all refinements ready to be implemented. 

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6 
CLINICAL TRIAL PLAN 
 
Trial Objective 
The objective of this randomized clinical trial is to evaluate the safety and effectiveness 
of therapeutic hypothermia, using the ZOLL Proteus IVTM System, as an adjunctive 
therapy for patients presenting with acute anterior myocardial infarction and undergoing 
PCI, in comparison with patients with acute anterior myocardial infarction and undergoing 
PCI only. 
 
Trial Endpoints 
6.2.1 Primary Effectiveness Endpoint 
Relative reduction of 20% in mean anterior myocardial infarct size (IS), as determined by 
Cardiac Magnetic Resonance (cMR) imaging at 4-6 days post-infarct in the Test Arm 
(cooling + PCI) compared to the Control Arm (PCI only). Infarction Size (IS) is defined 
as % Left Ventricular Mass as measured by Cardiac Magnetic Resonance (cMR) imaging. 
Infarct Size (IS) will be assessed by Cardiac Magnetic Resonance (cMR) at 4 – 6 days 
following the index procedure. The trial is considered to have met the primary efficacy 
endpoint if the Test Arm demonstrates a 20% relative reduction in infarct size compared 
to the Control Arm. 
The ITT analysis set will be used for primary statistical analyses and summaries. The ITT 
population includes those subjects who have signed an informed consent and have been 
randomized to the Test Arm or the Control Arm of the trial. ITT subjects will be evaluated 
according to the group to which they were randomized. 
The PP analysis set will also be evaluated. The PP population includes those subjects who 
met inclusion and exclusion criteria, were randomized to either the Test or Control arm, 
received the treatment to which they were randomized, and complied substantially with 
the treatment timeline and steps of this protocol without major protocol violations. 
6.2.2 Primary Safety Endpoint 
Per-patient rate of composite Major Adverse Cardiac Events (MACE) subjects, defined 
as Cardiac Death (CD), All Myocardial Infarction (All MI) and Clinically-Indicated 
Target Lesion Revascularization (CI-TLR) at 30 day follow-up; non-inferiority to the 
control. 
6.2.3 Additional Assessments: Demographics and Other Parameters 
Subject demographics and various baseline characteristics will also be collected. 
Additional clinical data collected and evaluated will include the number of patients who 
can successfully be enrolled and randomized, the timing of subject presentation to 
hospital, the timing of therapeutic and adjunctive interventions, the timing of reaching the 
target temperature zone, temperature at PCI, subsequent maintenance of hypothermia and 

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temperature data from the IVTM System. Observations will be evaluated relating to the 
use of the ZOLL Proteus IVTM System and how it performs in relation to the induction 
of therapeutic cooling and follow-up cMR imaging. New York Health Association24 
(NYHA) Functional Class and Kansas City Cardiomyopathy Questionnaire25 (KCCQ) 
will be evaluated at 12 month follow-up. 
 
Trial Design 
This clinical trial is a multicenter, prospective, interventional, randomized-controlled trial. 
Randomization will be in a 1:1 ratio, Test Arm (PCI + Cooling) or Control Arm (PCI 
alone) in up to a total of 500 patients (250 subjects in each arm), at up to 70 clinical sites. 
 
To enhance each site’s ability to successfully integrate steps of the protocol and for 
training purposes prior to randomization, each site may enroll up to 4 Roll-In subjects in 
a non-randomized fashion. Roll-In subjects will be treated and followed as subjects in the 
Test Arm of the protocol (PCI + Cooling). Up to a total of 280 Roll-In subjects (up to 4 
per site) may be enrolled. Due to limited cMR data in patients with inferior MI who 
received an adequate dose of cooling prior to revascularization, Inferior MI subjects will 
be allowed to be included as Roll-Ins to further evaluate inferior MI infarct size by cMR 
imaging. Evaluation will be done of cMR imaging at 4-6 days following the index 
procedure. 
 
Patient Population 
Subjects will include those who present to the Emergency Department (ED) and / or Cath 
lab, who meet the trial eligibility requirements and who can provide informed consent for 
cooling treatment. Subjects considered for enrollment inthis trial will include adult 
patients presenting with an acute anterior myocardial infarction. To qualify, patients must 
have symptoms consistent with AMI (i.e., chest pain, arm pain, etc.) unresponsive to 
nitroglycerin, qualifying ST-segment elevation of ≥ 0.2 mV in two or more anterior 
contiguous precordial leads (V1-V4), with symptom onset greater than 30 minutes, but 
less than 4.5 hours prior to presentation at hospital, and be eligible for PCI. This ensures 
that the overall ischemic time from symptom onset to time of wire crossing is less than 6 
hours.  
Subjects randomized to the Test Arm, as well as all Roll-In subjects, will receive 
intravascular cooling with the Proteus IVTM device.  While undergoing temperature 
management, the Anti-shivering Protocol must be followed (see Attachment II).  
 
Selection Criteria 
Patients shall be screened to the following inclusion and exclusion criteria. Patients are 
qualified for participation only if all Inclusion Criteria have been met and all Exclusion 
Criteria have been confirmed not present. 

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Inclusion Criteria 
All Inclusion Criteria must be answered YES for subject to satisfy Inclusion Criteria: 
 
1. The patient is ≥ 18 years of age. 
2. The patient has symptoms consistent with AMI (i.e. chest pain, arm pain, etc.) and 
unresponsive to nitroglycerin, with symptoms beginning greater than 30 minutes but 
less than 4.5 hours prior to presentation at hospital. 
3. Qualifying Infarct Location: 
a. Roll-In subjects:  Evidence of Acute Anterior or Inferior MI with ST- 
segment elevation of ≥ 0.2 mV in two or more anterior or inferior 
contiguous precordial leads (V1 –V4). 
b. Randomized subjects: Evidence of Acute Anterior MI only with ST- 
segment elevation of ≥ 0.2 mV in two or more anterior contiguous 
precordial leads (V1 –V4). 
4. The patient is eligible for PCI. 
5. The patient is willing to provide written informed consent to participate in this clinical 
trial. 
 
 
Exclusion Criteria 
All Exclusion Criteria must be answered NO for subject to satisfy Exclusion Criteria: 
 
1. The patient has had a previous Myocardial Infarction. 
2. The patient is experiencing cardiogenic shock, systolic blood pressure [SBP] <100 
mmHg, HR>100 bpm and arterial oxygen saturation (pulse oximetry) <92% without 
additional oxygen.   
3. The patient is presenting with resuscitated Cardiac Arrest, Atrial Fibrillation, or Killip 
risk stratification class II through IV. 
4. The patient has an aortic dissection or requires an immediate surgical or procedural 
intervention other than PCI. 
5. The patient has known history of Congestive Heart Failure (CHF), Hepatic Failure, 
end-stage kidney disease or severe Renal Failure (clearance < 30ml/min/1.73m²).  
6. The patient is febrile (temperature > 37.5 °C) or has experienced an Infection with 
Fever in the last 5 days. 
7. The patient has a known previous CABG. 
8. The patient has a known recent Stroke within 90 days of admission.  
9. Cardio-Pulmonary Decompensation that has occurred en route to the hospital or, in 
the opinion of the physician, that is imminent or likely to occur following presentation 
to the clinical site. 

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10. Contraindications to hypothermia, such as patients with known Hematologic 
Dyscrasias which affect thrombosis (e.g., cryoglobulinemia, sickle cell disease, serum 
cold agglutinins) or Vasospastic Disorders (such as Raynaud’s or thromboangitis 
obliterans). 
11. Any contraindication to cardiac MRI, or any implants in the upper body which may 
cause artifacts on cardiac MRI imaging. 
12. The patient has a known hypersensitivity or contraindication to aspirin, heparin, or 
sensitivity to contrast media, which cannot be adequately pre-medicated. 
13. The patient has a known history of Bleeding Diathesis, Coagulopathy, 
Cryoglobulinemia, Sickle Cell Anemia, or will refuse blood transfusions. 
14. The patient has a height of <1.5 meters (4 feet 11 inches). 
15. The patient has a known hypersensitivity or contraindication to buspirone 
hydrochloride or Pethidine (Meperidine) and/or has been treated with a monoamine 
oxidase inhibitor in the past 14 days. 
16. Patient has a known history of severe hepatic or renal impairment, untreated 
hypothyroidism, Addison’s disease, benign prostatic hypertrophy, or urethral stricture 
that in the opinion of the physician would be incompatible with Pethidine 
administration. 
17. The patient has an Inferior Vena Cava filter in place (IVC). 
18. The patient has a pre-MI life expectancy of <1 year due to underlying medical 
conditions or pre-existing co-morbidities. 
19. The patient has a known, unresolved history of drug use or alcohol dependency, or 
lacks the ability to comprehend or follow instructions. 
20. The patient is currently enrolled in another investigational drug or device trial. 
21. The patient is apprehensive about or unwilling to undergo the required MRI imaging 
at follow-up, has a documented or suspected diagnosis of claustrophobia, or has 
Gadolinium allergy, or is in permanent Atrial Fibrillation. 
22. The patient has received thrombolytic therapy en route to the hospital 
23. The patient shows clinical evidence of spontaneous reperfusion as observed 
symptomatically and/or from baseline ECG findings (partial or complete ST 
resolution in ECG prior to informed consent and randomization). 
24. The patient is a vulnerable subject, for instance, a person in detention (i.e., prisoner or 
ward of the state). 
25. The patient is a female who is known to be pregnant. 
 
 
Clinical Trial Procedures 
6.8.1 Patient Screening 
Patients presenting at participating centers with clinical signs and symptoms of AMI will 
be expeditiously triaged and offered the opportunity to participate in this clinical trial 

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without regard to age, gender or ethnicity.  To ensure that patients are approached for 
potential trial participation without bias, patient screening information will be maintained 
on a patient screening log at each site.  This log will track patients that were enrolled in 
the trial as well as patients who were excluded from participation and the reason(s) for 
their exclusion. The use of a patient screening log assures that all eligible subjects are 
given an opportunity to participate or decline participation in the trial. 
The subject’s eligibility for treatment with the Proteus IVTM System will be evaluated 
based on the medical and anatomical criteria outlined above in the inclusion/exclusion 
criteria section.  The Investigator will explain the elements of this clinical trial, including 
the risks, potential benefits and required interventional and follow-up procedures, to each 
subject prior to obtaining informed consent. 
If a subject is found to be ineligible during baseline screening and routine diagnostic tests, 
the subject shall be considered a screen failure and will be documented on the patient 
screening log.  Roll-In subjects are considered enrolled in the trial when all inclusion and 
exclusion criteria have been satisfied, and informed consent has been signed. Randomized 
subjects are considered enrolled in the trial when all inclusion and exclusion criteria have 
been satisfied, informed consent has been signed, and the patient is randomized to either 
Test or Control Arm of the trial. 
6.8.2 Informed Consent 
The reviewing Medical Ethics Committee (MEC) must review and approve an Informed 
Consent Form (ICF) specific to this study. The Sponsor will provide each study center 
with an example ICF. The study center, to meet specific requirements, may modify this 
example ICF; however, the ICF to be used for subject consent under this protocol must 
contain all of the elements required by the study Sponsor and the governing regulatory 
requirements for informed consent (21 CFR Part 50). Therefore, each investigational site 
will provide the Sponsor with a copy of the MEC approved ICF - as well as any 
amendments - for the duration of the study.  
Informed consent will be required from each subject.  The MEC approved Informed 
Consent document must be signed by the patient or by the  legal authorized representative 
(LAR) prior to any related procedures (or according to the MEC’s approved guidelines), 
including the collection of data on case report forms (CRFs). Only subjects that have the 
appropriate informed consent form will be included in the trial.  
The informed consent process (including time and date of discussion), should be 
documented in the subject’s medical record and signed/dated by the individual 
(investigator or designee) who recorded it.  The original signed consent form must be filed 
in the subject’s medical record and a copy of the signed informed consent documentation 
given to the subject.  

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All subjects must sign, date and note the time on the Institutional Medical Ethics 
Committee (MEC) approved informed consent prior to any clinical trial/investigation-
specific procedures. Obtaining the consent with the documented date and time, and the 
provision of a copy to the subject will be documented in the subject’s medical record.  
Due to the emergent nature of treating acute myocardial infarction, patients who have been 
enrolled in the study may receive a subsequent consent which provides more detailed 
information about their participation in the trial (based on MEC requirements), which may 
be reviewed and signed after the acute phase of their treatment has been completed.  If the 
patient decides they no longer want to be included in the study, they will be withdrawn 
and their data will be included in the analysis up until the time of withdrawal. 
If in the course of the pre-study evaluations prior to consent, the patient is found not to be 
eligible for inclusion in the study, the patient should be notified and the reason for 
ineligibility documented on the appropriate Screening Log. 
 
All information pertinent to this clinical investigation (including at a minimum the 
description and purpose of the study, potential benefits, potential risks and 
inconveniences, active procedures, confidentiality, compensation, circumstances for 
termination and site contact persons) will be provided to the subjects in writing and in 
their native, non-technical, language by Investigator or designee, who has been trained on 
the protocol.   
If new information becomes available that can significantly affect a subject's future health 
and medical care, this information shall be provided to the affected subject(s) in written 
form. If relevant, all affected subjects shall be asked to confirm their continuing informed 
consent in writing. 
6.8.3 Roll-In Enrollment  
Prior to randomizing patients, each participating center (except German centers) may 
enroll up to 4 patients Roll-In subjects in a non-randomized fashion. Roll-In subjects are 
treated and followed as patients in the Test Arm (PCI + Cooling) for training purposes. 
The justification for the number Roll-In patients in this study is based on ZOLL’s previous 
clinical trial experience in relationship to a site’s ability to successfully incorporate the 
cooling protocol including consent, anti-shivering regimen and an adequate dose of 
cooling without significantly delaying door-to-balloon time.  Successful implementation 
takes teamwork and often several cases to assure the cooling protocol is adhered to with 
consistent accuracy. 
In light of the fact that previous clinical trials (e.g., COOL –MI19, ICE-IT23 and CHILL-
MI37) have failed to provide an adequate dose of cooling prior to reperfusion, ZOLL has 
implemented a tool called a “Report Card”.  This Report Card notes the site’s success in 
achieving critical aspects of the protocol, called “Standards”, and is provided to the site 

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after every patient is enrolled into the trial.  The objective of the Report Card is to report 
back to the site their success in implementing a set of standards according to the protocol, 
and to encourage continuous improvement following each enrollment.  The Standards, as 
noted on the Report Card, include but are not limited to accuracy of antishivering regimen 
administration and 18 minutes of cooling delivered prior to the wire crossing the lesion. 
The Standard of 18 minutes of cooling has been demonstrated in previous ZOLL trials to 
be the amount of time required to deliver an optimal dose of cooling so the patient’s core 
body temperature is as close to target temperature as possible prior to reperfusion without 
significantly delaying door-to-balloon time. 
Consistent achievement of each standard allows sites to move from Roll-In to 
randomization and enables consistency in execution of the protocol. Feedback will be 
provided to the site after each enrollment to assure the standards have been met and an 
adequate dose of cooling has been achieved.  Use of the Report Card and Standards is 
intended to assist sites in ascending their learning curve as rapidly as possible.  All centers 
will transition from Roll-In to Randomization as soon as possible once they have 
demonstrated their ability to enroll patients while consistently meeting the standards, 
thereby minimizing the number of Roll-In patients but ensuring accurate, precise 
adherence to the investigational protocol. Based on the site’s performance with the Roll-
In patients, as determined by the Sponsor, the site will be notified of authorization to 
randomize patients in the trial. 
Additionally, Roll-In patients will undergo cMR as part of the cMR training process at 
each site.  This will allow the site to train and qualify acquisition of cMR images per cMR 
protocol and ensure high quality and consistent imaging throughout the study across sites.  
Roll-In patients will not be included in the primary endpoint analysis; however, they will 
be included in the safety endpoint analysis.  All performed activities on Roll-In subjects 
will be recorded as if performed in the Test Arm of the trial and hence documented in the 
Case Report Forms (CRF) for training and evaluation. 
Roll-In subjects will be considered to be enrolled when all inclusion and exclusion criteria 
have been met and the informed consent form has been signed. 
6.8.4 Approval to Randomize in the Trial 
It will be at the discretion of the sponsor to advance a site to Randomization.  Based on 
the site’s performance with the Roll-In patients, as determined by the Sponsor, the site 
will be notified of authorization to randomize patients in the trial. 
6.8.5 Randomization 
In the randomization phase, patients who meet eligibility criteria for participation will be 
randomly assigned to either the Test Arm (PCI + Cooling) or Control Arm (PCI alone) in 
a 1:1 ratio. 

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Randomization will be applied using an internet based Interactive Web Response Systems 
(IWRS). In the trial, randomization will be done using random permuted blocks (based on 
procedure outlined in Pocock SJ. Clinical Trials: A Practical Approach. Wiley, 
Chichester, 1983), stratified by site, with 1:1 allocation ratio using a randomization list. 
At randomization, inclusion and exclusion criteria will be verified, and confirmation of 
informed consent signature will be done. 
Subjects will be considered to be enrolled in the Test Arm and Control Arms of the trial 
when all inclusion and exclusion criteria have been met, the informed consent form has 
been signed, and randomization assignment has been completed. 
6.8.6 Acute Care and Emergency Room Triage  
Prior to the initiation of this trial at each participating institution, training will be 
conducted by the Sponsor targeted toward the integrated care of each trial subject and 
emphasizing the shared responsibility between the Departments of Emergency Medicine 
and Interventional Cardiology, where applicable at each center, with the goal of rapid 
screening, enrollment and treatment of appropriate patients. 
Each center will clearly delineate departmental responsibilities for the following: 
• Assessment of patient clinical features, signs and symptoms 
• Administration of Informed Consent 
• Review of Inclusion/Exclusion Criteria 
• Assurance that diagnostic procedures mandated by the protocol are completed 
prior to randomization into this trial and are appropriately documented 
• Patient Randomization 
• Administration of pre-treatment medication(s) 
• Administration of Anti-shivering medications to subjects randomized to the Test 
Arm of the trial 
• Consensus on location in hospital where cooling using the Proteus IVTM System 
will be initiated 
• Set-up of Proteus IVTM System, including insertion of the Proteus Catheter into 
the femoral vein induction of cooling, initiation of re-warming, Proteus IVTM 
System shutdown and catheter extraction for Test Subjects. 
6.8.7 Standardized Care Prior to the Cooling Procedure 
It is anticipated that subjects may receive one or more of the following therapies as part 
of current clinical practice in the treatment of acute myocardial infarction: 
• Intravenous fluids and electrolytes 
• Oxygen  
• Antiplatelets and/or antithrombotics  
• Vasoactive agents and diuretics 

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Clinicians will be encouraged to manage the subject in a standardized manner with 
respect to oxygenation, anti-coagulation and/or anti-platelet medications.  
6.8.8 Documentation Procedures 
Trial procedures and treatment data will be documented on standardized Case Report 
Forms (CRFs) which may be on paper or via an electronic data capture system (EDC). 
The completion of the CRFs may be delegated to a member of the study team (e.g., the 
study coordinator) as long as that person is listed on the Delegation of Authority Log.  
However, the Principal Investigator retains responsibility for the accuracy and integrity of 
the data entered on the CRF.  The CRF will be monitored for accuracy and completeness 
per the source documents (medical records, charts, interventional systems, worksheets as 
applicable, etc.) at each clinical center.  Temperature data from the Proteus IVTM System 
will be downloaded and sent to Sponsor.  A flow diagram for the Test Arm is represented 
in Figure 10. 
It is anticipated that technology and/or techniques such as edit checks and double entry of 
data may be utilized to minimize the rate of error.  Additionally, ZOLL or its assignees 
may ask for data clarification or re-check of data for accuracy.  Monitoring visits and CRF 
completion logs will be used to track data entry in accordance with trial logistics and 
expectations.  
Any source documentation (procedure reports, imaging studies, lab reports, death 
certificates, etc.) that is sent to the Sponsor should have all patient identifiers removed and 
replaced with the subject’s trial ID, and processes ensuring patient privacy and clinical 
data confidentiality will be followed in accordance with local regulations and applicable 
laws. 
 

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6.8.9 Study Flow and Procedures 
 
Figure 8 Screening and Enrollment Flow 
Admission to Hospital
Patient Screening
Eligible?
Patient Screening Log
(If Patient doesn’t qualify, document 
Reason for Screen Failure)
Complete Informed Consent Procedure
Roll-in Up to 4 subjects 
per site
No
Yes
Turn Proteus 
Console ON
1:1 Randomization
TEST ARM
Cooling + PCI
CONTROL ARM
PCI Only
Approved by Sponsor to 
Randomize?
Yes
No
 
 
 
 

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Figure 9 Control Arm Flow 
  
1:1 Randomization
CONTROL ARM
PCI Only
Perform PCI 
Procedure
Obtain Vital Signs 
and Core Body Temp 
at Baseline
Perform 12-lead ECG 
at Baseline
Record Troponin I or 
T at Baseline and 
until peak identified
Document All 
Medications and All 
Adverse Events
Post PCI
 

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Figure 10 Test Arm Flow 

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Figure 11 All Patient Procedures 
 
  

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6.8.10  
Pre-Cooling Assessment Procedures 
All required procedures and data collection from the time of subject screening (presentation at 
hospital) through the pre-cooling assessment period are given below in Table 11. 
 
Table 11:  Baseline / Screening and Enrollment Procedures/Evaluations and Data 
Collection for the Test & Control Arms of the Trial 
Procedures/ 
Evaluations  
Data 
Trial 
Eligibility 
At admission to the hospital 
Informed 
Consent  
Obtain Consent from patient before any trial-related procedure is initiated. 
Trial 
Enrollment  
- 
Follow randomization process to assign patient to Roll-In, Test or 
Control Arms of the trial 
- 
Complete Enrollment Form, document randomization, and FAX  or 
email to ZOLL at 
 
+1 800.243.0360 or ami-eu@zoll.com to enter in the eCRF 
Temperature 
Document subject’s temperature using a tympanic thermometer 
Vital Signs 
Blood Pressure, Heart Rate, Respiratory Rate, BSAS measurement 
Physical Exam  
Complete Physical Examination 
Blood Studies 
RBC’s, WBC’s, Hct, Hgb, Platelets,  
Lab Studies 
BUN, Creatinine, sodium, potassium, calcium, phosphate, magnesium, 
chloride, lactic acid, glucose, amylase, lipase 
Cardiac 
Markers  
Baseline and peak Troponin I or Troponin T including upper limit of normal 
ECG 
12-lead baseline 
Medications 
Document as indicated on Case Report Form since STEMI onset 
Adverse 
Events 
Collect all adverse events as soon as patients are enrolled in the trial 
 

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6.8.11 Initiation, Maintenance, and Reversal of Cooling with Proteus IVTM System 
Procedures / Evaluations and Data Collection for Subjects Enrolled in the 
Test Arm 
6.8.12 Test Arm: Temperature Management Protocol and Data Collection Time 
Points 
Treatment with therapeutic hypothermia will begin with a forced infusion of up to 1 L of cold 
saline (4°C) (according to the guideline) using pressure bags, and at the time of administration of 
the anti-shivering medication according to the anti-shivering guidelines, then will continue with 
the Proteus IVTM System as soon as possible.  Cooling will be initiated with the Proteus IVTM 
System set at a temperature of 32.0 °C, and the subject’s temperature will be measured with the 
Proteus IVTM System immediately before PCI has occurred (measured as time the wire crosses 
the target lesion). Cooling will be maintained for 3 hours and will be followed with active 
rewarming to attain normothermia 36.0 °C (96.8°F).  
Cooling induction, maintenance of hypothermia, and rewarming are described in the following 
Table 12. The data collection schedule for Test Arm subjects is summarized in Section 6.8.13. 
 
Table 12:  Initiation, Maintenance, and Reversal of Cooling with Proteus IVTM System 
Procedures / Evaluations and Data Collection for Subjects Enrolled in the Test Arm 
 
Phase 
Task 
Immediately Upon 
Arrival to the 
Hospital 
1. Turn the Proteus Console on (in preparation for cooling with the 
device) 
2. Document time of occurrence of STEMI and ECG 
3. Document time of arrival of Emergency Medical Service EMS 
(Paramedics) 

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Phase 
Task 
Baseline / 
Enrollment 
4. Immediately after informed consent is obtained and patient is 
randomized to the Test Arm of the trial, initiate anti-shivering 
medication protocol using Guidelines outlined in Attachment 
II. 
5. Begin cooling induction by forced infusion with 25mL/kg of 4°C 
cold saline using pressure bags up to 1 L of cold saline (4°C) 
(according to the guideline) at the physician’s discretion. Use Bair 
HuggerTM (CE marked device) for patient comfort. 
6. Document the time the Proteus console is turned on. The 
device will begin cooling the patient immediately; however, 
optimal cooling is achieved in 5-10 minutes after it is turned on. 
7. Perform Physical Examination and obtain Vital Signs. 
8. Obtain Blood and Lab studies. 
9. Obtain Troponin I or Troponin T . 
10. Obtain 12-lead baseline ECG. 
11. Document all medication use since STEMI onset. 
12. Measure body temperature using an independent tympanic 
thermometer.  The independent measurement is to be used in 
addition to the core body temperature collected by the Proteus 
Temperature Probe (X-Probe). 
13. Document all Adverse Events.  
 

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Phase 
Task 
Initiation of 
Cooling  
 
14. Document the volume of cold saline, the time the cold saline 
infusion is started and the time the cold saline infusion is finished. 
15. Following the ZOLL Proteus IVTM System Instructions for Use 
(IFU), insert the Proteus Catheter into the Inferior Vena Cava via 
either femoral vein.  The Proteus Catheter is then connected to the 
Cassette that has been inserted into the Proteus Console. 
16. Following insertion of the Proteus Catheter, insert the Proteus 
Temperature Probe (X-Probe). 
Access site selection may vary by both operator preference and 
anatomical considerations; however, the function of the system is not 
dependent on which femoral vein is chosen. 
17. Once the Proteus System Catheter & Proteus Temperature Probe 
(X-Probe) have been inserted, enter set point temperature to 
32.0°C on the Proteus Console and perform cooling at maximum 
power as soon as the console is ready to cool.  
18. Document the time of Proteus Catheter & X-Probe 
(temperature probe) insertion. 
19. Document the time cooling is initiated with the Proteus IVTM 
System. 
20. Document vital signs (BP, HR, RR), and temperature 
measurements (Tympanic and Proteus Console 
measurements). 
21. Document all medication use. 
22. Document all adverse events since the time of enrollment. 
23. Use Bair Hugger® warming blankets for counter-warming. 
If choosing to use low dose anticoagulation during the cooling phase, 
follow hospital’s guidelines for venous thromboembolism 
prophylaxis. 

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Phase 
Task 
Immediately Prior 
to Reperfusion 
24. If clinically relevant shivering (Bedside Shivering Assessment 
Scale (BSAS) of 2 or greater) occurs at 32° (see Anti-Shivering 
Guidelines, Attachment II, and BSAS Attachment III), increase 
the dose of Pethidine (Meperdine) as indicated in shivering 
protocol and increase set point temperature on the Proteus IVTM 
System to 32.5°C. If clinically relevant shivering continues (BSAS 
≥2), once again increase dose of Pethidine as indicated in Anti-
Shivering Protocol and increase set point temperature on the 
Proteus IVTM System to 33°C.  Continue this process until a 
temperature is reached where there is no shivering. Follow 
sedation procedures using Anti-Shivering Guidelines, 
Attachment II, and the BSAS Attachment III. 
25. Perform *angiogram after the induction of hypothermia has been 
initiated and just prior to PCI. 
26. Obtain vital signs (BP, HR, RR), BSAS and temperature 
measurements (Tympanic and Proteus Console 
measurements) just prior to PCI. 
27. Document all medication use since the initiation of cooling. 
28. Document all adverse events since the initiation of cooling. 
CAUTION: Anticipate changes in electrolytes and laboratories 
values secondary to hypothermia. 
29. Document core body temperature at the time of PCI. 
30. If subject has not reached 32.0 ± 1.0°C (or temperature where 
shivering does not occur, as indicated above) at the time of PCI, 
continue cooling induction until target temperature has been 
reached. 
31. Document the time wire crossed the target lesion. 

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Phase 
Task 
Maintenance of 
Hypothermia 
Target 
Temperature 32 
±1°C 
32. Maintain the patient at the set target temperature of 32.0 (or 
temperature where shivering does not occur, as indicated above) 
for 3 hours ± 15 minutes from the initiation of cooling with the 
Proteus System.  
33. Obtain vital signs (BP, HR, RR), BSAS and temperature 
measurements (Tympanic and Proteus Console 
measurements) every 30 minutes during the 3 hours of cooling. 
34. Document all medication use since the angiogram/ PCI procedure. 
35. Document all adverse events since the angiogram/ PCI procedure. 
36. If clinically relevant shivering [Bedside Shivering Assessment 
Scale  (BSAS) of 2 or greater] occurs at 32.0°C (See Anti-
Shivering Guidelines, Attachment II, and BSAS, Attachment 
III), increase dose of Pethidine (Meperidine) as indicated in 
shivering protocol and increase temperature on the Proteus IVTM 
System console to 32.5°C. 
37. If clinically relevant shivering continues (BSAS ≥ 2), once again 
increase dose of Pethidine as indicated in shivering protocol and 
increase temperature on the Proteus IVTM System to 33°C.  
Continue this process until a temperature is reached where there is 
no shivering.  Follow sedation procedures using Anti-Shivering 
Guidelines outlined in Attachment II and BSAS assessment in 
Attachment III. 

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Phase 
Task 
Rewarming 
38. After 3 hours of cooling with the Proteus IVTM System, begin 
active rewarming to normothermia.  Palliative care such as 
blankets, Bair Hugger patient warming systems, and warm liquids 
may be used. 
39. Using the Proteus System Console, press STOP and Increase 
target temperature to 36.0°C using the arrow touch buttons and 
then press Continue.  
40. Set rewarming rate to 1.0°C/hr using the arrow touch buttons and 
press Continue to start rewarming. 
41. Maintain the Pethidine infusion during rewarming using the Anti-
Shivering Protocol outlined in Attachment II. 
42. Obtain blood studies, lab studies and  record peak Troponin I or 
Troponin T including upper limit of normal for site. 
43. Document all medication use during the rewarming phase. 
44. Document all adverse events during the rewarming phase.  
CAUTION: Anticipate changes in electrolytes and laboratories 
secondary to re-warming 
Catheter Removal  
45. Document core body temperature at time of Proteus Catheter 
removal. 
46. Remove Proteus Catheter and X-Probe per IFU and document 
time of removal. 
47. Dispose of the Proteus Catheter, X-Probe and Proteus Cassette per 
institution’s guidelines (single-use). 
48. Assess catheter access site for signs of bleeding, access vessel 
trauma, or hematoma formation. 
49. Download temperature data from the Proteus Console after 
the cooling phase has been completed. Send downloaded data 
to amidatadownload@zoll.com immediately upon 
downloading.  Device data must be saved according to Section 
16.1, Investigator Records.  
50. Document all medication use during the hypothermic phase. 
51. Document all adverse events during the hypothermic phase. 
DO NOT DISCARD SPLITTER CABLE (MULTI–USE  
TEMPERATURE CABLE) 

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Phase 
Task 
Normothermia 
52. Document all adverse events until patient is discharged from the 
hospital. 
Post-Procedure 
 
53. If required, provide additional Informed Consent document to 
patients who were consented with the short consent form (if 
required by MEC or country-specific regulations). 
NOTE:  All post-PCI times will be measured from the start of PCI, defined as time the wire 
crosses the target lesion. In the event that PCI is not performed, the time of the first 
cineangiogram of the infarct related artery will be referenced. If PCI is staged for the non-
culprit lesion, then the PCI will be performed after the 4-6 day cMR 
*Angiograms are to be uploaded for all adjudicable events.  
 

 
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6.8.13 Trial Schedule for Test Arm Subjects 
Procedure/ Interval 
Baseline / 
Enrollment 
Initiation 
of 
Cooling  
Immediately prior 
to reperfusion 
(PCI) 
Maintenance of 
Target Temp  
32 ±1°C 
Rewarming to 36°C 
Catheter 
Removal 
Discharge 
Follow-Up 
@ 4-6 Days  
Follow-Up @ 
30 Days 
(±7 days) 
Follow-Up @ 
12 months 
(±14 days) 
Unschedul
ed Visit 
Trial Eligibility & Informed 
Consent 
upon arrival 
to hospital 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
X 
 
 
 
 
Anti-Shivering Protocol 
X 
 
 
X∞ 
 
 
 
 
 
 
 
Cold Saline Infusion 
 
X 
 
 
 
 
 
 
 
 
 
Catheter Insertion Time 
 
X 
 
 
 
 
 
 
 
 
 
Catheter Removal Time 
 
 
 
 
 
X 
 
 
 
 
 
Temperature Documented 
X 
X 
X 
every 30 min 
during 3 hr cooling 
every 60 min 
during rewarming 
 
 
 
 
 
 
Temperature Data Download   
 
 
 
 
 
X 
 
 
 
 
 
Vital Signs 
X 
X 
X 
every 30 min 
every 60 minutes 
 
 
 
 
 
 
Blood Studies  
RBC’s, WBC’s, Hct, Hgb, 
Platelets,  
X 
 
 
 
X 
upon reaching 
normothermia 
 
 
 
 
 
 
NT-pro BNP 
 
 
 
 
 
 
 
 
 
X 
 
Lab Studies  
BUN, Creatinine, Na, K, Ca, 
Mg, Cl, P, lactic acid, 
glucose, amylase, lipase 
X 
 
 
 
upon reaching 
normothermia 
 
 
 
 
 
 
Any Medication Use 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Troponin I or T(including 
ULN) during hospitalization 
X 
Perform Troponin until peak value identified  
 
 
 
 
 
 
12 lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
SAE only 
X** 
 
Catheter Access Site 
Assessment  
 
 
 
 
 
X 
X 
X 
 
 
 
Cardiac Magnetic Resonance 
(cMR) imaging 
 
 
 
 
 
 
 
X 
 
 
 
NYHA Assessment 
 
 
 
 
 
 
 
 
 
X 
 
KCCQ  
 
 
 
 
 
 
 
 
 
X 
 
∞For persistent clinically relevant shivering (BSAS ≥ 2), increase dose of Pethidine as indicated in shivering protocol and increase temperature on Proteus IVTM System console by 0.5°C.  Continue this process until a temperature is reached where there is 
no shivering.  Follow sedation procedure using Anti-Shivering Guidelines outlined in Attachment II and BSAS assessment in Attachment III Include BSAS measurement and temperatures from independent method.  
**If unscheduled visit occurred within 30 days follow-up, report all AEs. However, if unscheduled visit occurred after 30 days follow-up within 12 months, report only SAEs. 
 

 
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6.8.14 Trial Schedule for Control Arm Subjects 
Procedure/ Interval 
Baseline / Enrollment 
Immediately prior 
to reperfusion 
(PCI)Post-PCI 
Discharge* 
Follow-Up @ 4-6 
Days  
Follow-Up @ 30 
Days 
(±7 days) 
Follow-Up @ 12 months 
(±14 days) 
Unscheduled 
Visit 
Trial Eligibility & Informed Consent 
upon arrival to 
hospital 
 
 
 
 
 
 
Physical Exam 
X 
 
X 
 
 
 
 
Catheter Insertion Time 
X 
 
 
 
 
 
 
Catheter Removal Time 
 
 
 
 
 
 
 
Temperature Documented 
X 
 
 
 
 
 
 
Vital Signs 
X 
 
 
 
 
 
 
Blood Studies  
RBC’s, WBC’s, Hct, Hgb, Platelets,  
X 
 
 
 
 
 
 
 
NT-pro BNP 
 
 
 
 
 
X 
 
Lab Studies  
BUN, Creatinine, Na, K, Ca, Mg, Cl, P, 
lactic acid, glucose, amylase, lipase 
X 
 
 
 
 
 
 
 
Any Medication Use 
X 
X 
X 
X 
X 
X 
X 
Troponin I or T(including ULN) 
X 
Perform 
Troponine until 
peak value 
identified  
 
 
 
 
 
 
12 lead ECG 
X 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
SAE only 
X** 
 
Cardiac Magnetic Resonance (cMR) 
 
 
 
X 
 
 
 
NYHA Assessment 
 
 
 
 
 
X 
 
KCCQ  
 
 
 
 
 
X 
 
**If unscheduled visit occurred within 30 days follow-up, report all AEs. However, if unscheduled visit occurred after 30 days follow-up within 12 months, report only SAEs.

 
 
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6.8.15 Control Arm Protocol and Data Collection Time Points 
The data collection schedule for Control Arm subjects is summarized in Section 6.8.14. For 
patients randomized to the Control Arm, i.e., PCI alone, the following procedures will be 
performed: 
i. 
Document time of occurrence of the STEMI & ECG results 
ii. 
Document time of arrival of Emergency Medical Service EMS (Paramedics) & 
time of arrival at hospital 
iii. 
Collect all adverse events as soon as patients are enrolled in the trial 
iv. 
Perform Blood Studies, Labs, and record Baseline and peak Troponin I or T  
v. 
Perform PCI. If PCI is staged for the non-culprit lesion, then the PCI will be 
performed after the 4-6 day cMR 
vi. 
Monitor and record the patient’s vital signs, temperature, blood pressure, heart 
rate and respiratory rate, at baseline  
vii. 
Obtain 12-lead baseline ECG  
viii. Monitor and record all pharmacological agents 
ix. 
Measure and record  baselineTroponin I or T including upper limit of normal, 
and when a peak is identified. 
x. 
Monitor and record all adverse events for the duration of 30 days follow-up and 
serious adverse events for the duration of 12 month follow-up. 
xi. 
Complete physical exam prior to discharge.  
6.8.16 Follow-up at 4-6 days and at 30 days following the PCI Procedure 
Subjects enrolled in the Test and Control Arms, and Roll-In patients, will undergo Cardiac 
Magnetic Resonance (cMR) to assess infarct size at 4-6 days. In addition, the following procedures 
are to be performed at 4 - 6 days and at 30 days after the index procedure (PCI) for  all patients: 
i. 
Monitor and record all adverse events for the duration of 30 days follow-up. 
ii. 
Review and record all medication changes since index. 

 
 
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6.8.17 Follow-up at 12 months following PCI 
Following completion of the 30 day follow-up and, all subjects will be followed through 12 months 
for the incidence of Serious Adverse Events, Death and Heart Failure (as assessed by NYHA and 
Kansas City Cardiomyopathy Questionnaire (KCCQ)) 
i. 
 Monitor and record all serious adverse events for the duration of 12 month 
follow-up. 
ii. 
 Collect NT-pro BNP value to assess clinical prognosis of Heart Failure. 
iii. 
Review and record all medication changes 
iv. 
Perform blinded NYHA Assessment. and administer Kansas City 
Cardiomyopathy Questionnaire (KCCQ). 
6.8.18 Use of other Cooling Methods 
For the purposes of this trial, no other cooling methods may be used. 
6.8.19 Transferring Subject during Cooling 
Although interruption during the induction phase of hypothermia is not recommended, if subject 
transfer is required during any phase of the cooling, follow relevant instructions in the device 
Instructions for Use.   
 
For additional detail, refer to the Proteus IVTM System Instructions for Use. The console screen 
also provides prompts for entry of user-defined parameters and system start-up.  
6.8.20 Patient Withdrawal and Discontinuation 
The term “patient withdrawal” refers to the patient deciding to terminate their participation in the 
trial.  The term “discontinuation” refers to the physician deciding that the patient will not continue 
trial participation as defined below.   
A subject has the right to withdraw from the trial at any time and for any reason without prejudice 
to his or her future medical care by the physician or the institution. Trial withdrawal by a subject 
specifically means withdrawal of consent from further participation in the trial. Subjects who 
withdraw consent after enrollment will be evaluated to the time of withdrawal, and withdrawal of 
consent precludes any further trial related treatment or data collection. If possible, a complete, 
final physical examination should be performed on all subjects who withdraw from the trial. At a 
minimum, every effort should be made to document subject outcome at the time of trial 
withdrawal.   
A subject may withdraw from the clinical investigation for the following reason:  

 
 
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o 
Subjects may choose to withdraw from the clinical investigation under the terms 
of the Declaration of Helsinki and their consent documentation without having to 
give a reason;  
A subject may be discontinued from the clinical investigation for the following reasons: 
o 
Any unanticipated adverse reaction which is, in the opinion of the Investigator, 
related to the treatment and will endanger the well-being of the patient if treatment 
is continued;  
o 
Development of any illness(es), infection or condition(s) that might interfere with 
the Clinical Investigational Plan;  
o 
Non-compliance with the clinical investigation procedures deemed by the 
Investigator to be sufficient to cause discontinuation;  
o 
Any problem deemed by the Investigator to be sufficient to cause discontinuation.  
- Investigator will treat all subjects discontinued from the investigation due to an 
unanticipated adverse reaction, directly related to the investigation, until the reaction 
resolves.  
- Investigator will not replace subjects who have withdrawn from the clinical 
investigation if they have received the investigational device. If possible, Investigator 
will perform any procedures or assessments planned for the subject at the time of 
withdrawal.  
All subjects are expected to continue in the trial through the final follow-up assessment or until 
ZOLL notifies the Investigator in writing that further follow-up is no longer required, except in 
the event of death or upon the subject's request for early withdrawal from the clinical trial.  
6.8.21 Patient Lost to Follow-up  
The investigator will attempt to contact a subject at least three times prior to designating them as 
lost-to-follow-up subjects. The investigator will document the date and type of attempted 
communication. The investigator will complete and sign the Study Exit Form when a subject is 
lost to follow-up.  
6.8.22 Early Termination of a Clinical Investigation 
Both the Sponsor and Investigator reserve the right to terminate the clinical investigation at any 
time. If necessary, and after review and consultation with the Principal Investigator, the Sponsor 
will make a final determination on whether to terminate the study. 

 
 
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A clinical investigation or Investigator may be terminated at a clinical center for any of the 
following reasons, or for reasons not listed that affect patient safety or integrity of the trial: 
• Unsatisfactory rate of patient enrollment or compliance to eligibility criteria. 
• Repeated noncompliance with the investigational plan. 
• Inaccurate, incomplete, and/or untimely submission of data. 
• Inadequate accountability of the investigational device. 
 
The sponsor may terminate this trial if there are new, previously unknown adverse events related 
to device or cooling procedure, deaths, SAEs/AEs exceeding those reported as related to 
device/cooling procedures in previous trials, and/or if recommended by DMC (Data Monitoring 
Committee) to stop the trial. The sponsor will make the final determination on whether to terminate 
the study. 
The sponsor may terminate the trial for any other unforeseen circumstances. In case of premature 
termination/suspension, ZOLL will stop the enrollment, inform all investigators at all sites and all 
regulatory agencies governing the study. ZOLL will perform complete device accountability of all 
investigational devices and retrieve them from the clinical sites. All study subjects will be followed 
through the specified follow-up periods. ZOLL will issue a final report of the clinical study. 
6.8.23 Amendments and Protocol Deviations 
Investigator will not deviate from the CIP without prior written confirmation by Sponsor, or their 
designee, except as required in a medical emergency. In medical emergencies, Sponsor does not 
require prior confirmation for protocol deviations, but Investigator will notify Sponsor within 5 
days of the incident and will notify the EC according to local requirements. Investigator, or 
designee, will record deviations with an explanation for the deviation. Investigator will report to 
Sponsor who will analyze them and assess their significance.  Significant deviations from the CIP 
will be reported to the Competent Authority. 
 
Examples of protocol deviations may include those relating to: 
• Eligibility 
• Enrollment and randomization 
• Informed consent 
• Protocol adherence (e.g., tests and assessments done as required in Trial Schedule, etc.) 
 
Routine monitoring will assess Investigator compliance to the protocol.  
 

 
 
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Investigator must not modify the CIP without the prior and written permission from Sponsor. All 
modifications to the clinical protocol must be submitted to the Competent Authority (where 
required) to allow the Competent Authority review and approval.  
 
The Sponsor is responsible for management, processing and approval of any amendment to the 
Investigational Plan. Should the site consider an amendment necessary, the Sponsor will work with 
the site to make the appropriate changes. The Sponsor will manage documentation of such changes 
through the existing document control system. A history of changes and a redline version of the 
documentation will be maintained per the applicable quality system procedures. The proposed 
amendment will be submitted to the reviewing MEC/ IRB and government agency as applicable. 
Any necessary approvals will be received in writing before the requested change is implemented. 
 
This study will be conducted in compliance with ISO 14155, ICH E6 Consolidated Good Clinical 
Practice Guidance, 21 CFR 812, 21 CFR Part 50, and any requirements imposed by countries with 
participating clinical sites. The study will not commence until the necessary government and 
MEC/IRB approvals have been obtained. 
6.8.24 Trial Exit 
The Trial Exit Form (CRF) should be completed at the time a subject is exited from the trial.  A 
subject will be considered to have exited from the trial for any of the following reasons. 
• Subject completes follow-ups required by the investigational plan. 
• Subject dies. 
• Subject requests to be withdrawn. 
• Physician requests that patient be withdrawn to protect the welfare of the patient. 
• Patient is lost to follow-up. 
• Other (specify) 
6.8.25 Subject Confidentiality 
Subject confidentiality will be maintained throughout the clinical trial to the extent permitted by 
law.  That is, every attempt will be made to remove patient identifiers from clinical trial documents.  
For this purpose, a unique subject identification code (site number, subject number and subject 
initials) will be assigned and used to allow identification of all data reported for each subject.  This 
will also ensure that the information can be traced back to the source data.  
Trial data may be made available to third parties, e.g., in the case of an audit performed by 
regulatory authorities, provided the data are treated confidentially and that the subject’s privacy is 
guaranteed.  The identity of a subject will never be disclosed in the event that trial data are 
published. 

 
 
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Security and Unique usernames and passwords will be utilized by data entry, data verification and 
other personnel who have database access to insure confidentiality and protection of data. 
Trial sites must comply with Health Insurance Portability and Accountability Act (HIPPA) and/or 
the subject confidentiality provisions and privacy laws of each participating country, local 
regulations, and institutional requirements, whichever is stricter. 
6.8.26 Device Accountability 
ZOLL is responsible for the availability and traceability of all investigational products.  
Documentation is required at each step of the process via a device accountability log.  
Investigational product will be reconciled on a regular basis. 
The investigator also is required to maintain adequate records of the receipt and disposition of all 
investigational devices.  A device accountability log will be provided for this purpose. 
All unused product must be returned to ZOLL prior to the close of the trial. 
6.8.27 Return of Materials upon Trial Termination 
Sponsor will ship investigational devices only to qualified Investigators participating in this 
clinical investigation. Sponsor will not ship investigational devices to any site until evidence of 
EC approval has been provided to Sponsor, or designee.  
Investigator will control access to investigational devices, and will only use investigational devices 
in the clinical investigation and according to the CIP.  
Sponsor will keep investigational device records to document the physical location of each device. 
Record(s) will include information documenting devices shipped, devices at investigation sites, 
devices disposed of, and devices returned.  
Investigator, or designee, will keep records documenting the receipt, use, return and disposal of 
the investigational devices, which will include:  
• Date of receipt,  
• Identification of each investigational device (serial number or unique code),  
• Expiry date, if applicable,  
• Date or dates of use,  
• Subject identification,  
• Date on which the investigational device was returned, or explanted from subject, if 
applicable, and  
• Date of return of unused, expired or malfunctioning investigational devices, if applicable.  
 

 
 
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After the trial procedures have been completed, all unused devices must be accounted for and 
returned to ZOLL.  Instructions for device return to ZOLL will be reviewed at the site initiation 
visit. 
6.8.28 Trial Closure 
Trial closure can occur under the following circumstances: 
a. termination of site participation in the trial (i.e., closure that occurs prior to meeting 
defined endpoints) of the trial 
b. upon completion of the trial (i.e., when all patients enrolled have completed the follow-
up visits or previously exited the trial, and the CRFs and queries have been completed)  
Under any circumstance for closure of the trial at the site, ZOLL and/or its designees will notify 
the site of this occurrence in writing.  Trial closeout visits will be performed once a determination 
has been made that the trial is closed.  All unused trial devices and any unused trial materials and 
equipment will be collected and returned to ZOLL and/or its designees.  The monitors will ensure 
that the investigator’s regulatory files are current and complete and that any outstanding issues 
from previous visits have been resolved.  Other issues that will be reviewed at this visit include:  
discussing record retention requirements (refer to Section 14.1—Investigator Records), device 
accountability, possibility of site audits, publication policy, and notifying the Medical Ethics 
Committee and Competent Authorities of trial closure, etc., as applicable. 
 
Cardiac Magnetic Resonance (cMR) imaging Core Laboratory 
Cardiac Magnetic Resonance (cMR) imaging must be collected per the Manual of Operations 
provided by the sponsor. Images must be submitted to the core laboratory designated by the 
sponsor for analysis. 
7 
ADVERSE EVENTS & DEVICE DEFICIENCIES 
 
Definitions 
7.1.1 Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in subjects, users or other persons, whether or not 
related to the investigational medical device. 
NOTE 1- This definition includes events related to the investigational medical device or the 
comparator. 
NOTE 2- This definition includes events related to the procedures involved. 

 
 
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NOTE 3- For users or other persons, this definition is restricted to events related to investigational 
medical devices.  
7.1.2 Serious Adverse Event (SAE) 
Adverse event that:  
a) led to a death, injury or permanent impairment to a body structure or a body 
function.  
b) led to a serious deterioration in health of the subject, that either resulted in:  
- a life-threatening illness or injury, or  
- a permanent impairment of a body structure or a body function, or  
- in-patient hospitalization or prolongation of existing hospitalization, or  
- in medical or surgical intervention to prevent life threatening illness  
c) led to foetal distress, foetal death or a congenital abnormality or birth defect.  
NOTE 1: Planned hospitalization for pre-existing condition, or a procedure required by the Clinical 
Investigation Plan, without a serious deterioration in health, is not considered a serious adverse 
event. 
7.1.3 Device Deficiency (DD) 
Inadequacy of an investigational medical device related to its identity, quality, durability, 
reliability, safety or performance. This may include malfunctions, use error, or inadequacy in the 
information supplied by the manufacturer. 
7.1.4 Adverse Device Effect (ADE) 
Adverse event related to the use of an investigational medical device. 
NOTE 1- This includes any adverse event resulting from insufficiencies or inadequacies in the 
instructions for use, the deployment, the implantation, the installation, the operation, or any 
malfunction of the investigational medical device. 
NOTE 2- This includes any event that is a result of a use error or intentional abnormal use of the 
investigational medical device. 
7.1.5 Serious Adverse Device Effect (SADE) 
A adverse device effect that has resulted in any of the consequences characteristic of a serious 
adverse event. 

 
 
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7.1.6 Unanticipated Serious Adverse Device Effect (USADE) 
Serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report. 
NOTE: Anticipated SADE (ASADE): an effect which by its nature, incidence, severity or outcome 
has been previously identified in the risk analysis report. 
 
Adverse Event Reporting 
7.2.1 Adverse Event Reporting from Site to Sponsor and MEC 
The collection of AEs will begin after the informed consent is signed. All AEs that occur through 
completion of the final follow-up visit, whether observed by the investigator or by the subject, and 
whether or not thought to be device related, will be reported in detail on the appropriate CRF and 
followed to resolution or the end of trial participation. 
The description of the AE will include the date and time of onset, seriousness, relationship to the 
device or procedure, the results of any diagnostic procedures or laboratory tests, any treatment 
recommended, and the outcome of the event.  In the circumstance that an AE has not resolved by 
the time of the subject’s completion of the trial, an explanation will be entered on the appropriate 
CRF. 
ZOLL will implement and maintain a system to ensure that the reporting of the reportable events 
by the investigator to ZOLL occur immediately, but no later than 3 calendar days after 
investigational site study personnel awareness of the event. 
7.2.2 Serious Adverse Event Reporting to Sponsor and MEC 
Serious adverse events (SAEs) and device deficiencies should be reported as soon as possible. 
Serious adverse events and device deficiencies must be reported no later than 3 calendar days from 
the site becoming aware of the event or as per the investigative site’s local requirements if the 
requirement is more stringent than those outlined. 
The date the site staff became aware of the SAE must be recorded in the source document. The 
Investigator will further report the event to the IRB/EC according to the institution’s IRB/EC 
reporting requirements. 
Serious adverse events that do not occur in the study subject but occur in the user or other persons 
need to be reported on the fax notification form titled SAE Notification Form. Serious adverse 
events that occur in the user or other persons other than the study subject should not be entered 
into the clinical database. 

 
 
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Serious adverse events should be reported on the SAE Notification Form in the occurrence that 
the clinical database is not available. This does not replace the electronic clinical database. All 
information must still be entered in the clinical database once the system is back to normal 
function. 
7.2.3 UADE/USADE Reporting to Sponsor and MEC 
ZOLL requires the Investigator to report any USADE to the sponsor within 3 calendar days of the 
investigator’s knowledge of the event and to the EC per EC requirements. 
7.2.4 Sponsor Reporting to NCAs (National Competent Authority) when European 
Sites Participate in the Trial 
7.2.4.1 What to Report 
The following events are considered reportable events: 
• any SAE, 
• any Device Deficiency that might have led to a SAE if: 
o suitable action had not been taken or 
o intervention had not been made or 
o if circumstances had been less fortunate 
• new findings/updates in relation to already reported events. 
7.2.4.2 Report to Whom 
Reportable events must be reported at the same time to all NCAs where the clinical investigation 
has commenced using the summary tabulation featured in the of MEDDEV 2.7/3. 
7.2.4.3 Reporting Timelines 
ZOLL must report to the NCAs where the clinical investigation has commenced: 
- for all reportable events as described in section 7.2.4.1 which indicate an imminent risk of death, 
serious injury, or serious illness and that requires prompt remedial action for other 
patients/subjects, users or other persons or a new finding to it: immediately, but not later than 2 
calendar days after awareness by ZOLL of a new reportable event or of new information in relation 
with an already reported event. 
- any other reportable events as described in section 7.2.4.1 or a new finding/update to it: 
immediately, but not later than 7 calendar days following the date of awareness by the ZOLL of 
the new reportable event or of new information in relation with an already reported event. 

 
 
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Device Relationship 
Determination of whether there is a reasonable possibility that an investigational product or device 
caused or contributed to an AE is to be determined by the Investigator and recorded on the 
appropriate CRF form. Determination should be based on assessment of temporal relationships, 
biologic plausibility, association (or lack of association) with underlying disease and presence (or 
absence) of a more likely cause. 
7.3.1.1 Causality Assessment 
The relationship between the use of the medical device (including the medical - surgical procedure) 
and the occurrence of each adverse event shall be assessed and categorized. 
The above considerations apply also to the serious adverse events occurring in the comparison 
group. 
The following definitions are used to assess the relationship of the serious adverse event to the 
investigational medical device or procedures. 
1) Not related: relationship to the device or procedures can be excluded when: 
• the event is not a known side effect of the product category the device belongs to or of 
similar devices and procedures; 
• the event has no temporal relationship with the use of the investigational device or the 
procedures; 
• the serious event does not follow a known response pattern to the medical device (if the 
response pattern is previously known) and is biologically implausible; 
• the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible – and reintroduction of its use (or increase 
of the level of activation/exposure), do not impact on the serious event; 
• the event involves a body-site or an organ not expected to be affected by the device or 
procedure; 
• the serious event can be attributed to another cause (e.g. an underlying or concurrent 
illness/ clinical condition, an effect of another device, drug, treatment or other risk factors); 
• the event does not depend on a false result given by the investigational device used for 
diagnosis, when applicable; 
• harms to the subject are not clearly due to use error; 
• In order to establish the non-relatedness, not all the criteria listed above might be met at 
the same time, depending on the type of device/procedures and the serious event. 
2) Unlikely: the relationship with the use of the device seems not relevant and/or the event can be 
reasonably explained by another cause, but additional information may be obtained. 

 
 
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3) Possible the relationship with the use of the investigational device is weak but cannot be ruled 
out completely. Alternative causes are also possible (e.g. an underlying or concurrent illness/ 
clinical condition or/and an effect of another device, drug or treatment). Cases were relatedness 
cannot be assessed or no information has been obtained should also be classified as possible. 
4) Probable the relationship with the use of the investigational device seems relevant and/or the 
event cannot reasonably explained by another cause, but additional information may be obtained. 
5) Causal relationship: the serious event is associated with the investigational device or with 
procedures beyond reasonable doubt when: 
• the event is a known side effect of the product category the device belongs to or of similar 
devices and procedures; 
• the event has a temporal relationship with investigational device use/application or 
procedures; 
• the event involves a body-site or organ that 
• the investigational device or procedures are applied to; 
• the investigational device or procedures have an effect on; 
• the serious event follows a known response pattern to the medical device (if the response 
pattern is previously known); 
• the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible); 
• other possible causes (e.g. an underlying or concurrent illness/ clinical condition or/and an 
effect of another device, drug or treatment) have been adequately ruled out; 
• harm to the subject is due to error in use; 
• the event depends on a false result given by the investigational device used for diagnosis 
17, when applicable; 
• In order to establish the relatedness, not all the criteria listed above might be met at the 
same time, depending on the type of device/procedures and the serious event. 
ZOLL and the investigators will distinguish between the serious adverse events related to the 
investigational device and those related to the procedures (any procedure specific to the clinical 
investigation). An adverse event can be related both to procedures and the investigational device. 
Complications of procedures are considered not related if the said procedures would have been 
applied to the patients also in the absence of investigational device use or application. 
In some particular cases the event may be not adequately assessed because information is 
insufficient or contradictory or the data cannot be verified or supplemented. The ZOLL and the 

 
 
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Investigators will make the maximum effort to define and categorize the event and avoid these 
situations. 
Particular attention shall be given to the causality evaluation of unanticipated serious adverse 
(device) events. The occurrence of unanticipated events related to the use of the device (USADE) 
could suggest that the clinical investigation places subjects at increased risk of harm than was to 
be expected beforehand. 
8 
MONITORING BY DATA MONITORING COMMITTEE 
The Data Monitoring Committee (DMC) is used to ensure safety by reviewing cumulative data 
from the clinical trial at pre-defined intervals for the purpose of safe-guarding the interest of trial 
participants. The DMC will serve in an advisory role in this trial. The composition, guiding 
policies, and operating procedures governing the DMC are described in a separate DMC charter. 
Based on safety data, the DMC may recommend a modification to the protocol or that the sponsor 
stops the clinical trial/investigation. All final decisions regarding clinical trial/investigation 
modifications, however, rest with the Sponsor. 
9 
ADJUDICATION OF EVENTS 
The Clinical Events Committee (CEC) is comprised of qualified physicians who are not 
investigators in the trial. The Clinical Events Committee is responsible for adjudicating specified 
clinical endpoints based on the specific criteria used for the categorization of clinical events in the 
trial. 
Periprocedural MI will be adjudicated according to the Clinically Relevant Myocardial Infarction 
After Coronary Revascularization (CRMI) definition.40 Death, Stent Thrombosis, Spontaneous 
MI, and Revascularization will be adjudicated per ARC definitions.27 
Hospitalization due to Heart Failure will be adjudicated per ACC/AHA definition.48 
The composition, guiding policies, and operating procedures governing the CEC are described in 
a separate CEC Manual of Operations. 
When applicable, sites will provide patients’ source documentation per request from the Sponsor 
and will aploade angiograms into AMBRA website through software service Dicom Grid, Inc., 
which will de-identify angiograms. 

 
 
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10 RECOMMENDATION FOR DAPT AND STENTS 
Control and intervention group patients should receive dual antiplatelet therapy (DAPT) and 
anticoagulation medication as recommended by the ESC Guideline for the management of acute 
myocardial infarction in patients presenting with ST-segment elevation. 
• This includes aspirin 162 or 325 mg po chewed as soon as feasible. 
• This should be followed by loading dose of ticagrelor (preferably crushed or chewed) 180 
mg before PCI. If ticagrelor not available, loading dose of prasugrel (60 mg) can be used. 
o Clopidogrel can be used only if the patient cannot take ticagrelor or prasugrel. 
• This also includes unfractionated heparin (UFH) given as an intravenous bolus as soon as 
feasible with subsequent boluses targeted to an activated clotting time of 200 to 250 
seconds. If Bivalirudin is used, the infusion should continue for 1-2 hours after PCI is 
finished. 
• Use of an intravenous GP IIb/IIIa inhibitor should be used according to the decision of 
interventional cardiologist. 
• In patients with STEMI in whom clopidogrel was initiated before coronary angiography, 
it is recommended to switch to either ticagrelor or prasugrel before, or during, or at latest 
immediately after PCI, if ticagrelor or prasugrel are not contraindicated. 
o Switching from clopidogrel to ticagrelor or prasugrel should include a loading dose 
of ticagrelor 180 mg (preferably crushed or chewed if before or during PCI) or 
prasugrel 60 mg if the patient is not at high risk of bleeding, irrespective of the prior 
dose of clopidogrel. 
• Recommended maintenance therapy consists of aspirin 81 mg once daily (or per local 
practice); ticagrelor 90 mg twice daily for at least 12 months. If ticagrelor not available, 
prasugrel 5 or 10 mg according to label recommendation can be used. 
• If needed, transition to clopidogrel can take place after 30 days post index PCI. 
o The recommended first dose of clopidogrel is 600 mg po 12 h after the last dose of 
ticagrelor or prasugrel. If maintenance therapy consists of aspirin and clopidogrel, 
the recommended doses are aspirin 81 mg once daily (or per local practice) and 
clopidogrel 75 mg once daily. 
• Use second or third generation DES. Do not use BMS or BVS or BRS such as Absorb in 
study patients. 

 
 
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11 RISK ANALYSIS 
 Risk Assessment Process 
 
ZOLL has a documented EN ISO 14971:2012 compliant Risk Management process, which 
includes the identification of risks, risk assessment, identification, implementation and verification 
of adequate controls (mitigations) to ensure that identified risks have been reduced as low as 
possible and to ensure the benefits of the intended use as compared to any residual risk is 
acceptable. 
The intent of the Risk Management process is to identify potential hazardous situations related to 
the design, manufacture, and use of the Proteus IVTM System, evaluate each risk and implement 
controls to reduce the risks as low as possible. 
Risks related to the IVTM System and Sub-Systems (Console, Catheter, Cassette and Temperature 
Probe) have been evaluated in a number of ways: 
• Hazard Analysis – The purpose of the Hazards Analysis is to identify, evaluate 
and control potential hazards to the patient, user and the environment. 
• Software Hazards Analysis - The Software Hazards Analysis is used to 
investigate potential device Software related hazards and control the potential 
hazards.  
• Design FMECA - The purpose of the Design FMECA is to evaluate failure modes 
of the device components, or subsystems, to identify potential design failure risk, 
then evaluate and control potential hazards. 
• Process FMECA - The purpose of the Process FMECA is to evaluate failure 
modes of the device manufacturing process steps to identify process failure risks, 
then evaluate and control potential hazards. 
The results of the Proteus IVTM System Risk Management process was reviewed, and concluded 
that the risk controls are effective to reduce the risks as low as possible. The ZOLL Proteus IVTM 
System presents an acceptable risk benefit ratio when used in accordance with its labeling for its 
proposed intended use: The Proteus IVTM System is intended for use in adult subjects with acute 
anterior myocardial infarction to induce and maintain hypothermia prior to percutaneous coronary 
intervention as an adjunctive therapy to reduce anterior infarct size.  

 
 
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Note: See the Investigator Brochure for additional information on the Proteus IVTM System, as 
applicable. 
 Expected Clinical Observations 
In subjects who have been treated for myocardial infarction, there are many sequelae of such an 
event that may be thought to be “normal” effects and not due to the treatment provided.  These 
events may be outside the range of what is considered to be “normal” (e.g., a high lab value such 
as a shift in potassium), but do not put the patient at risk for harm.  These events are therefore 
expected physiological responses to treatment with therapeutic hypothermia in all patients.  
Prospectively, these observations may include but are not limited to the following: 
• Shift in Potassium levels 
• High or low levels of glucose 
 
The expected clinical sequelae of patients treated with hypothermia include, but are not limited 
to, the following28: 
• Shivering 
• Prolonged ECG intervals 
• Bradycardia defined as a heart rate of 40 beats per minute and not requiring treatment 
(e.g., pacemaker, medications, etc.) 
• J wave (also called Osborne wave) can occur at any temperature < 32.3°C 
• Blood electrolyte shifts: Calcium, Phosphorus, Magnesium, Chloride 
• High or low levels of glucose: Decreased insulin sensitivity and insulin secretion 
• Asymptomatic shifts in serum amylase and lipase levels 
• Peripheral pulses may be difficult to detect 
Cold Diuresis: Increased resistance to ADH or Vasopressin resulting in decreased water or solute 
reabsorption. 
 Potential Clinical Risks 
Adverse events that are inherent to a PCI procedure and expected to occur in most subjects for a 
projected duration according to the opinion of the investigator may be considered unavoidable.  
Such events include, but are not limited to, those listed in Table 14.  These adverse events should 
not be reported during this trial. 
Table 14 Expected and unavoidable adverse events related to the PCI procedure 
Description of the Event 
Time Frame from the Index Procedure (PCI) 
Back pain related to laying on Cath lab table 
Within 48 hours 
Peripheral vasoconstriction  
Within 24 hours 

 
 
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Thermal discomfort  
Within 24 hours 
Incisional pain (pain at access site) 
Within 72 hours 
Sleep problems or insomnia 
Within 72 hours 
Mild to moderate bruising or ecchymosis 
Within 168 hours 
 
A list of potential (expected) risks that may be associated with use of the Proteus IVTM System is 
provided below.  Since this clinical study utilizes an investigational device, all risks may not be 
known.   However, they are believed to be similar to those associated with the existing intra-
vascular temperature management devices in clinical use or commercially available. 
The following potential adverse events may occur during the course of the clinical trial. 
11.3.1 Potential Adverse Events associated with the Proteus Catheter and Cooling 
System: 
Potential risks related to the Proteus Catheter are reasonably believed to be consistent with the 
common, known risks of central venous catheters and/or venous introducer sheaths.  Potential risks 
related to cooling, re-warming, and/or the Proteus IVTM System include but are not limited to the 
following: 
• Catheter related injury [embolism (air, thrombus, catheter fragment), clinically significant 
hematoma, vascular perforation or dissection, arteriovenous fistula, nerve injury, 
excessive bleeding, pseudoaneurysm] 
• Deep vein thrombosis (DVT) requiring treatment 
• Infection [local or systemic (pneumonia, sepsis, meningitis, visceral organ)] 
11.3.2 Potential Adverse Events associated with the cooling procedure include but 
are not limited to the following:   
• Acute renal failure  
• Acute renal insufficiency 
• Adverse drug reaction 
• Angina 
• Blood lysis 
• Congestive Heart Failure  
• Clinically relevant shivering (BSAS ≥ 2) that cannot be controlled by the antishivering 
medication regimen 

 
 
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• Dysrhythmia [ventricular tachycardia, ventricular fibrillation or atrial fibrillation 
requiring intervention, bradycardia (HR ≤ 40 bpm, block)] 
• Hyperglycemia / Hypoglycemia 
• Hyperkalemia / Hypokalemia 
• Hyperphosphatemia / Hypophosphatemia 
• Hypotension  
• Infection (local, systemic) 
• Liver Failure 
• Myocardial infarction 
• Multi-system organ failure 
• Overcooling (temperature <31.0°C for ≥ 20 continuous minutes) 
• Overwarming (temperature >38°C for ≥ 20 continuous minutes including dehydration, 
burns and neurological damage) 
• Pancreatitis 
• Pulmonary edema  
• Peripheral vascular insufficiency  
• Thrombocytopenia 
• Rebound hyperthermia 
• Respiratory failure during cooling or rewarming 
• Seizures 
• Stroke [Cerebral vascular Accident (CVA)] 
• Transient Ischemic Attack (TIA) 
• Unstable angina 
11.3.3 Risks Associated with Anti-shivering Medications 
In order to preserve patient comfort and suppress the shivering response during cooling, a 
combination of recommended buspirone, where available (or equivalent alternative) and required 
Pethidine (Meperidine) should be used (see Attachment II).  As identified in their labeling, the 
risks associated with the use of these pharmacologic agents in this trial population include the 
following:  
Buspirone (or equivalent alternative) 
• Interaction with MAO Inhibitors  
• Dizziness  
• Nausea  
• Headache  

 
 
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• Nervousness  
• Lightheadedness  
• Excitement 
 
Pethidine (Meperidine) 
• CNS Depression  
• Hypotension  
• Respiratory Depression  
• Circulatory Depression  
• Respiratory Arrest  
• Shock  
• Cardiac Arrest 
 
Other reported reactions:  
• Lightheadedness  
• Dizziness  
• Nausea  
• Vomiting  
• Sweating 
 Additional investigations due to the trial 
Participation in the clinical trial will involve extra blood sampling for laboratory markers 
(electrolytes, complete blood count, baseline and peak troponin including upper limit of normal), 
additional ECGs and the need for cardiac MRI imaging.  All of these are standard clinical 
procedures, and the risks to participants are low.  Sites will be carefully monitored for adherence 
to the protocol.  Patients will be screened for appropriateness for MRI prior to enrollment. 
11.4.1 Delay in PCI through the use of hypothermia therapy 
The probability for potential delay in PCI is considered Occasional.  In prior trials of hypothermia 
for STEMI, the increase in door to balloon time ranged from 9 minutes to 18 minutes.  It is 
noteworthy that this delay was not associated with an increase in infarct size hypothermia patients 
compared to controls.  In fact, patients with anterior STEMI with < 35°C at the time of reperfusion 
showed smaller infart size.  Sites will be trained to incorporate hypothermia into the cath lab 
workflow while minimizing delay.  Feedback will be provided for each case to help maintain 
efficiency. 

 
 
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11.4.2 Implementation of PCI in patients undergoing hypothermia (patient-related 
risks). 
Potential risks related to the use of hypothermia therapy in patients are outlined in sections  11.2.1 
and 11.2.2 above. These risks include: potential adverse events associated with the Proteus 
Catheter and Cooling System, potential adverse events associated with cooling, and potential risks 
associated with the anti-shivering medications. 
11.4.3 Implementation of PCI with concurrent use of endovascular hypothermia. 
The addition of hypothermia as adjunctive treatment of STEMI will potentially lead to more 
difficult conditions for the Investigator and other users.  The ability to integrate hypothermia into 
the cath lab workflow has been demonstrated successfully in prior clinical trials.  Again, thorough 
training, frequent monitoring, and rapid feedback will help mitigate the challenges of incorporating 
hypothermia into treatment for STEMI. 
11.4.4 The concurrent medication. 
Patients who have received medications such as monoamine oxidase inhibitor within a 14 day 
period will be excluded from the trial to prevent potential interaction with the anti-shivering 
medications.  In patients that receive morphine prior to arrival to the hospital, the pethidine dose 
will be lowered to decrease the likelihood of respiratory depression. 
11.4.5 The supply of 4°C cooled saline solution 
The amount of cooled saline solution is limited to 1,000 ml, an amount shown to be well tolerated 
in the CHILL-MI trial, where the average amount of cooled saline was 1475 ml.  Again, careful 
training and monitoring will help to avoid unnecessary exposure to larger volumes of saline. 
11.4.6 Other procedures within the clinical trial 
The risk of adverse interaction or influence of other procedures within the clinical trial are deemed 
to be low.  In prior hypothermia trials in STEMI, there was no interference with the stenting 
procedure, with resuscitation efforts for arrhythmias or cardiogenic shock.  Hypothermia does 
inhibit the absorption and metabolism of clopidogrel, a anti-platelet inhibitor, given to reduce the 
risk of stent thrombosis.  This risk will be mitigated by calling for adherence to ESC guidelines 
which recommend either prasugrel or ticagrelor, both of which are less affected by hypothermia. 

 
 
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 Potential Clinical Benefits 
Although no assurances or guarantees can be made, there is a reasonable expectation that the use 
of this investigational device is safe within the context of the trial and may be beneficial.  Cooling 
using the device, for instance, may result in improved temperature control relative to the standard 
techniques already in use at the sites. 
The primary benefits of therapeutic hypothermia have been shown to be:  
• Improved patient survival 
• Improved heart tissue salvage after the ischemic event 
Additional potential benefits of therapeutic hypothermia with the Proteus System may include: 
• Faster cooling 
• More accurate control of the cooling procedure than with surface cooling 
• Further improved survival  
There is no guarantee that participation in this trial or use of hypothermia will benefit the trial 
subject.  However, collection of such trial data may provide added benefit for future myocardial 
infarction subjects. 
 Methods to Minimize Risk 
All efforts will be made to minimize risks by selecting investigators who are experienced and 
skilled in using minimally invasive catheter-based cardiovascular interventions and who have been 
adequately trained.  Also, risk minimization activities were performed during development and 
design verification tests of the device.  Activities intended to minimize risks include the following. 
• Investigator and trial personnel training will be conducted to share information regarding 
the design of the Proteus IVTM System, its application, pre-clinical results, and clinical 
trials on comparable intra-vascular cooling devices. 
• Adherence to eligibility criteria and screening procedures will ensure that appropriate 
patients are enrolled.   
• Adherence to the Proteus IVTM System Instructions for Use packaged with the device.  
• 
Corrective and preventative actions will be implemented by ZOLL, as necessary, if 
deviations from recommendations in the protocol or IFU are observed.  
• 
Clinical support by ZOLL representative will be provided during the enrollment in the 
study and thereafter if needed.  ZOLL representatives will only have advisory role.  
• The subjects will be carefully monitored throughout the trial period.   
• The investigator will evaluate the subject adverse events during the course of the trial. 
• Data submitted from the investigative centers will be monitored during the course of the 
trial.   

 
 
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• Monitoring visits will be conducted to evaluate protocol compliance and data quality. 
• Safety and effectiveness data obtained during the course of the trial will be shared with 
investigators in periodic reports to increase understanding of the device and potential 
adverse events. 
• An independent Data Safety Monitoring Board (DSMB) will monitor safety throughout the 
clinical trial. Stopping rules will be discussed with the DSMB and applied for subject safety 
through enrollment. 
 
Detailed trial procedures are provided in Section 6.8 - Clinical Trial Procedures. 
 Risk – Benefit Assessment 
To date, there have been five clinical trials that have reported on the safety and effectiveness of 
therapeutic hypothermia in AMI and one in Radio-Contrast nephropathy (COOL-RCN Trial), with 
a total of more than eleven hundred patients being enrolled in total with at least half of those treated 
with therapeutic hypothermia.  The rate of adverse events are well reported in these populations 
(see section 5, Prior Investigations), and the risks are clearly categorized for these trials.  In 
summary, the number of trials, patients enrolled, and low numbers of safety events reported 
indicate that therapeutic hypothermia in this patient population is at an acceptable risk level to 
engage in this trial. 
There is significant morbidity and mortality associated with the numerous clinical conditions 
outlined in this report, and therapeutic hypothermia has shown promise to greatly improve clinical 
outcomes in these patients.  In particular, patients with anterior STEMI have a higher incidence of 
congestive heart failure, cardiogenic shock, and cardiac mortality.  A significant reduction in 
infarct size in these patients, with therapeutic hypothermia, has the promise to reduce these adverse 
clinical outcomes.  Risks associated with the use of the Proteus IVTM system have been reduced 
via the Risk Management Process, and are deemed acceptable, considering the potential benefits.  
We conclude that the use of the Proteus IVTM system for medical practice is justified and 
warranted. 
 
Risk assessment of the Proteus IVTM System has been performed in accordance with the ISO 
14971:2012.30  The Proteus IVTM System is safe and presents an acceptable risk benefit ratio to 
provide cooling or warming of patients when: 
• Used by and under the supervision of a qualified medical practitioner 
• In patients for whom the risks of a central line are acceptable 

 
 
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• In intensive care environments equipped to handle clinical conditions warranting 
use of the device under this protocol 
• Used according to the Instructions For Use (IFU) 
12 RECORDS AND REPORTS 
Throughout the course of this clinical trial, ZOLL, the investigators, and reviewing MEC are 
responsible for the records and reports detailed in the following sections.  
 Investigator Records 
Investigators must retain all trial records required by ZOLL and by the applicable regulations in a 
secure and safe facility.  The investigator must consult a ZOLL representative before disposal of 
any trial records and must notify ZOLL of any change in the location, disposition, or custody of 
the trial files. 
Trial records are those that individually and collectively permit evaluation of the conduct of the 
trial and the quality of the data produced.  ZOLL’s SOP requires that all clinical trial data be kept 
for a minimum of 15 years and all data used in submissions be kept for the life of the corporation.  
It is the site’s obligation to inform ZOLL if their own policy does not comply with the sponsor’s 
requirement so necessary arrangements can be negotiated.  It is ZOLL’s responsibility to inform 
the investigator/institution as to when these documents no longer need to be retained. 
The investigator is responsible for the preparation (review and signature) and retention of the 
records cited below. 
• All correspondence with another investigator, MEC, ZOLL, a monitor, or FDA, including 
required reports and trial documents which pertain to the investigation. 
• Records of receipt, use, and final disposition of a device.    
• Records of each subject's case history and exposure to the device.  Case histories include 
the Case Report Forms (CRFs) and supporting source data (signed and dated informed 
consent forms, medical records, e.g., progress notes of the physician, patient’s hospital 
chart, nursing notes).   
• The clinical investigational plan, with documents showing the dates of and reasons for each 
deviation from the protocol.  
• Any other records that are required to be maintained by local regulations or by specific 
regulatory requirements for a category of investigations or a particular investigation. 
• Any other record that the reviewing MEC requires to be maintained for the subject 
investigation. 

 
 
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 Investigator Responsibilities 
The participating investigator is responsible for adhering to this Clinical Investigational Plan 
(CIP), FDA CFR,  ISO 14155 and Declaration of Helsinki  (Regulatory requirements of his/her 
country local law). 
Specifically, the Principal Investigator at each site shall: 
a) indicate his/her acceptance of the CIP in writing, 
b) conduct the clinical investigation in compliance with the CIP, 
c) create and maintain source documents throughout the clinical investigation and make 
them available as requested during monitoring visits or audits, 
d) ensure that the investigational device is used solely by authorized users as specified in 
6.2, and in accordance with the CIP and instructions for use, 
e) propose to the sponsor any appropriate modification(s) of the CIP or investigational 
device or of the use of the investigational device, 
f) refrain from implementing any modifications to the CIP without agreement from the 
sponsor, EC and regulatory authorities, if required, 
g) document and explain any deviation from the approved CIP that occurred during the 
course of the clinical investigation, 
h) ensure that an adequate investigation site team and facilities exist and are maintained 
and documented during the clinical investigation, 
i) ensure that maintenance and calibration of the equipment relevant for the assessment of 
the clinical investigation is appropriately performed and documented, where applicable, 
j) ensure the accuracy, completeness, legibility and timeliness of the data reported to the 
sponsor in the CRFs and in all required reports, 
k) maintain the device accountability records, 
l) allow and support the sponsor to perform monitoring and auditing activities, 
m) be accessible to the monitor and respond to questions during monitoring visits, 
n) allow and support regulatory authorities and the EC when performing auditing 
activities, 
o) ensure that all clinical-investigation-related records are retained as required by the 
applicable regulatory requirement(s), and 
p) sign the clinical investigation report, where applicable. 
 
The investigator is responsible for the preparation and submission of the reports cited in Table 15.  
Reports must be prepared in complete, accurate and timely manner.  These reports may be subject 
to regulatory inspection (and ZOLL) and copying, and the retention requirements described above 

 
 
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for Investigator Records.  In addition to the reports listed in Table 15, the reviewing MEC may 
request reports pertaining to any aspect of the clinical trial. 
Written approval from the Medical Ethics Committee (MEC) with authority for the participating 
site will be obtained prior to the start of the study. The investigator or if applicable, the Sponsor, 
is responsible for submitting all required documents to the MEC. At a minimum the following 
documents will be submitted: 
• Clinical Investigational Plan (CIP) 
• Patient Informed Consent documents in the local language 
• Any other written information to be provided to the subjects in the local language 
• Investigator Brochure (IB) (as required) 
• Other documents will be submitted as per local requirements 
After obtaining MEC approval, the investigator will submit the approval letter indicating the 
approved version of the CIP, Patient Informed Consent, IB and any other reviewed documentation 
to ZOLL. 
 
 

 
 
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Table 15 Investigator Reporting Responsibilities to Sponsor and MEC 
REPORT 
SUBMIT TO 
DESCRIPTION/CONSTRAINTS 
Withdrawal of 
MEC Approval 
Sponsor 
The investigator must report a withdrawal of the reviewing 
authority within 5 working days.  
Case Report Form  
(CRF)  
Sponsor & 
Monitor 
CRFs should be completed as soon as possible after any trial 
related procedure takes place. 
Deviation from 
Investigation Plan 
(Emergency) 
Sponsor & 
MEC 
Notification must be made within 5 working days if the 
deviation was made to protect the life or physical well-being of 
a subject. 
Deviation from 
Investigation Plan 
(Other – Non 
Emergency) 
Sponsor & 
MEC 
If the deviation may affect the scientific soundness of the plan 
or the rights, safety and welfare of the subjects (and is not an 
emergency), then the deviation must be approved by ZOLL, 
the MEC, and the reviewing authority prior to its 
implementation.  If the deviation does not affect these issues 
(trial soundness, rights, safety, etc.) then only ZOLL must 
approve it, (except in cases which are beyond the control of the 
investigator—see section on Protocol Deviations). 
Failure to Obtain 
Informed Consent 
Sponsor & 
MEC 
The Investigator must notify ZOLL and the reviewing authority 
within 5 working days after device use. The investigator must 
submit notification after device use or after the investigator 
first learns of the absence of informed consent. The report must 
include a brief description of the circumstances surrounding the 
failure to obtain informed consent and include written 
concurrence by a licensed physician not involved in the 
investigation. Failure to obtain informed consent must be 
reported to the MEC as required by local regulations. 
Final Report 
Sponsor & 
MEC 
This report must be submitted within 3 months after 
termination or completion of the investigation. 
 
 Sponsor Records  
All Sponsor documents and records shall be maintained as indicated by ZOLL’s Quality System. 
ZOLL will maintain the following trial -related records in accordance with ZOLL record retention 
policies and procedures following the completion of this investigational plan. Clinical data for 
regulatory submissions and publications will be retained for the life of the corporation. 
• All correspondence pertaining to the investigation with the sponsor, a monitor, an 
investigator, an MEC, regulatory agencies, including required reports.    

 
 
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• Records of shipment and disposition of the investigational device.  
• Signed investigator agreements including the financial disclosure information required to 
be collected and current signed and dated curriculum vitae.  
• Records of adverse events and device deficiencies.  
• List of participating institutions 
• Investigational product accountability reports including record of receipt, use, or 
disposition of the device(s) that relate to type, quantity, serial numbers of devices, and date 
of receipt, names of persons who received, used, or disposed of each device and why and 
how many devices have been returned to ZOLL or otherwise disposed 
• All signed and dated case report forms submitted by investigator, samples of patient 
informed consents, and other information provided to the subjects 
• Copies of all MEC approval letters and relevant MEC correspondence 
• Names and evidence of the institutions in which the clinical investigation will be conducted 
• Insurance certificates 
• Forms for reporting adverse events and device deficiencies  
• Names/contact addresses of monitors 
• Statistical analyses and underlying supporting data 
• Final report of the clinical investigation 
• The Clinical Investigational Plan, Clinical Monitoring Plan (CMP), Investigator Brochure 
(as applicable), and study related reports 
• Study training records for center personnel and ZOLL personnel participating in the trial 
• Any other records that MEC and /or competent authority requires to be maintained by 
regulation or by specific requirement for a category of investigation or a particular 
investigation. 
 Sponsor Reports 
ZOLL Circulation, Inc. is responsible for the classification and reporting of reportable adverse 
events and device deficiencies and ongoing safety evaluation of the clinical investigation in line 
with local regulatory requirements. 
ZOLL Circulation, Inc. will assure that all Serious Adverse Events and reportable Device 
Deficiencies are reported to the Competent Authorities in accordance with European Medical 
Devices directives and all applicable national regulations. 
ZOLL Circulation, Inc. is responsible for the reports cited in Table 16.  These reports are subject 
to regulatory retention and inspection requirements.  Governing Regulatory Agencies or the 
reviewing MEC may request reports pertaining to any aspect of the clinical trial. 

 
 
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Table 16:  ZOLL Reporting Responsibilities 
REPORT 
SUBMIT TO 
DESCRIPTION 
Unanticipated 
Adverse Device 
Effects; SAEs and 
Reportable DDs 
Relevant 
authorities and 
MECs 
Reporting timeframe as per local regulatory 
requirements. 
Investigators 
Notification throughout the course of the trial 
when appropriate (based on perceived risk) 
Premature 
termination or 
suspension of the 
Clinical 
investigation 
Investigators, 
MECs, Relevant 
Authorities 
Provide prompt notification of termination or 
suspension and reason(s). 
Subject 
enrollment 
Completed 
Investigators, 
MEC and 
Relevant 
regulatory 
Authorities upon 
request 
ZOLL will notify the investigators within 30 
working days of the completion of 
enrollment. Investigators will, in turn, inform 
their MECs, when required. 
Withdrawal of 
MEC approval 
Investigators, 
MECs 
Notification within five working days. 
Final Report 
Investigators, 
MECs, (and other 
relevant 
Authorities upon 
request) 
A final report will be submitted to 
investigators, and MECs within six months 
after completion or termination of this study. 
The investigators shall have the opportunity 
to review and comment on the final report. If 
a clinical investigator does not agree with the 
final report, his/her comments shall be 
communicated to the other investigators. The 
principal clinical investigator in each center 
shall sign the report. 
13 MONITORING AND AUDITING PROCEDURES 
 Clinical Trial Sponsor and Monitors 
ZOLL is the Sponsor of the clinical trial.  It is the responsibility of the sponsor to ensure that proper 
monitoring of the investigation is conducted.  Clinical trial monitoring and auditing will be done 

 
 
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by appropriately trained personnel appointed by the trial sponsor to ensure that the investigation 
is conducted in accordance with ZOLL’s requirements and applicable laws and regulations. 
A monitor is an individual designated by a sponsor or contract research organization to oversee 
the progress of an investigation.  The monitor may be an employee of a sponsor or a consultant to 
the sponsor, or an employee of or consultant to a contract research organization.  The monitor will 
be trained on the device, investigational plan, informed consent, instructions for use, applicable 
ZOLL procedures, electronic data capture system, and regulatory requirements.  The monitor will 
periodically check and report on the progress of the clinical trial at an investigational site or other 
data gathering organization or ZOLL facility.   
 Monitoring Methods 
Monitoring of the clinical trial will be a continuous, interactive process to ensure that high-quality 
data is obtained in compliance with the clinical investigational plan and regulatory requirements.  
Monitoring functions will be conducted by ZOLL, and/ or a contract research organization and/or 
other designees. Specific monitoring requirements are detailed in the Trial Monitoring Plan 
(maintained in the ZOLL COOL-AMI clinical trial project files).  Frequent communication will 
be maintained with each investigational site to keep both the clinical center and ZOLL up-to-date 
and aware of the trial progress.  Case Report Forms will be reviewed for completeness and 
accuracy.   
ZOLL will monitor sites in accordance with the monitor’s tasks set under Section 8.2.4 of Standard 
DIN EN ISO 14155:2012-01. These include visits to the clinical trial sites before the start of, 
during and at the end of the clinical trial. On-site monitoring of all trial centers will be frequent 
enough (at a minimum annually) to assure continued integrity and acceptability of the data.  
Accuracy of data reported on case report forms will be verified by comparison to source 
documents.  Reports of monitoring visits will be provided to the clinical trial personnel at each 
site.  Corrective action will be taken to resolve any issues of noncompliance.  If ZOLL finds that 
an investigator is not complying with the executed trial agreements, the investigational plan, the 
applicable national regulations, or the requirements of the reviewing MEC, then prompt action will 
be taken to secure compliance.  In addition, shipment of the device may be stopped or the 
participation of the investigator may be terminated.  Additional information is provided in Section 
6.30 – Trial Closure. 
 Monitoring Visits 
Scheduled visits to the clinical investigational site will occur at the following times:  prior to the 
start of the clinical trial (pre- trial qualification visit), at initiation of the trial (during first index 

 
 
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procedure or shortly thereafter), interim visits throughout the clinical trial as required, annually, 
and upon completion of the clinical trial. 
 Pre-trial Qualification Visit 
A pre- trial visit will be conducted by ZOLL personnel (or designees) to review the clinical 
investigational plan and regulatory requirements with the investigator and the trial personnel to 
assure that they:  
• Understand the investigational status of the device and the requirements for its use and 
accountability. 
• Understand the clinical investigational plan. 
• Understand the requirements for an adequate and well-controlled clinical trial. 
• Understand and accept the obligation to conduct the clinical investigation in accordance 
with the national regulations. 
• Understand and accept the obligation to obtain informed consent in accordance with the 
national regulations. 
• Understand and accept the obligation to obtain MEC approval before the clinical trial is 
initiated, ensure continuing review of the trial by the MEC, and keep ZOLL informed of 
MEC approval and actions concerning the clinical trial. 
• Have access to an adequate number of eligible patients to participate in the trial (at a 
minimum: 1 patient/center/month). 
• Have adequate facilities and resources to conduct the trial.  This includes resources 
appropriate for use of electronic data capture systems. 
• Have sufficient time from other obligations to carry out the responsibilities of the clinical 
trial. 
• Sign the Investigator Agreement and trial contracts (prior to enrollment of patients). 
A report of the pre- trial qualification visit will be completed.  Resolution of any concerns or 
completion of any appropriate follow-up activities stemming from the pre- trial visit also will be 
documented. 
 Initiation Visit 
ZOLL clinical personnel (or designees) will provide assistance for both technical concerns and 
trial management issues during the initiation visit.  Enrollment of the first patient at each clinical 
site may or may not coincide with this visit.  Any observations will be documented and issues 
requiring follow-up will be identified on a monitoring report.  Training of trial personnel also will 
be documented. 

 
 
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 On-Site Interim Monitoring Visits 
On-site monitoring visits will be made on an as-required basis (and at least annually) to assess 
adherence to the clinical investigation plan, MEC review of trial progress, maintenance of records 
and reports, and selected review of source documents for accuracy, completeness, legibility, and 
omissions.  The monitors will acquire information to assess the progress of the trial (toward 
meeting trial objective) and identify any concerns that stem from observation of device 
performance and/or review of the investigator's patient records, trial management documents, and 
patient informed consent documents.  Monitoring reports will be generated along with 
communications to the investigator, which document the result of the monitoring visit and any 
recommended actions.  Resolution of concerns and completion of assigned tasks will be 
documented. 
 Audits 
An on-site audit may be completed periodically throughout the trial at each clinical site by an 
independent group.  The purpose of the audit will be to ensure compliance to the investigational 
plan and regulatory requirements, e.g., written informed consent was documented, information 
recorded on the case report forms is complete and accurate as compared to source documentation, 
protocol deviations are noted, and device accountability is accurate and complete.  A randomly 
selected number of patient records and other supporting documents will be compared to the case 
report forms.  A record of the findings and recommended actions to correct deficiencies will be 
documented on the audit report. 
 Final Monitoring Review 
Depending upon the status of the trial at each center, a close-out or final visit may be conducted.  
Any ongoing responsibilities will be discussed with the investigator and the trial center 
coordinator.  A final monitoring report, which includes, at a minimum, disposition of any unused 
devices, will be completed. 
14 DATA MANAGEMENT PROCEDURES 
 
ZOLL will oversee all data management functions.  ZOLL will be responsible for database 
development, system maintenance, user training, data queries, and report generation. 

 
 
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 Case Report Forms 
ZOLL will use an electronic data capture (EDC) system to collect patient data.  The electronic case 
report forms (eCRFs) are the primary component of EDC and are based on the sample forms that 
will be provided in a separate document.  Training on use of the system will be provided to the 
trial site personnel.  Instructions for completion of the eCRFs also will be provided. 
The eCRFs must be completed, saved, and locked via electronic signature by the Investigator using 
a unique ID and password.  This ID and password are for the use of the investigator only and may 
not be used by any other person.  Because of the potential for errors or inaccuracies in transcribing 
data into eCRFs, source documentation must be maintained in each subject’s hospital chart and/or 
electronic medical record.  The eCRFs and source documentation must be available at all times for 
inspection by the trial monitors or regulatory inspectors. 
Changes made to eCRFs will be electronically recorded in a complete audit trail that cannot be 
changed, but can be accessed by authorized personnel at any time.  All data are transmitted via the 
Internet in an encrypted fashion.  When received at the server site, the data are decrypted and 
stored.  Data can be extracted for ZOLL review and analysis at any time. 
 Source Documentation 
Regulations require that an investigator maintain information in the trial subject’s medical records 
to corroborate data collected on the eCRF.  To comply with these regulatory requirements, the 
following information will be maintained and made available as required by ZOLL and/or its 
designees and/or regulatory inspectors.  Shadow charts are not appropriate or adequate source 
documentation.  Complete medical (clinical and hospital) records include the following 
documentation.   
• Medical history/physical condition of the patient before involvement in the trial sufficient 
to verify clinical protocol eligibility criteria. 
• Description of cooling procedure (material used, drugs administered during the procedure, 
device identification information and disposition, date, time, angiographic and clinical 
findings, etc.).  
• Electronic data downloaded from the ZOLL Proteus IVTM System. 
• Signed notes in the subject’s medical record on the enrollment day that identify and 
include:  the subject’s date of enrollment, procedure date, the trial sponsor (ZOLL), clinical 
site name, the subject-assigned identification number, the subject- assigned enrollment 
number, and documentation and confirmation that the appropriate informed consent was 
obtained. 
• Dated and signed notes for each subject’s trial visit. 

 
 
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• Lab results.   
• Baseline ECG, angiogram, and MRI reports, etc.   
• Dated printouts or reports of special assessments (ECG baseline report, imaging report, 
etc.). 
• Adverse event reporting and follow-up of the adverse events.  Information in the medical 
chart should include at a minimum the following:  event description, severity, seriousness, 
onset date, date site became aware of event, duration, relation to trial device, treatment, 
and outcome of the adverse event. 
• Trial subject’s condition upon completion of or withdrawal from the trial. 
• Trial subject’s medical status, including all SAEs out to 1 year following trial enrollment. 
• All notes related to trial subject’s KCCQ and the New York Heart Association Functional 
Class questionnaires. 
 Transmission of Data 
Required data will be recorded on the appropriate eCRF at the time of or as soon as possible after 
the patient visit.  The eCRFs and any requested supporting source documents must be sent to ZOLL 
and/or retrieved from the investigator during monitoring visits.  Questions about completion of the 
eCRFs may be directed to the ZOLL COOL AMI clinical team at Clin-safety@zoll.com 
 Data Queries  
During monitoring visits, the Monitor will perform a 100% review of all variables, i.e., 
demography, inclusion/exclusion criteria, safety, effectiveness, on the eCRFs with each subject’s 
source documents. Any discrepancies will be queried by ZOLL or its designee and must be 
resolved by the investigational site staff and investigator in a timely manner.  Queries also will be 
generated by ZOLL data management personnel during routine review of the data on the electronic 
data capture system. 
15 STATISTICAL ANALYSIS PLAN 
The objective of this trial is to evaluate the safety and effectiveness of therapeutic hypothermia, 
using the ZOLL Proteus IVTM System, as an adjunctive therapy for patients presenting with acute 
anterior myocardial infarction (AMI) and undergoing percutaneous coronary intervention (PCI). 
An analysis summarizing outcomes for the Primary Effectiveness Endpoint and the Primary Safety 
Endpoint will be created after the last randomized subject has completed the 30 day follow-up 
interval. The results of the primary endpoints will be summarized in the final clinical study report. 
Two interim analyses are planned to be performed at approximately 50% and 75% of 
randomization, once subjects have completed 4-6 day cMR follow-up. At the interim stage, the 

 
 
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trial will be stopped to reject the null hypothesis of no difference or continue enrolling. Another 
report will be issued summarizing all endpoints after all subjects have completed 12 month 
follow-up.  
 
 Data Analysis 
Analysis Data Sets 
The Intention-to-Treat (ITT) analysis set will be used for primary statistical analyses and 
summaries. The ITT population includes subjects who have signed an informed consent and have 
been randomized to the Test Arm or the Control Arm of the trial. ITT subjects will be evaluated 
according to the group to which they were randomized. 
The Per-Protocol (PP) analysis set will also be evaluated. The PP population includes those 
subjects who met inclusion and exclusion criteria, were randomized to either the Test or Control 
arm, received the treatment to which they were randomized, and complied substantially with the 
treatment timeline and steps of this protocol without major protocol violations. 
The Safety Analysis Set will be used to evaluate safety endpoints. These will be all of the subjects 
included in the study as defined by the ITT analysis set and will include Roll-In subjects. For the 
safety analysis, subjects will be followed for all adverse events for 30 days post procedure. 
Additionally, all subjects will be followed for 12 months for the incidence of Serious Adverse 
Events (SAEs), Death and Heart Failure (as assessed by NYHA and Kansas City Cardiomyopathy 
Questionnaire (KCCQ)). 
Infarction Size (IS) is defined as % Left Ventricular Mass as measured by Cardiac Magnetic 
Resonance (cMR) imaging. Infarct Size (IS) will be assessed by Cardiac Magnetic Resonance 
(cMR) at 4 – 6 days following the index procedure. Infarct Size will be assessed in subjects in the 
ITT analysis set and also in the Per-Protocol analysis set. 
 
The Safety Analysis Set will be used to evaluate safety endpoints. These will be all of the subjects 
included in the study as defined by the ITT analysis set and will include the following clinical 
components evaluated at 30 day follow-up visit (30 day ± 7 days): 
Secondary Endpoint Analysis: 
The following clinical components of MACE will be evaluated at 30 day follow-up visit (30 day 
± 7 days): 

 
 
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o Death (Cardiac, Vascular, Non-Cardiovascular) 
o Myocardial Infarction (MI) 
 Attributable to target vessel (TV-MI) 
 Not attributable to target vessel (NTV-MI) 
o Target Lesion Revascularization (TLR) 
 Clinically-indicated TLR (CI-TLR) 
 Not clinically-indicated TLR (NCI-TLR) 
o Target Vessel Revascularization (TVR non TLR,) 
 Clinically-indicated TVR non TLR 
 Not clinically-indicated TVR non TLR 
o Non-Target Vessel Revascularization (NTVR,) 
 Clinically-indicated NTVR 
 Not clinically-indicated NTVR 
o All coronary revascularization 
In addition, Stent Thrombosis will be evaluated at 30 day follow-up visit (30 day ± 7 days): 
 Evidence (Definite and Probable) 
 
 Timing (Acute, Sub-acute) 
Additional Observational and Descriptive Analysis:  
In addition to the secondary endpoint, safety of the trial is also analysed by the following 
observational and descriptive analysis.  These events are not endpoints for the study: 
o the following serious adverse events will be evaluated at 30 day follow-up visit (30 day 
± 7 days): 
 Stroke 
 Cardiogenic shock 
 Pulmonary embolism 
 Pulmonary edema 
 Atrial fibrillation 
 Ventricular fibrillation 
 Vascular complications requiring intervention 
 Bleeding requiring transfusion of 2 units or greater 
 Cooling catheter access site infection 
 Systemic infection 
 Deep Venous Thrombosis (DVT) 
 Bradycardia 
 Hypotension 

 
 
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o The following serious adverse events will be evaluated at 12 month follow-up visit 
(12 month ± 14 days): 
 Death (Cardiac, Vascular, Non-Cardiovascular) 
 Stent Thrombosis 
• Timing (Acute, Sub-acute) 
• Evidence (Definite and Probable) 
 Hospitalizations due to Heart Failure 
 
 Statistical Methods 
Baseline demographic and clinical characteristics will be summarized for each arm using 
descriptive statistics. Continuous variables will be reported with mean, standard deviation, median, 
and range. Discrete variables will be reported as frequency and proportion. A χ2 test or Fisher 
exact test (for small frequencies) will be used to compare discrete variables; t-test or Wilcoxon test 
(for non-normal data) will be used to compare the 2 arms with continuous variables for randomized 
subjects in the trial. 
 
The primary effectiveness endpoint is to detect a 20% reduction of mean infarct size in the Test 
Arm compared to Control Arm where infarct size (%LV Mass) is measured by cMR at 4-6 days. 
The mean, median, standard deviation, and range will be presented for infarct size. A two sample 
t-test will be used to test the null-hypothesis of no difference in average infarct size test and control 
arm P-value will be reported with p<0.05 considered statistically significant. Infarct size will 
further be evaluated in subgroups and with ANOVA models. 
 
For the primary safety endpoint of MACE (as defined by CD, All MI, and CI-TLR) at 30 days, all 
events will be tabulated and reported. Per-patient rate of composite MACE will be compared 
between the two arms with 1-sided Fisher’s exact test. 
Two interim analyses are planned to be performed at approximately 50% and 75% of 
randomization, once subjects have completed 4-6 day cMR follow-up. At the interim stage, the 
trial will be stopped to reject the null hypothesis of no difference or will continue enrolling. Based 
on the Lan-DeMets method for group sequential trials using O’Brien-Fleming boundaries, the 
levels of significance for the interim analyses are alpha=0.00305 (50% information fraction), 
alpha=0.01832 (75% information fraction), and alpha=0.044 (final analysis).  
 
All analyses for effectiveness will be conducted in intent-to-treat and per-protocol analyses set. 
All analyses for safety will be conducted in the safety dataset. Imputation will be made for missing 
infarct size (LV%) in intent-to-treat analyses set per Intention-to-Treat principle; details are 
described in the Statistical Analysis Plan.  

 
 
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 Sample Size Justification 
The primary effectiveness analyses is designed to detect a relative reduction of 20% in mean 
anterior myocardial infarct size (IS), as determined by Cardiac Magnetic Resonance (cMR) 
imaging at 4-6 days post infarct in the Test Arm (cooling + PCI) compared to the Control Arm 
(PCI only). The absolute magnitude of a relative reduction of 20% depends on the mean IS in the 
control arm, which is assumed to be approximately 17 %LV.  Therefore, the treatment effect of 
interest is an absolute difference of 3.5 %LV.  
 
The hypothesis for the primary effectiveness endpoint is the following for patients randomized 1:1 
in Treatment Arm vs Control Arm: 
H0:  µT = µC   
HA: µT ≠ µC  
 
Null hypothesis:  
 
The null hypothesis is that the mean infarct size in the Test Arm is equal to the mean IS in the 
Control Arm.   
 
Alternative hypothesis:  
 
The mean infarct size in the control arm is not equal to mean infarct size of control arm. 
This 20% relative reduction is defined as absolute value 3.5 %LV and accounted for in our sample 
size calculation as minimally detectable effect. This assumption is based on previous studies with 
anterior infarct size measured with cMR reporting between 17-20% absolute %LV in anterior 
infarct (Tables 17 & 18). Therefore, a relative reduction of 20% can vary depending on the mean 
infarct size of the control arm. Assuming a representative mean infarct size of ~17% in controls, 
we assume absolute difference of 3.5 %LV is equivalent to 20% mean anterior infarct size would 
be an adequate detection limit for effect. 
Based on these assumptions--standard deviation of 12.0 %LV, two-tailed t-test of difference 
between means, a normal distribution, 80% power (beta=0.2), with the final analysis will be 
conducted using a two-sided test at the alpha=0.044 level of significance (adjusted for the two 
interim analyses)-- the required total sample to detect a mean difference of 3.5 %LV with 80% 
power is 384 subjects (192 subjects per group).  Assuming 24% loss to follow-up, the trial plans 
for an enrolment up to 500 randomized subjects (250 in each arm) for 4-6 days cMR imaging 
follow-up. 
 
 

 
 
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Table 17: Clinical trials reporting anterior mean infarct size measured by cMR 4-6 days in 
PCI trials (Control Group Only) and calculated 20% relative reduction  
Study name 
Anterior n 
Mean 
infarct size 
Standard 
Deviation 
20% relative 
reduction 
APEX-AMI41 
60 
16.6 
10.7 
3.3 
LIPSIAABCIXIMAB42 
63 
25.3 
16.1 
5.1 
LIPSIA-STEMI43 
38 
18 
16.0 
3.6 
CRISP-AMI 44* 
142 
37.5 
20.1 
7.5 
INFUSE-AMI45 
172 
17.3 
10.2 
3.5 
RAPID-MI ICE1 
7 
19.7 
8.5 
3.9 
CHILL-MI37 
21 
26.5 
10.9 
5.3 
AMI EU PILOT  
21 
23.3 
12.0 
4 
*>60% are large proximal infarcts 
 
A range of standard deviation in the table expected is represented by anterior infarct data measured 
with cMR from separate and pooled analyses of previous hypothermia trials with AMI patients 
cooled below 35°C: RAPID-MI ICE (2009), CHILL-MI (2013), AMI EU Pilot (ongoing) as 
described below in Table 18. 
Table 18: Hypothermia trials using cMR measured infarct size as primary outcome 
RAPID-MI 
ICE (2009) 
CHILL-MI 
(2013) 
AMI EU 
Pilot (2017) 
Pooled  
AMI EU Pilot, RAPID-
MI-ICE, CHILL-MI 
n (Control vs 
Cooled) 
7 vs 5 
21 vs 15 
21 vs 19 
49 vs 39 
Control Mean 
LV% 
19.7 
26.5 
23.3 
24.5 

 
 
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RAPID-MI 
ICE (2009) 
CHILL-MI 
(2013) 
AMI EU 
Pilot (2017) 
Pooled  
AMI EU Pilot, RAPID-
MI-ICE, CHILL-MI 
20% reduction 
in infarct 
3.94 
5.3 
4.7 
4.9 
Std Dev 
(control) 
8.5 
10.9 
12.0 
10.5 
Std Dev (cooled) 
6.5 
9.3 
10.3 
11.0 
 
The potential impact of variations in control infarct size and variability is presented in Table 19.  

 
 
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Table 19: Sample size estimates with alternative standard deviation and detection limit 
Mean Difference 
in infarct size for 
detection (%) 
 Standard Deviation Estimated Sample Size 
Total Enrollment 
(with 24% drop-out) 
3.0 
 
9 
288 
380 
3.0 
 
10 
355 
468 
3.0 
 
11 
430 
566 
3.0 
 
12 
506 
666 
3.5 
 
9 
212 
280 
3.5 
 
10 
260 
342 
3.5 
 
11 
314 
414 
3.5 
 
12 
374 
500 
4.0 
 
9 
162 
214 
4.0 
 
10 
200 
264 
4.0 
 
11 
240 
316 
4.0 
 
12 
286 
376 
 
The primary safety endpoint is a composite endpoint. For the sample size calculation, expected 
incidence is based on a literature review of acute MI hypothermia trials that combined six studies: 
Dixon et al, COOL MI, ICE-IT, RAPID MI-ICE, CHILL-MI, VELOCITY46 which resulted in a 
30-day MACE rate of 6.6% in the Control patients and 7.5% in treatment patients. Previously, 
AMIHOT II trial defined 30-day MACE rate comprised of death, reinfarction, target vessel 
revascularization, and stroke used a non-inferiority hypothesis with a 6% equivalence delta and 
7% in the Control patients47. 
The hypothesis for the primary safety endpoint is the following:  

 
 
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H0: πT ≥ πC + 6%  
HA: πT < πC + 6%  
πT and πC are the underlying proportion of patients having a MACE event.  
An enrollment of 500 patients would be able to demonstrate 91% power and 95% 1-sided 
significance. The safety endpoint will be considered to have been met if there is a high posterior 
probability of non-inferiority [i.e. P (πt < πc + 6% >95%)]. With a drop-out rate of 20%, the power 
is calculated to be 86%. 
 
16 PUBLICATION 
At the conclusion of the trial, a multi-center manuscript will be prepared for publication. 
Publications will be managed by the Sponsor, its designee and the Advisory board. Additional 
publications from any single site will be considered but only after the multi-center publication. 
17 INTELLECTUAL PROPERTY 
In all documents the company name of ZOLL Circulation® will be referred to in short hand as 
ZOLL.  ZOLL® is a registered trademark of ZOLL Medical Corporation.  The Proteus IVTM 
System is a trademark of ZOLL Circulation, Inc.  Proteus Catheters, Cassettes and Temperature 
Probes (X-Probe) are registered trademarks of ZOLL Circulation, Inc. 
18 STATEMENT OF COMPLIANCE 
1. Sponsor and Investigator will conduct the clinical investigation in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki. 
2. Sponsor and Investigator will comply with ISO 14155:2011 and any regional or national 
regulations, as appropriate. 
3. Investigator will not begin the clinical investigation until Investigator obtains the required 
written approval or favorable opinion from the MEC or regulatory authority, if appropriate.  
4. Investigator will follow any additional requirements imposed by the MEC or regulatory 
authority, if appropriate. 

 
 
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ATTACHMENT I – REFERENCES 
  
1. Gotberg, M, Olivecrona, G, Koul, S, Carlsson, M., Engblom, H, Ugander, M, van der Pals, J, 
Algotsson, L, Hakan, A, & Erlinge, D.  A Pilot Study of Rapid Cooling by Cold Saline and 
Endovascular Cooling Before Reperfusion in Patients with ST-Elevation Myocardial 
Infarction.  Circulation: Cardiovascular Interventions.  2010; 3: 400-407. 
2. Good Clinical Practice Guidelines 
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7. Yellon DM, Hausenloy DJ: Myocardial reperfusion injury. N Eng J Med. 2007;357:1121. 
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9.  Hausenloy DJ, Botker HE, Engstrom T, Erlinge D, Heusch G, Ibanez B, Kloner R, Ovize M,  
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11. Duncker DJ, Klassen CL, Ishibashi Y, Herrlinger SH, Pavek TJ, Bache RJ.  Effect of 
temperature on myocardial infarction in swine.  Am J Physiol 1996; 270(4 Pt 2):H1189-H1199. 
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14. Dae M, Gao D, Sessler D, Chair K, Stillson C: Effect of endovascular cooling on myocardial 
temperature, infarct size, and cardiac output in human-sized pigs. 2002 Am J Physiol 
282:H1584-91. 
15. Hale SL, Dae MW, Kloner RA.  Hypothermia during reperfusion limits 'no-reflow' injury in a 
rabbit model of acute myocardial infarction.  Cardiovasc Res 2003; 59(3):715-722. 

 
 
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16. Gotberg M, Olivecrona GK, Engblom H et al.  Rapid short-duration hypothermia with cold 
saline and endovascular cooling before reperfusion reduces microvascular obstruction and 
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17. Chien G, Wolff R, Davis R, et al. Normothermic range temperature affects myocardial infarct 
size. Cardiovascular Research 1994; 28:1014-1017. 
18. Schwartz L, Verbinshi S, Vander Heide R, et al. Epicardial temperature is a major predictor of 
myocardial infarct size in dogs. J Mol Cell Cardiol 1997; 29:1577-1583. 
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segment elevation myocardial infarction: A patient-level pooled analysis from randomized 
trials. J Interven Cardiol. 2017;1–8. 
20. Montalescot G, Barragan T, Wittenberg O, et al for the ADMIRAL Investigators. Platelet 
glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Engl 
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21. Stone, G, Tcheng, J, Kandzari, D, Grines, C, Cox, D, Effron, M, Gardia, E, Griffin, J, 
Guagliumi, G, Stuckey, T, Turco, M, Fahy, M, Lansky, A, & Mehran, R.   Benefits and Risks 
of Abciximab Use in Primary Angioplasty for Acute Myocardial Infarction:  The Controlled 
Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) 
Trial.  Circulation 2003; 108: 1316-1323. 
22. Seiersten, M, Maynarc, C, Clemmensen, P, DANAMI-2 Investigators.  Effects of Abciximab 
as Adjunctive Therapy in Primary Percutaneous Coronary Intervention Patients (results from 
the DANAMI-2 Trial).  Acute Card Card, 2006: 8(2), 75-82. 
23.  Grines CL, on behalf of the ICE-IT Investigators (2004).  Intravascular cooling adjunctive to 
percutaneous coronary intervention for acute myocardial infarction. Presented at Transcatheter 
Cardiovascular Therapeutics 2004. 
24. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: A Report of the 
American College of Cardiology Foundation/American Heart Association Task Force on 
Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am 
Coll Cardiol. 2011;58(24):e44-e122.  
25. Green, CP, Porter, CB, Breshnahan, DR, Spertus, JA. Development and evaluation of the 
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Am Coll Cardiol. 2000 Apr; 35(5):1245-55. 
26. Islam S, et al. Setting up an Efficient Therapeutic Hypothermia Team in Conscious ST 
Elevation Myocardial Infarction Patients: A UK Heart Attack Center Experience. Ther 
Hypothermia Temp Manag. 2015 5(4):1-6. 
27. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, Steg PG, Morel MA, 
Mauri L, Vranckx P, McFadden E, Lansky A, Hamon M, Krucoff MW, Serruys PW; Academic 
Research Consortium. Clinical end points in coronary stent trials: a case for standardized 
definitions. Circulation. 2007 May 1;115(17):2344-51. 

 
 
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28. Polderman K, Ingeborg H. Therapeutic hypothermia and controlled normothermia in the ICU: 
Practical considerations, side effects and cooling methods. Critical Care Medicine 2009. 37: 
1101 -1120. 
29. EN ISO 10993-1 Biological Evaluation and Biocompatibility Testing of Medical Devices 
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Recurrent ischaemia during continuous multilead ST-segment monitoring identifies patients 
with acute coronary syndromes at high risk of adverse cardiac events; meta-analysis of three 
studies involving 995 patients. Eur Heart J. 2001 Nov; 22(21):1997-2006.  
32. Piazza G, Goldhaber SZ. Acute pulmonary embolism: part I: epidemiology and 
diagnosis. Circulation. 2006; 114(2):e28–32. 
33. K. A. Wlodzimirow, S. Eslami, A. Abu-Hanna, M. Nieuwoudt, R. A. F. M. Chamuleau. 
Systematic Review: Acute Liver Failure — One Disease, More Than 40 Definitions. Aliment 
Pharmacol Ther. 2012;35(11):1245-1256. 
34. The Criteria Committee of the New York Heart Association. (1994 (9th ed)). Nomenclature 
and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. Boston: Little, Brown 
& Co. pp. 253–256. 
35. Kidney International Supplements (2012) 2, 8–12; doi:10.1038/kisup.2012.7 
36. Thoeni RF. The revised Atlanta classification of acute pancreatitis: its importance for the 
radiologist and its effect on treatment. Radiology. 2012 Mar; 262(3):751-64. doi: 
10.1148/radiol.11110947. 
37. Erlinge, David MD PhD et al. “Rapid Endovascular Catheter Core Cooling Combined With 
Cold Saline as an Adjunct to Percutaneous Coronary Intervention for the Treatment of Acute 
Myocardial Infarction”, J Am Coll Cardiol 2014;63:1857–65 
38. Nichol, Graham, MD, MPH, et al.. Prospective, Multicenter, Randomized, Controlled Pilot 
Trial of Peritoneal Hypothermia in Patients With ST-Segment– Elevation Myocardial 
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Circ 
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2015;8:e001965. 
DOI: 
10.1161/CIRCINTERVENTIONS.114.001965. 
39. Dixon, Simon R, MBCHB, FRACP, et al. Induction of Mild Systemic Hypothermia With 
Endovascular Cooling During Primary Percutaneous Coronary Intervention for Acute 
Myocardial Infarction J Am Coll Cardiol 2002;40:1928 –34) © 2002 by the American College 
of Cardiology Foundation. 
40. Issam D. Moussa, et al., 2013. Consideration of a New Definition of Clinically Relevant 
Myocardial Infarction After Coronary Revascularization, An Expert Consensus Document 
From the Society for Cardiovascular Angiography and Interventions (SCAI), J Am Coll 
Cardiol. 2013 Oct 22; 62(17): 1563–1570. doi:  10.1016/j.jacc.2013.08.720. 
41. Patel MR, Worthley SG, Stebbins A, et al. Pexelizumab and infarct size in patients with acute 
myocardial infarction undergoing primary percutaneous coronary intervention: a delayed 

 
 
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enhancement cardiac magnetic resonance substudy from the APEX-AMI trial. J Am Coll 
Cardiol Img 2010;3:52–60. 
42. Thiele H, Schindler K, Friedenberger J, et al. Intracoronary compared with intravenous bolus 
abciximab application in patients with STelevation myocardial infarction undergoing primary 
percutaneous coronary intervention: the randomized Leipzig immediate percutaneous coronary 
intervention abciximab IV versus IC in ST-elevation myocardial infarction trial. Circulation 
2008;118:49–57. 
43. Thiele H, Eitel I, Meinberg C, et al. Randomized comparison of pre-hospital-initiated 
facilitated percutaneous coronary intervention versus primary percutaneous coronary 
intervention in acute myocardial infarction very early after symptom onset: the LIPSIA-
STEMI trial (Leipzig immediate prehospital facilitated angioplasty in ST-segment myocardial 
infarction). J Am Coll Cardiol Intv 2011;4:605–14. 
44. Patel MR, Smalling RW, Thiele H, et al. Intraaortic balloon counterpulsation and infarct size 
in patients with acute anterior myocardial infarction without shock: the CRISP AMI 
randomized trial. JAMA 2011;306:1329–37. 
45. Stone GW, Maehara A, Witzenbichler B, et al. Intracoronary abciximab and aspiration 
thrombectomy in patients with large anterior myocardial infarction: the INFUSE-AMI 
randomized trial. JAMA 2012;307:1817–26. 
46. Villablanca PA, Rao G, Briceno DF, et al. Therapeutic hypothermia in ST elevation myocardial 
infarction: a systematic review and meta-analysis of randomised control trials. Heart 
2016;102:712-9. 10.1136/heartjnl-2015-308559 
47. Stone GW, Martin Jack L., de Boer Menko-Jan, et al. Effect of supersaturated oxygen delivery 
on infarct size after percutaneous coronary intervention in acute myocardial infarction. 
Circulation: Cardiovascular Interventions. 2009;2:366-375, originally published October 20, 
2009 
48. Karen A.Hicks et all. 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular 
Endpoint Events in Clinical Trials. JACC, Vol  66, NO 4, 2015. 
49. Noc M1, Erlinge D, Neskovic AN, et al. COOL AMI EU pilot trial: a multicentre, prospective, 
randomised controlled trial to assess cooling as an adjunctive therapy to percutaneous 
intervention in patients with acute myocardial infarction) 2017 May 17.  
50.  2017 ESC Guidelines for the management of acute myocardial infarction in patients 
presenting with ST-segment elevation. European Heart Journal (2017) 00, 1–66.  
 
 
 
 

 
 
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ATTACHMENT II – ANTI-SHIVERING PROTOCOL  
Shivering Suppression Guidelines 
Turn on IVTM System console to initiate system and begin cooling of coldwell 
↓ 
Obtain Informed Consent 
↓ 
Administer Buspirone 60 mg PO/NG x 1 immediately 
↓ 
Place Bair Hugger on upper body; set to “high”; forced-air cover should be adjacent to skin.   
Put one blanket on top. 
↓ 
Closer to the time of device deployment, Pethidine 1 mg/kg IV (up to 100 mg)  
 
***Morphine and/or other sedatives are often administered in the setting of an acute MI 
Morphine and Pethidine (Demerol) are both opiate narcotics and if possible, morphine should 
be held as the combination may cause over-sedation.  Consider 0.5 mg/kg Pethidine 
IV, if Morphine has been administered. 
↓ 
At 15 minutes, Pethidine 0.5mg/kg IV should be administered. 
 
Then a 25 mg/hr IV infusion of Pethidine (up to 80 kg patient) or 35mg/hr (> 80 kg 
patient) should be initiated and maintained for the duration of device deployment. 
***Make sure the patient has a respiratory rate ≥ 10 breaths/minute. 
 
What to do if shivering occurs: 
First, try repositioning the Bair Hugger or changing its settings to increase the heat delivered to 
the patient’s surface. 
 
Second, consider increasing dose of Pethidine.  Prior to giving additional Pethidine, look for 
signs of respiratory depression (i.e. decreased Respiratory Rate, decreased O2 Saturation by 
Pulse Ox.)  If it is decided that the patient can tolerate additional Pethidine the following may be 
tried: 
1. An IV dose of 25 mg x 1 may be given 
2. If Infusion rate is 25mg/hr, the rate may be increased to a maximum of 35 mg/hr 

 
 
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If the shivering persists following the above measures, consider raising the target temperature 
on the Proteus Console by 0.5°C (i.e. from 32.0°C to 32.5°C).  If this does not work after 5-10 
minutes at the new target temperature, then the process can be repeated until a temperature where 
no shivering is obtained. 
 

 
 
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ATTACHMENT III – BEDSIDE SHIVERING ASSESSMENT SCALE (BSAS) 
SCORE 
SEVERITY 
DEFINITION 
0 
None 
No shivering noted on palpation of the masseter, neck or chest 
wall 
1 
Mild 
Shivering localized to the neck and/or thorax only 
2 
Moderate 
Shivering involves gross movement of the upper extremities in 
addition to neck and thorax 
3 
Severe 
Shivering involves gross movements of the trunk, upper and lower 
extremities 
SCORE 
SEVERITY 
DEFINITION 
0 
None 
No shivering noted on palpation of the masseter, neck or chest 
wall 
1 
Mild 
Shivering localized to the neck and/or thorax only 
2 
Moderate 
Shivering involves gross movement of the upper extremities in 
addition to neck and thorax 
3 
Severe 
Shivering involves gross movements of the trunk, upper and lower 
extremities 

 
 
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ATTACHMENT IV – SPECIFIC NEW-ONSET ADVERSE EVENT DEFINITIONS 
SPECIFIC NEW-
ONSET ADVERSE 
EVENT  
DEFINITION 
1. All-Cause  
Mortality 
Deaths will be classified as cardiac, vascular or 
noncardiovascular as defined by the Academic Research 
Consortium.27 
 
All deaths are considered cardiac unless an unequivocal non-
cardiac cause can be established. Specifically, any 
unexpected death even in patients with coexisting potentially 
fatal non-cardiac disease (e.g. cancer, infection) should be 
classified as cardiac.  
 
Cardiac death (CD):  
Any death due to proximate cardiac cause (e.g. MI, low-
output failure, fatal arrhythmia), unwitnessed death and death 
of unknown cause, all procedure related deaths including 
those related to concomitant treatment.  
 
Vascular death:  
Death due to non-coronary vascular causes such as 
cerebrovascular disease, pulmonary embolism, ruptured 
aortic aneurysm, dissecting aneurysm, or other vascular 
cause.  
 
Non-cardiovascular death:  
Any death not covered by the above definitions such as death 
caused by infection, malignancy, sepsis, pulmonary causes, 
accident, suicide or trauma. 
2. Recurrent MI 27,31 
Recurrent MI or re-infarction may be diagnosed when cardiac 
biomarker levels are stable on 2 samples that are >6 hours 
apart or are in decline if a subsequent value 3 to 6 hours after 
the procedure is increased by > 20% from the baseline 
sample. If the baseline value is not stable, then insufficient 
data exists to recommend biomarker criteria for diagnosis, 
and the Academic Research Consortium27,31recommends that 
the event be considered as pre-procedure MI.  Periprocedural 
MI is that which occurs within the first 48 hrs after PCI or 
within the first 72 hrs after coronary artery bypass grafting 
(CABG). 
 

 
 
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Q wave MI:  
Development of new, pathological Q wave on the baseline 
ECG (≥ 0.04 seconds in duration and ≥ 1 mm in depth) in ≥ 2 
contiguous precordial leads or ≥ 2 adjacent limb leads)  
 
Non-Q wave MI:  
Those MIs which are not Q-wave MI. 
3. Need for 
revascularization of 
the target vessel 
(TVR)27 
TVR is defined as any repeat percutaneous intervention or 
surgical bypass of any segment of the target vessel. The target 
vessel is defined as the entire major coronary vessel proximal 
and distal to the target lesion, which includes upstream and 
downstream branches and the target lesion itself.  
4. Stroke 
Development of a new neurological deficit that persists > 24 
hours, or worsening of previous neurological symptoms that 
persist > 24 hours. 
5. Cardiogenic shock 
Systolic blood pressure of less than 90 mmHg for at least 30 
minutes which is secondary to myocardial dysfunction, 
leading to decreased cardiac output and evidence of tissue 
hypoxia in the presence of adequate intravascular volume.  
6. Pulmonary 
embolism 
Sudden onset of pleuritic chest pain, cough, hemoptysis, 
hypoxia, tachycardia, and a positive ventilation/perfusion 
scan or a CT scan. 
7. Ventricular 
Fibrillation (V-  
Fib) 
Rapid uncoordinated fluttering contractions of the heart 
ventricles recognized by the occurrence on the 
electrocardiogram of coarse and irregular oscillations without 
discernible QRS complexes or T waves 
8. Vascular 
complications 
requiring 
intervention 
Complications arising from the use of the Proteus Catheter 
including the development of a vessel tear, hematoma, 
pseudoaneurysm, arteriovenous (AV) fistula, or 
retroperitoneal bleeding which require an additional surgical 
intervention for treatment. 
9. Bleeding requiring 
transfusion of 2 units 
or greater 
Any periprocedural bleeding which occurs as a result of the 
PCI and/ or cooling procedure which requires transfusing > 2 
units. 
10. Systemic 
Infection  
Sepsis with confirmed positive blood cultures. 
11. Cooling Catheter 
Access Site Wound 
infection 
Infection and inflammation of the incision or puncture site 
requiring drainage and/or debridement in addition to 
antibiotic therapy, e.g., cellulitis. 
12. Pulmonary 
Edema 
Abnormal accumulation of fluid in the lungs 

 
 
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13. Deep Venous 
Thrombosis 
(DVT)32 
Formation of one or more blood clots in one of the body’s 
large veins, most commonly in the lower limbs. The clot(s) 
can cause partial or complete blocking of circulation in the 
vein, which in some patients leads to pain, swelling, 
tenderness, discoloration, or redness of the affected area, and 
skin that is warm to the touch.  As many patients enrolled in 
the trial will have pre-existing DVT, for the purposes of this 
trial DVT is defined as the de novo onset of DVT following 
enrollment which required treatment or worsening of pre-
existing DVT. 

 
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ATTACHMENT V – ADVERSE EVENT DEFINITIONS 
Adverse Event Definitions 
In addition to the definitions provided in Attachment IV– Specific New Onset Serious 
Adverse Event Definitions, the following definitions apply to expected adverse events 
that may occur and must be reported throughout this clinical trial.  Events reported should 
represent a new onset or increase in the severity of the condition from the time of 
enrollment. 
A. CARDIAC  
COMPLICATIONS 
DEFINITION 
Recurrent 
Myocardial 
ischemia 31 
Recurrent Myocardial Ischemia : is evidenced through baseline 
ECG changes identified during continuous multilead baseline 
ECG–ischemia monitoring (or Holter monitoring) which may 
be accompanied by the development of new clinical symptoms 
suggesting an ischemic cardiac episode.  
Arrhythmias 
The development of a new atrial and/or ventricular arrhythmia, 
significant increase in the severity of a preexisting arrhythmia, 
or any episode of cardiac arrest. 
Congestive Heart 
Failure34 
Defined as patients with defined or presumed cardiac disease 
and one of the following: Class I: without limitations of 
physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, or dyspnea. Class II: slight 
limitation of physical activity. They are comfortable at rest. 
Ordinary physical activity results in fatigue, palpitation, or 
dyspnea. Class III: marked limitation of physical activity. They 
are comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, or dyspnea. Class IV: inability to carry on 
any physical activity without discomfort. Symptoms are 
present even at rest or minimal exertion. 
 
B. PULMONARY 
COMPLICATIONS 
DEFINITION 
Pneumonia 
Clinical evidence as determined by physical, radiographic, and 
laboratory findings requiring treatment with antibiotics, 
inhalation therapy, intubation, or suctioning. 
Atelectasis 
Clinical evidence as determined by physical, radiographic, and 
laboratory findings requiring treatment with antibiotics, 
inhalation therapy, intubation, or suctioning. 

 
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Respiratory Failure 
Need for mechanical ventilation for > 24 hours 
postoperatively, or reintubation for any reason. 

 
 
 
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C. RENAL 
COMPLICATIONS 
DEFINITION 
Acute Kidney 
injury (AKI)35 
AKI is defined as any of the following:  
Increase in SCr by ≥.3 mg/dl (≥26.5 µmol/l) within 48 hours; 
or Increase in SCr to ≥ 1.5 times baseline, which is known or 
presumed to have occurred within the prior 7 days; or Urine 
volume < 0.5 ml/kg/h for 6 hours.  
 
D. VASCULAR 
COMPLICATIONS 
DEFINITION 
Arteriovenous 
Fistula 
Formation of an abnormal connection between the lumens of 
an artery and a vein as documented by CT, ultrasound, 
angiography, or direct observation. 
Embolism 
The obstruction of a blood vessel by a blood clot or foreign 
substance, e.g., air, fat, bacteria. 
Vessel perforation 
Defined as perforation of the access vessel wall or vena cava 
confirmed by extravasation of contrast under fluoroscopy, 
angiography, CT scan, and/ or direct observation at surgery or 
autopsy.  
Hematoma 
An abnormal localized collection of blood (clotted or partially 
clotted) and situated within an organ or a soft tissue space, 
such as within a muscle.  Development of an incisional or 
retroperitoneal hematoma requiring surgical intervention, 
evacuation, transfusion or prolonged hospitalization. 
Hemorrhage 
Post-procedural bleeding requiring transfusion of ≥ 2 units. 
Hypotension 
Abnormally low systolic blood pressure that is < 80 mm Hg 

 
 
 
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D. VASCULAR 
COMPLICATIONS 
DEFINITION 
Peripheral vascular 
insufficiency (PVI) 
Inadequate peripheral blood flow resulting from the occlusion 
of vessels by atherosclerotic plaques, thrombi, or emboli; 
damaged, diseased, or intrinsically weak vascular walls; 
arteriovenous fistulas; hematologic hypercoagulability; and 
heavy smoking. Signs of vascular insufficiency include pale, 
cyanotic, or mottled skin over the affected area; swelling of an 
extremity; absent or reduced tactile sensation; tingling; 
diminished sense of temperature; muscle pain, such as 
intermittent claudication in the calf; and, in advanced disease, 
ulcers and atrophy of muscles in the involved extremity.  
As many patients enrolled in the trial will have pre-existing 
Peripheral Vascular Insufficiency (PVI), for the purposes of 
this trial PVI is defined as the de novo onset of PVI following 
enrollment which requires treatment or worsening of pre-
existing PVI. 
Pseudoaneurysm 
Enlargement of the aorta, iliac, or femoral arteries, which 
contain some or all of the medial layer, the adventitia, and 
periaortic tissue most commonly associated with previous 
aortic operative procedures, trauma, and/or infection.  
Pseudoaneurysms typically present as a well-defined collection 
of blood outside the vessel wall from contained rupture.  
Stenosis 
A reduction in the diameter of the vessel lumen when 
compared to the reference diameter, as documented by 
angiography, which requires intervention and is related to the 
procedure, e.g., access vessel.  
Thrombosis  
Clotting within a blood vessel which may cause infarction of 
tissues supplied by the vessel; it may be occlusive or attached 
to the vessel or heart wall without obstructing the lumen. 
Transient Ischemic 
Attack (TIA) 
A brief episode of neurological dysfunction caused by focal 
brain or retinal ischemia with clinical symptoms typically 
lasting 1 - 24 hours and without evidence of acute infarction. 
 
 
E. WOUND 
COMPLICATIONS 
DEFINITION 

 
 
 
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Hematoma 
An abnormal localized collection of blood (clotted or 
partially clotted) and situated within an organ or a soft tissue 
space, such as within a muscle.  Development of an 
incisional or retroperitoneal hematoma requiring surgical 
intervention, evacuation, transfusion or prolonged 
hospitalization. 
Arteriovenous Fistula 
Formation of an abnormal connection between the lumens 
of an artery and a vein as documented by CT, ultrasound, 
angiography, or direct observation. 
Nerve 
Injury/Peripheral 
Neuropathy 
Direct damage to nerves surrounding the access site, 
operative field, or catheter deployment site, and the resultant 
signs and/or symptoms of such damage which may include 
pain and numbness in the affected area associated with 
muscle weakness and decreased patellar reflex lasting > 1 
month after treatment. 
 
F. SYSTEMIC 
COMPLICATIONS 
DEFINITION 
Coagulopathy 
The development of an abnormal bleeding disorder, e.g., 
disseminated intravascular coagulopathy or thrombocytopenia, 
documented by appropriate laboratory studies and requiring 
therapy with medication or transfusion. 
Anesthetic 
Complications 
Reaction or complication caused by administration of an 
anesthetic. 
Liver failure33 
Acute liver failure is defined as the rapid development of 
hepatocellular dysfunction, specifically coagulopathy and 
mental status changes (encephalopathy) in a patient without 
known prior liver disease.  
 
 
 

 
 
 
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F. SYSTEMIC 
COMPLICATIONS 
DEFINITION 
Pancreatitis36 
Evidenced on two of the following three conditions: 1) 
abdominal pain suggestive strongly of acute pancreatitis 
(epigastric pain often radiating to the back), 2) serum amylase 
and/or lipase activity at least 3 times greater than the upper 
limit of normal, (imaging is to be used if the elevated values 
are <3 times normal); and 3) characteristic findings of acute 
pancreatitis on transabdominal ultrasound or on Contrast 
Enhanced Computed Tomography (CECT) 32 
 
 
 
 
 
 
 

 
 
 
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ATTACHMENT VI – INVESTIGATOR LIST 
 
 
 

 
 
 
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ATTACHMENT VII – LIST OF ABBREVIATIONS 
AAR 
Area at Risk 
ACC 
American College of Cardiology 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AHA 
American Heart Assocation 
AKI 
Acute Kidney Injury 
AMI 
Acute Myocardial Infarction 
ASADE 
Anticipated Serious Adverse Device Effect 
AV 
Arteriovenous 
BSAS 
Bedside Shivering Assessment Scale 
CABG 
 Coronary Artery Bypass Grafting  
CD 
Cardiac Death 
CEC 
Clinical Events Committee 
CHF 
Congestive Heart Failure 
CIP 
Clinical Investigation Plan 
CI-TLR 
Clinically-Indicated Target Lesion Revascularization 
CMP 
Clinical Monitoring Plan 
cMR 
Cardiac Magnetic Resonance 
CNS 
Central Nervous System 
CRO 
Clinincal Research Organization 
CRF 
Case Report Form 
CRMI 
Clinically Relevant Myocardial Infarction 
CVA 
Cerebral Vascular Accident 
CVP 
Central Venous Pressure 
DAPT 
Dual Antiplatelet Therapy 
DD 
Device Deficiency 
DES 
Drug Eluting Stent 
DMC 
Data Monitoring Committee 
DP 
Dorsalis Pedis        
DSMB 
Data Safety Monitoring Board 
DTB 
Door-to-Balloon 
DVT 
Deep Vein Thrombosis 
EC 
Ethics Committee 

 
 
 
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COOL-AMI EU Pivotal Trial EDC-3135 Rev 6 
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ECG 
Electrocardiography 
EDC 
Electronic Data Capture 
ED 
Emergency Department 
ER 
Emergency Room 
ESC 
European Society of Cardiology 
EU 
European Union 
Fr 
French 
FMECA 
Failure Mode, Effects and Criticality Analysis 
FEP 
Fluorinated Ethylene Propylene 
GLP 
Good Laboratory Practice 
HDPE 
High-density Polyethylene 
HIPPA 
Heath Insurance Portability and Accountability Act 
HTN 
Hypertension 
ICF 
Informed Consent Form 
IEC 
International Electrotechnical Commission 
IFU 
Instructions for Use 
IQR 
Interquartile Range 
IRB 
Institutional Review Board 
IRI 
Ischemia Reperfusion Injury 
IS 
Infarct Size 
ISO 
International Organization for Standardization 
ITT 
Intention-to-Treat 
IVC 
Inferior Vena Cava 
IVTM 
Intravascular Temperature Management 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LAL 
Limulus Amebocyte Lysate 
LED 
Light-emitting Diode 
LV 
Left Ventricular 
LVEF 
Left Ventricular Ejection Fraction 
MACE 
Major Adverse Cardiac Events 
MAO 
Monoamine Oxidase 
MaR 
Myocardium at Risk   
MEC 
Medical Ethics Committee 

 
 
 
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MEM 
Minimum Essential Medium 
MI 
Myocardial Infarction 
MRI 
Magnetic Resonance Imaging 
NCA 
National Competent Authority 
NYHA 
New York Health Association 
OD 
Outer Diameter 
PCI 
Percutaneous Coronary Intervention 
PETG 
Polyethylene Terephthalate - Glycol modified 
PP 
Per-protocol 
PVI 
Peripheral Vascular Insufficiency 
PVP 
Polyvinylpyrrolidone 
RCN 
Radio-Contrast Nephropathy 
RF 
Radiofrequency 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Events 
SBP 
Systolic Blood Pressure 
SOP 
Standard Operating Procedure 
SPECT 
Single-photon Emission Computed Tomography  
STEMI 
ST-segment Elevation Myocardial Infarction 
SVT 
Supraventricular Tachycardia 
TIA 
Transient Ischemic Attack 
TIMI 
Thrombolysis In Myocardial Infarction 
TH 
Therapeutic Hypothermia 
TVR 
Target Vessel Revascularization 
UADE 
Unanticipated Adverse Device Effect 
UFH 
Unfractioned Heparin 
USADE 
Unanticipated Serious Adverse Device Effect 
USP 
United States Pharmacopeia 
UTI 
Urinary Tract Infection 
 
 

 
 
 
 
 
 
 
 
 
APPENDIX B 
 
COOL-AMI EU Pivotal Trial Clinical Investigational Plan 
 
Germany Protocol (Rev. 6) 
 
(122 pages) 
 
 

Page 1 of 122 
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Clinical Investigation Plan 
 
 
COOL-AMI EU PIVOTAL TRIAL: A MULTICENTER, PROSPECTIVE, 
RANDOMIZED-CONTROLLED TRIAL TO ASSESS THE SAFETY AND 
EFFECTIVENESS OF COOLING AS AN ADJUNCTIVE THERAPY TO 
PERCUTANEOUS INTERVENTION IN PATIENTS WITH ACUTE 
MYOCARDIAL INFARCTION 
 
PROTOCOL NO.: EDC-3135 
Revision: 6 
 
EFFECTIVE DATE: JUNE 19, 2018 
 
 
 
 
CONFIDENTIAL & PROPRIETARY 
 
The information in this Protocol is confidential and proprietary and is to be used 
only in connection with matters authorized by ZOLL and no part is to be disclosed 
to others without prior written permission from ZOLL 
 
 

CLINICAL INVESTIGATION PLAN APPROVAL PAGE 
CLINICAL INVESTIGATION PLAN: 
COOL-AMI EU Pivotal Trial: A 
multicenter, prospective, randomized 
controlled Trial to assess the safety and 
effectiveness of cooling as an adjunctive 
therapy to percutaneous intervention in 
patients with acute myocardial infarction 
PROTOCOL No.: 
SPONSOR: 
EDC-3135 
ZOLL Circulation, Inc. 
2000 Ringwood A venue 
San Jose, CA 95131 
SPONSOR 
REPRESENTATIVE: 
ZOLL Medical Deutschland GmbH 
Emil-Hoffmann - StraBe 13 
CLINICAL TRIAL SPONSOR'S 
CONTACT: 
REVISION NUMBER : 
50996 Koln, Germany 
Philippa Hill 
6 
f Clinical Investigation Plan by Sponsor: 
Philippa Hill 
Date 
Senior Director, Clinical Affairs 
COOL-AMI EU Pivotal Trial EDC-3135 Rev 6 
CONFIDENTIAL & PROPRIETARY , 
Page 2 of122 

Page 3 of 122 
COOL-AMI EU Pivotal Trial EDC-3135 Rev 6 
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Signature Page 
 
Clinical Investigation Plan  
 
COOL-AMI EU PIVOTAL TRIAL: A MULTICENTER, PROSPECTIVE, RANDOMIZED-
CONTROLLED TRIAL TO ASSESS THE SAFETY AND EFFECTIVENESS OF COOLING AS 
AN ADJUNCTIVE THERAPY TO PERCUTANEOUS INTERVENTION IN PATIENTS WITH 
ACUTE MYOCARDIAL INFARCTION 
PROTOCOL NO.: EDC 3135 
Revision: 6 
Effective Date: JUNE 19, 2018 
 
Signatures of Investigator below constitute their approval of this clinical investigation 
plan (CIP) and provide necessary assurances that they have read the CIP, understand it, 
and will work according to all stipulations of it, and to the ethical principles stated in the 
latest version of the Declaration of Helsinki and the ISO 14155:2011 (Clinical 
Investigation of Medical Devices for Human Subjects – Good Clinical Practice). 
 
 
 
 
Investigator Name (Please Print) 
 
 
 
 
 
 
Investigator Signature 
 
Date 
 
 
 
 
 
 
Institution Name 
 
 
 
 
 
Institution Address 
 
 
 
 
 
ZOLL Circulation, Inc. 
 
 
Sponsor Name 
 
 
 
 
 
2000 Ringwood Avenue, San Jose CA 95131 
Sponsor Address 
 
 
 
 
 
ZOLL Medical Deutschland GmbH 
 
 
Sponsor Representative 
 
 

Page 4 of 122 
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Table of Contents 
 
1 
SYNOPSIS .............................................................................................................. 9 
Inclusion Criteria ...................................................................................................... 10 
Exclusion Criteria ..................................................................................................... 10 
 
INTRODUCTION ................................................................................................ 14 
 
BACKGROUND .................................................................................................. 16 
 
INTENDED USE, SYSTEM OVERVIEW, & DEVICE DESCRIPTION .......... 17 
 
Intended Use / Indication for Use ..................................................................... 17 
 
System Overview .............................................................................................. 17 
 
Device Description ............................................................................................ 18 
4.3.1 Proteus Catheter ................................................................................................ 18 
4.3.2 Proteus Temperature Probe ............................................................................... 18 
4.3.3 Proteus Cassette................................................................................................. 18 
4.3.4 Proteus Console ................................................................................................. 19 
4.3.5 Device Labeling ................................................................................................ 20 
 
PRIOR INVESTIGATIONS ................................................................................. 20 
 
Pre-Clinical Studies ........................................................................................... 20 
 
Human Clinical Studies ..................................................................................... 21 
5.2.1 COOL MI Trial ................................................................................................. 21 
5.2.2 COOL MI II Trial .............................................................................................. 28 
5.2.3 COOL RCN Trial .............................................................................................. 31 
5.2.4 ICE- IT Trial...................................................................................................... 34 
5.2.5 RAPID-MI ICE Trial ........................................................................................ 35 
5.2.6 CHILL-MI Trial ................................................................................................ 35 
5.2.7 Induction of Mild Systemic Hypothermia With Endovascular Cooling During 
Primary Percutaneous Coronary Intervention for Acute Myocardial Infarction .......... 36 
5.2.8 VELOCITY Trial .............................................................................................. 36 
5.2.9 EU AMI Case Series ......................................................................................... 38 
5.2.10 COOL-AMI EU PILOT Trial ........................................................................... 39 

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Summary and Clinical Trial Rationale .............................................................. 40 
 
CLINICAL TRIAL PLAN .................................................................................... 41 
 
Trial Objective................................................................................................... 41 
 
Trial Endpoints .................................................................................................. 41 
6.2.1 Primary Effectiveness Endpoint ........................................................................ 41 
6.2.2 Primary Safety Endpoint ................................................................................... 41 
6.2.3 Additional Assessments: Demographics and Other Parameters ....................... 41 
 
Trial Design ....................................................................................................... 42 
 
Patient Population ............................................................................................. 42 
 
Selection Criteria ............................................................................................... 42 
 
Inclusion Criteria ............................................................................................... 42 
 
Exclusion Criteria .............................................................................................. 43 
 
Clinical Trial Procedures ................................................................................... 44 
6.8.1 Patient Screening ............................................................................................... 44 
6.8.2 Informed Consent .............................................................................................. 45 
6.8.3 Simulated Training Program (German centers only) ........................................ 46 
6.8.4 Approval to Randomize in the Trial .................................................................. 46 
6.8.5 Randomization .................................................................................................. 46 
6.8.6 Acute Care and Emergency Room Triage......................................................... 47 
6.8.7 Standardized Care Prior to the Cooling Procedure ........................................... 47 
6.8.8 Documentation Procedures ............................................................................... 47 
6.8.9 Study Flow and Procedures ............................................................................... 49 
6.8.10  Pre-Cooling Assessment Procedures ................................................................ 53 
6.8.11 Initiation, Maintenance, and Reversal of Cooling with Proteus IVTM System 
Procedures / Evaluations and Data Collection for Subjects Enrolled in the Test Arm 54 
6.8.12 Test Arm: Temperature Management Protocol and Data Collection Time 
Points ………………………………………………………………………………...54 
6.8.13 Trial Schedule for Test Arm Subjects ............................................................... 61 
6.8.14 Trial Schedule for Control Arm Subjects .......................................................... 62 
6.8.15 Control Arm Protocol and Data Collection Time Points .................................. 62 
6.8.16 Follow-up at 4-6 days and at 30 days following the PCI Procedure ................. 63 

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6.8.17 Follow-up at 12 months following PCI ............................................................. 63 
6.8.18 Use of other Cooling Methods .......................................................................... 63 
6.8.19 Transferring Subject during Cooling................................................................. 64 
6.8.20 Patient Withdrawal and Discontinuation........................................................... 64 
6.8.21 Patient Lost to Follow-up .................................................................................. 65 
6.8.22 Early Termination of a Clinical Investigation ................................................... 65 
6.8.23 Amendments and Protocol Deviations .............................................................. 66 
6.8.24 Trial Exit ........................................................................................................... 67 
6.8.25 Subject Confidentiality ...................................................................................... 67 
6.8.26 Device Accountability ....................................................................................... 67 
6.8.27 Return of Materials upon Trial Termination ..................................................... 68 
6.8.28 Trial Closure ...................................................................................................... 68 
 
Cardiac Magnetic Resonance (cMR) imaging Core Laboratory ....................... 69 
 
ADVERSE EVENTS & DEVICE DEFICIENCIES ............................................ 69 
 
Definitions ......................................................................................................... 69 
7.1.1 Adverse Event (AE) .......................................................................................... 69 
7.1.2 Serious Adverse Event (SAE) ........................................................................... 69 
7.1.3 Device Deficiency (DD).................................................................................... 70 
7.1.4 Adverse Device Effect (ADE)........................................................................... 70 
7.1.5 Serious Adverse Device Effect (SADE) ........................................................... 70 
7.1.6 Unanticipated Serious Adverse Device Effect (USADE) ................................. 70 
 
Adverse Event Reporting .................................................................................. 70 
7.2.1 Adverse Event Reporting from Site to Sponsor and MEC................................ 70 
7.2.2 Serious Adverse Event Reporting to Sponsor and MEC................................... 71 
7.2.3 UADE/USADE Reporting to Sponsor and MEC .............................................. 71 
7.2.4 Sponsor Reporting to NCAs  (National Competent Authority) when European 
Sites Participate in the Trial ......................................................................................... 71 
 
Device Relationship .......................................................................................... 72 
 
MONITORING BY DATA MONITORING COMMITTEE .............................. 74 
 
ADJUDICATION OF EVENTS........................................................................... 75 
 
RECOMMENDATION FOR DAPT AND STENTS........................................... 75 

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RISK ANALYSIS ................................................................................................. 76 
 
Risk Assessment Process .................................................................................. 76 
 
Expected Clinical Observations ........................................................................ 77 
 
Potential Clinical Risks ..................................................................................... 78 
11.3.1 Potential Adverse Events associated with the Proteus Catheter and Cooling 
System: ......................................................................................................................... 78 
11.3.2 Potential Adverse Events associated with the cooling procedure include but are 
not limited to the following: ......................................................................................... 79 
11.3.3 Risks Associated with Anti-shivering Medications .......................................... 80 
 
Additional investigations due to the trial .......................................................... 81 
11.4.1 Delay in PCI through the use of hypothermia therapy ...................................... 81 
11.4.2 Implementation of PCI in patients undergoing hypothermia (patient-related 
risks)……….. ............................................................................................................... 81 
11.4.3 Implementation of PCI with concurrent use of endovascular hypothermia. ..... 81 
11.4.4 The concurrent medication. ............................................................................... 81 
11.4.5 The supply of 4°C cooled saline solution ......................................................... 82 
11.4.6 Other procedures within the clinical trial .......................................................... 82 
 
Potential Clinical Benefits ................................................................................. 82 
 
Methods to Minimize Risk ................................................................................ 82 
 
Risk – Benefit Assessment ................................................................................ 83 
 
RECORDS AND REPORTS ................................................................................ 84 
 
Investigator Records .......................................................................................... 84 
 
Investigator Responsibilities ............................................................................. 85 
 
Sponsor Records ................................................................................................ 87 
 
Sponsor Reports ................................................................................................ 88 
 
MONITORING AND AUDITING PROCEDURES............................................ 89 
 
Clinical Trial Sponsor and Monitors ................................................................. 89 
 
Monitoring Methods .......................................................................................... 90 
 
Monitoring Visits .............................................................................................. 90 
 
Pre-trial Qualification Visit ............................................................................... 91 
 
Initiation Visit ................................................................................................... 91 

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On-Site Interim Monitoring Visits .................................................................... 92 
 
Audits ................................................................................................................ 92 
 
Final Monitoring Review .................................................................................. 92 
 
DATA MANAGEMENT PROCEDURES........................................................... 92 
 
Case Report Forms ............................................................................................ 93 
 
Source Documentation ...................................................................................... 93 
 
Transmission of Data ........................................................................................ 94 
 
Data Queries ...................................................................................................... 94 
 
STATISTICAL ANALYSIS PLAN ..................................................................... 94 
 
Data Analysis .................................................................................................... 95 
 
Statistical Methods ............................................................................................ 97 
 
Sample Size Justification .................................................................................. 98 
 
PUBLICATION .................................................................................................. 102 
 
INTELLECTUAL PROPERTY ......................................................................... 102 
 
STATEMENT OF COMPLIANCE .................................................................... 102 
ATTACHMENT I – REFERENCES ......................................................................... 103 
ATTACHMENT II – ANTI-SHIVERING PROTOCOL ........................................ 107 
ATTACHMENT III – BEDSIDE SHIVERING ASSESSMENT SCALE (BSAS) 109 
ATTACHMENT IV – SPECIFIC NEW-ONSET ADVERSE EVENT 
DEFINITIONS ............................................................................................................. 110 
ATTACHMENT V – ADVERSE EVENT DEFINITIONS ..................................... 113 
ATTACHMENT VI – INVESTIGATOR LIST ........................................................ 119 
ATTACHMENT VII – LIST OF ABBREVIATIONS .......................................... 120 
 
 
 

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1 
SYNOPSIS 
Clinical Trial 
Title 
COOL-AMI EU PIVOTAL TRIAL: A MULTICENTER, 
PROSPECTIVE, RANDOMIZED-CONTROLLED TRIAL TO 
ASSESS THE SAFETY AND EFFECTIVENESS OF COOLING 
AS AN ADJUNCTIVE THERAPY TO PERCUTANEOUS 
INTERVENTION IN PATIENTS WITH ACUTE 
MYOCARDIAL INFARCTION 
Clinical Trial 
Sponsor 
ZOLL® Circulation, Inc. 
Clinical Trial 
Sponsor’s 
Contact 
Philippa Hill 
Senior Director, Clinical Affairs 
ZOLL Circulation, Inc. 
2000 Ringwood Ave. 
San Jose, CA 95131 
Main:    +1 (408) 541-2140 
Fax:  +1 (408) 541-1030 
PHill@zoll.com@zoll.com 
 
Trial Number 
EDC-3135 
Investigational 
Device 
Proteus™ Intravascular Temperature Management (IVTM) 
System 
Trial Objective The objective of this trial is to evaluate the safety and effectiveness of 
therapeutic hypothermia, using the ZOLL Proteus IVTM System, as an 
adjunctive therapy for patients presenting with acute anterior 
myocardial infarction (AMI) and undergoing percutaneous coronary 
intervention (PCI)  in comparison with patients with acute anterior 
myocardial infarction and undergoing PCI only. 
Trial Design 
A multicenter, prospective, interventional, randomized-controlled trial. 
Randomization will be in a 1:1 ratio, Test Arm (PCI + Cooling) or 
Control Arm (PCI alone) in up to 500 randomized subjects (250 
subjects in each arm). 
Primary 
Effectiveness 
Endpoint  
Relative reduction of 20% in mean anterior myocardial infarct size as 
determined by Cardiac Magnetic Resonance (cMR) imaging at 4-6 
days post infarct in the Test Arm (cooling + PCI) relative to the 
Control Arm (PCI only). 

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Primary Safety 
Endpoint 
Per-patient rate of composite Major Adverse Cardiac Events (MACE) 
in randomized subjects, defined as Cardiac Death (CD), All 
Myocardial Infarction (All MI) and Clinically-Indicated Target Lesion 
Revascularization (CI-TLR) at 30 day follow-up; non-inferiority to the 
control. 
Investigational 
Sites 
Up to 70 clinical sites in the Europe 
Inclusion & 
Exclusion 
Criteria 
Patients shall be screened to the following inclusion and exclusion 
criteria. Subjects are qualified for participation only if all Inclusion 
Criteria have been met and all Exclusion Criteria have been confirmed 
not present. 
 
Inclusion Criteria 
All Inclusion Criteria must be answered YES for subject to satisfy 
Inclusion Criteria: 
 
1. The patient is ≥ 18 years of age. 
2. The patient must have symptoms consistent with AMI (i.e. chest 
pain, arm pain, etc.) and unresponsive to nitroglycerin, with 
symptoms beginning greater than 30 minutes but less than 4.5 
hours prior to presentation at hospital. 
3. Qualifying Infarct location:  Evidence of Acute Anterior MI only 
with ST-segment elevation of  ≥ 0.2 mV in two or more anterior 
contiguous precordial leads (V1 –V4). 
4. The patient is eligible for PCI. 
5. The patient is willing to provide written informed consent to 
participate in this clinical trial. 
 
Exclusion Criteria 
All Exclusion Criteria must be answered NO for subject to satisfy 
Exclusion Criteria: 
 
1. The patient has had a previous Myocardial Infarction. 
2. The patient is experiencing cardiogenic shock (systolic blood 
pressure [SBP] <100 mmHg, HR> 100 bpm and arterial oxygen 
saturation (pulse oximetry) <92% without additional oxygen  The 
patient is presenting with resuscitated cardiac arrest, atrial 
fibrillation, or Killip risk stratification class II through IV. 

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3. The patient has an aortic dissection or requires an immediate 
surgical or procedural intervention other than PCI. 
4. The patient has known history of Congestive Heart Failure (CHF), 
hepatic failure, end-stage kidney disease or severe renal failure 
(clearance < 30ml/min/1.73m²).  
5. The patient is febrile (temperature > 37.5 °C) or has experienced 
an infection with fever in the last 5 days. 
6. The patient has a known previous CABG. 
7. The patient has a known recent stroke within 90 days of admission.  
8. Cardio-pulmonary decompensation that has occurred en route to 
the hospital or, in the opinion of the physician, that is imminent or 
likely to occur following presentation to the clinical site. 
9. Contraindications to hypothermia, such as patients with known 
hematologic dyscrasias which affect thrombosis (e.g., 
cryoglobulinemia, sickle cell disease, serum cold agglutinins) or 
vasospastic disorders (such as Raynaud’s or thromboangitis 
obliterans).. 
10. Any contraindication to cardiac MRI, or any implant in the upper 
body which may cause artifacts on cardiac MRI imaging.                  
11. The patient has a known hypersensitivity or contraindication to 
aspirin, heparin, or sensitivity to contrast media, which cannot be 
adequately pre-medicated. 
12. The patient has a known history of bleeding diathesis, 
coagulopathy, cryoglobulinemia, sickle cell anemia, or will refuse 
blood transfusions. 
13. The patient has a height of <1.5 meters (4 feet 11 inches). 
14. The patient has a known hypersensitivity or contraindication to 
buspirone hydrochloride or Pethidine (Meperidine) and/or has 
been treated with a monoamine oxidase inhibitor in the past 14 
days. 
15. Patient has a known history of severe hepatic or renal impairment, 
untreated hypothyroidism, Addison’s disease, benign prostatic 
hypertrophy, or urethral stricture that in the opinion of the 
physician would be incompatible with Pethidine administration. 
16. The patient has an Inferior Vena Cava filter in place (IVC). 
17. The patient has a pre-MI life expectancy of <1 year due to 
underlying medical conditions or pre-existing co-morbidities. 
18. The patient has a known, unresolved history of drug use or alcohol 
dependency, or lacks the ability to comprehend or follow 
instructions. 

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19. The patient is currently enrolled in another investigational drug or 
device trial. 
20. The patient is apprehensive about or unwilling to undergo the 
required MRI imaging at follow-up, has a documented or 
suspected diagnosis of claustrophobia, or has Gadolinium allergy, 
or is in permanent Atrial Fibrillation. 
21. The patient has received thrombolytic therapy en route to the 
hospital. 
22. The patient shows clinical evidence of spontaneous reperfusion as 
observed symptomatically and/ or from baseline ECG findings 
(partial or complete ST resolution in baseline ECG prior to 
informed consent and randomization). 
23. The patient is a vulnerable subject, for instance, a person in 
detention (i.e., prisoner or ward of the state). 
24. The patient is a female who is known to be pregnant. 
Clinical Trial 
Population 
Adult male and female patients presenting with an acute myocardial 
infarction. To qualify, patients must have symptoms consistent with 
AMI (i.e. chest pain, arm pain, etc.) unresponsive to nitroglycerin, 
with symptom onset greater than 30 minutes but less than 4.5 hours 
prior to presentation at hospital and be eligible for PCI. 
 
Randomized subjects must have evidence of Acute Anterior MI only 
with ST-segment elevation of ≥ 0.2 mV in two or more anterior 
contiguous precordial leads (V1 –V4) will be included. 
Intervention 
Intravascular permissive hypothermia as an adjunct to PCI.  Cooling 
will be initiated prior to PCI with infusion of up to 1 L of cold saline 
(4°C) (according to the guideline) and with the Proteus Console set at 
32.0 degrees Celsius.  Total cooling time will be 3 hours (± 15 
minutes) and will be followed with active rewarming with the Proteus 
IVTM System to attain normothermia [36 °C (96.8°F)]. 
Length of 
Follow Up 
12 months 
Enrollment 
Initiation of enrollment: January 2017 
Completion of Enrollment: June 2019 
Follow up completed: June 2020 

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Summary of 
Statistical 
Analysis 
Primary efficacy endpoint of infarct size measured as percentage of 
total LV mass by cMR, the null hypothesis of equal infarct size 
between two arms will be tested with t-test for the study population. 
For the safety endpoint, comparison of per patient MACE rate for non-
inferiority will be made with Fisher’s exact Test. 
Planned 
Interim 
Analyses 
Two interim analyses are planned to be performed at approximately 
50% and 75% of randomization, once subjects have completed 4-6 day 
cMR follow-up. At the interim stage, the trial will be stopped to reject 
the null hypothesis of no difference or continue enrollment. 
Analysis Sets 
The Intention-to-Treat (ITT) population will be used for primary 
statistical analyses and summaries for all analyses except for Safety 
endpoints. The ITT population includes subjects who have signed an 
informed consent and have been randomized to the Test Arm or the 
Control Arm of the trial. ITT subjects will be evaluated according to 
the group to which they were randomized. 
The Per-Protocol (PP) population includes those subjects who met 
inclusion and exclusion criteria, were randomized to either the Test 
Arm or Control Arm, received the treatment to which they were 
randomized, and complied substantially with the treatment timeline 
and steps of this protocol without major protocol violations. 
The Safety Analysis Set will be used to evaluate safety endpoints. 
These will be all subjects included in the study as defined by the ITT 
analysis set. For the safety analysis subjects will be followed for all 
Adverse Events 12 months post procedure. Additionally, all subjects 
will be followed through 12 months post procedure for the incidence 
of Serious Adverse Events (SAEs), Death and Heart Failure (as 
assessed by NYHA and Kansas City Cardiomyopathy Questionnaire 
(KCCQ)). 
Trial 
Oversight 
Each participating site will dedicate one Principal Investigator to 
oversee the execution of the clinical trial in accordance with the 
protocol. 

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 INTRODUCTION 
Clinical investigations have shown that induction of hypothermia before reperfusion of 
acute coronary occlusion reduces infarct size.  A pilot study from Lund University 
demonstrated that the induction of mild hypothermia (<35°C) in ST Elevation Myocardial 
Infarction (STEMI) patients prior to performing Percutaneous Coronary Intervention 
(PCI) can save (preserve) 38% more cardiac tissue compared with the PCI alone.1 
Hypothermia has proven to be one of the most potent and consistent adjunctive therapies 
for infarct size reduction in numerous preclinical studies, when administered prior to 
reperfusion.  This is unlike the well accepted approach for therapeutic hypothermia for 
cardiac arrest, where cooling is applied after reperfusion. The mechanisms leading to 
protection are multifactorial.  However, unlike the consistent findings in preclinical 
studies, clinical trials (COOL -MI, ICE-IT, CHILL-MI) have failed to show a decrease in 
infarct size.  The major reason is likely due to the difficulty in achieving adequate cooling 
prior to reperfusion.  As shown in Table 1 below, none of the clinical trials to date has 
reached target temperature prior to reperfusion, as has been done in all of the animal 
studies. 
Table 1: Major Cooling Trials in STEMI. 
Major Cooling Trials in STEMI 
Trial 
Sample 
Size 
Target 
Temp 
(°C) 
Actual 
Temp at 
Reperfusion 
(°C) 
Temp Miss 
(°C) 
Cooling Time 
before 
Reperfusion 
(min) 
COOL -MI 168 – 
Hyp 
157 – 
Control 
33.0 
35.0 
2.0 
18 
ICE-IT 
105 – 
Hyp 
99 – 
Control 
33.0 
35 
2.0 
16 
CHILL-MI 61 – 
Hyp 
59 – 
Control 
33.0 
34.7 
1.7 
13 
 
The target temperature for each trial was 33.0 °C.  The actual temperature at the time of 
reperfusion was 1.7-2.0 °C higher than target.  This is a miss in temperature “dose” of 
around 50% [normal temperature is 37.0 °C, target temperature was 33.0 °C, (37.0 – 35.0) 
/ (37.0 – 33.0) = 50%].     

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Post hoc analysis of these trials showed that patients with anterior MI that were cooled to 
less than 35°C at the time of PCI showed a significant reduction in infarct size, supporting 
the idea of a dose response (See Figure 1).  Recent preclinical results (Stanford-ZOLL 
data) have shown that temperature at reperfusion of 32 °C is superior to 35 °C for reducing 
infarct size, confirming a dose response.  Future clinical trials will require more powerful 
cooling devices, and more consistency in implementing 18 minutes of cooling before 
reperfusion across all study sites in order to evaluate the actual effectiveness of therapeutic 
hypothermia as a protection strategy. 
 
 
Figure 1: Temperature at reperfusion for the Major Therapeutic Hypothermia in 
AMI Clinical trials. 
 
The Proteus device has a confirmed faster cooling rate.  With a duration of cooling of 18 
minutes prior to reperfusion, as occurred in the COOL -MI trial, the expected temperature 
at reperfusion is 33.3°C with the Proteus device.  This is significantly better than the 35°C 
achieved in COOL -MI and ICE-IT, and 34.7°C achieved in CHILL-MI. The relative 
effectiveness of the Proteus device for cooling, compared to the performance of the prior 
studies is shown in Figure 1 above. The addition of a bolus infusion of 4°C cold saline is 
expected to further enhance the temperature achieved at reperfusion with the Proteus 
System.  

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This Investigational Plan was developed in accordance with the requirements set forth in 
the Good Clinical Practices (E6)2, ISO 14155:2011 Clinical investigation of medical 
devices for human subjects3 - Good clinical practice, the Declaration of Helsinki, and the 
local regulatory requirements an adjunctive therapy to PCI. 
 
BACKGROUND 
Coronary heart disease complicated by acute myocardial infarction (AMI) remains a 
leading cause of death and disability worldwide.  AMI most commonly occurs when a 
coronary artery becomes occluded by thrombus following the rupture of an atherosclerotic 
plaque. Factors that may affect the size of the subsequent infarction include duration of 
ischemia, size of ischemic territory, collateral blood flow, and myocardial metabolic rate. 
Long-term sequelae of AMI include ventricular remodeling, loss of ventricular function, 
congestive heart failure, dysrhythmias, and sudden death. 
Although major gains have been made in improving the outcome of patients suffering 
AMI, and early myocardial reperfusion with the use of thrombolytic therapy or primary 
percutaneous coronary intervention (PCI) are effective, morbidity and mortality remain 
substantial.  This may be because restoration of blood flow to the ischemic myocardium 
can itself induce injury through myocardial “ischemia reperfusion injury” (IRI), which 
can be defined as that portion of the ischemia-reperfusion continuum which is preventable 
by treatment initiated after restoration of blood flow.4 It has been proposed that 50% of 
the final infarct size may be a function of IRI. 4 
Ischemia reperfusion injury is protean in its components, likely including free radical and 
reactive oxygen species, disordered vasculature, inflammatory injury, programmed cell 
death, and pathologic remodeling among others.5   Unfortunately, the cascading nature of 
these events challenge and, in the end, may defeat the single molecular target 
pharmacologic model.  The long list of failed IRI pharmacologic agents includes 
antioxidants, calcium channel blockers, anti-inflammatory drugs, sodium hydrogen 
exchange inhibitors, among others, has led some to question the importance of reperfusion 
injury in the myocardium.6 Large infarctions still occur despite timely reperfusion, due to 
reperfusion injury.  Numerous treatments have been studied to reduce reperfusion injury, 
with little success to date. 7-9 
Therapeutic hypothermia (TH) has been studied for many years as a potential therapy for 
ischemia and reperfusion.10 -16 The past few years have seen development of a broad 
literature reporting both laboratory and clinical trials of mild post-reperfusion TH in the 
treatment of disease entities as diverse as acute cardiac arrest, stroke, and myocardial 
infarction, among others.  Unlike single pharmacologic agents, TH has the potential to 
modify and ameliorate multiple pathways of injury. 

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INTENDED USE, SYSTEM OVERVIEW, & DEVICE DESCRIPTION 
 
Intended Use / Indication for Use 
The ZOLL® Proteus™ Intravascular Temperature Management (IVTM) System is 
indicated for use in adult subjects with acute myocardial infarction to induce and maintain 
hypothermia prior to percutaneous coronary intervention as an adjunctive therapy to 
reduce anterior infarct size.  The Proteus IVTM System is to be used only as part of the 
clinical investigation. 
 
System Overview 
The Proteus Intravascular Temperature Management (IVTM) System consists of four 
primary components: a single-use heat exchange catheter; heat exchange cassette; a 
temperature probe and a reusable microprocessor-driven console.  The system is designed 
to achieve and maintain patient temperatures within the range of 32 - 37°C. Its 
performance profile includes: 
1. Rapid patient cooling and warming 
2. Precise achievement and maintenance of a desired patient target temperature 
3. Quick and simple deployment: See the catheterization lab, critical care unit, 
emergency department, and other hospital settings 
Reference the Investigator Brochure for additional information on the Proteus 
IVTM System. 
The Proteus IVTM System couples a heat exchange catheter with a dual microprocessor-
driven controller to manage patient temperature. The Proteus IVTM System is designed 
to rapidly cool and warm patients, achieve and precisely maintain a target patient 
temperature and to be quickly and easily deployed. 
Cool or warm sterile saline is continuously circulated through the catheter, thereby cooling 
or warming the blood as it flows over the catheter without perfusion of fluids into the 
body. The saline is transported from the catheter to the cassette (mounted in the console) 
via extension lines. The cassette has an integral heat exchange element and a pump that 
couples with the console to cool or warm the saline being pumped through the closed 
circuit comprised of the cassette and catheter. The Proteus IVTM Console continuously 
monitors the patient temperature and controls the catheter temperature to cool, warm or 
maintain the target temperature. 

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Device Description 
4.3.1 Proteus Catheter 
The Proteus Catheter (Figure 2) is a single-use, heparin coated, endovascular heat 
exchange catheter consisting of a triple lobed, helically wound balloon mounted on the 
distal portion of a multi-lumen shaft.  The catheter is designed for placement in the Inferior 
Vena Cava via the femoral vein using a 12Fr or a 14Fr hemostatic introducer sheath.  The 
catheter has a fluid supply lumen, a fluid return lumen, a guidewire port at the proximal 
end of the catheter connecting to a guidewire lumen that accommodates guidewires with 
diameters up to 0.038”.  The expanded balloon portion of the catheter has an expanded 
diameter of 17 mm and a length of 26 cm during system operation.  The catheter has a 
radiopaque marker mounted at the distal and proximal end of the balloon portion of the 
catheter.  The distal end of the catheter has a non-traumatic soft tip.  The fluid supply and 
fluid return lumens of the catheter are connected to the cassette via extension lines 
approximately 2 meters in length, which provide the closed heat transfer fluid circuit.  The 
0.038”, 145-cm. stainless steel guidewire included in the package has a soft atraumatic 
tip. 
Figure 2 Diagram of  Proteus Catheter 
 
4.3.2 Proteus Temperature Probe 
The Proteus System measures a patient’s core body temperature using a heparin-coated 
endovascular dual output probe (X-Probe) advanced through the guidewire lumen of the 
Proteus Catheter after the catheter is placed. 
4.3.3 Proteus Cassette 
The single-use Proteus Cassette consists of a heat exchange element, a pump, a pump 
coupling to interface with the motor drive in the console and fluid lines to interface with 
the heat transfer fluid circulated by the console.  The cassette is designed to be removed 
from the portable control console allowing the catheter to remain in the patient to facilitate 

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moving the patient to another location where temperature management can continue using 
the same or another control console. 
4.3.4 Proteus Console 
The Proteus Console (Figure 3) consists of solid-state thermoelectric modules, a motor 
drive, dual fluid level detection systems and dual microprocessors.  A dilute 
polypropylene glycol/water mixture (process fluid) circulates within the console to 
provide heat exchange with the saline heat transfer fluid loop in the cassette.  This 
technology along with microprocessor proportional control of both the saline and the 
patient temperature enable the following features: 
• Designated patient temperature between 32-37°C is maintained within ± 0.3°C 
continuous calculation and display, in all ambient lighting conditions, of patient 
actual temperature, target temperature, and rate of cooling/warming 
• Redundant safety system to shut down and warn user of patient overheat or 
overcool, saline leakage, sensor failure, and electrical or mechanical malfunction 
• Control console automatically performs a hardware and software diagnostic check 
of all functional and safety systems upon startup 
• Maximum cooling and heating rates vary from patient to patient depending on the 
patient’s cardiac output, size and weight, room temperature and humidity, and the 
successful implementation of the anti-shivering medication regimen, type and 
amount anesthesia, combined use with blankets or active heating/cooling 
apparatus, body cavity exposure to the environment during surgery and other 
factors. 
Figure 3:  Proteus Console 
                                  
 
 

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Figure 4:  Proteus Catheter and Interconnection between Catheter, Temperature 
Probe (X-Probe), Cassette and Console. 
 
4.3.5 Device Labeling 
Written Instructions for Use, Operation Manual, Quick Reference Guide, and Service 
Manual for the Proteus IVTM System will be packaged with product shipped to the 
investigational sites.  The Proteus IVTM System is to be used only as part of the clinical 
investigation.  (See Proteus IVTM System Labeling) 
 
PRIOR INVESTIGATIONS 
 
Pre-Clinical Studies 
Hypothermia has been shown to reduce metabolic demand and provide ischemic 
protection.  Recent studies across numerous different animal models have demonstrated a 
strong direct relationship between myocardial temperature and infarct size.11,10,14- 18  Mild 
to moderate degrees of hypothermia (32-35°C) have resulted in significant reductions in 
infarct size when applied either before or after the onset of coronary occlusion in animal 
studies.   
In other studies, in 1996, Duncker et al, and in 1998 Miki et al, both demonstrated a dose 
response relationship between myocardial temperature and infarct size using a laboratory 
model of AMI.11,12 Subsequently, Dae et al in collaboration with Radiant Inc. 
demonstrated that therapeutic hypothermia can be induced safely and rapidly in animal 

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models using intravascular cooling.13 They then showed that hypothermic therapy initiated 
late during ischemia and continuing for several hours after reperfusion significantly 
improved reflow and reduced macroscopic zones of no-reflow and necrosis in this 
model.15  The study showed:  
• A striking reduction of myocardial infarct size.  The cooled group had an infarct 
of 9 ± 6% of the area at risk vs. 45 ± 8% of the area at risk for controls 
• Preservation of myocardial perfusion and viability in the cooled group as 
demonstrated by radionuclide imaging 
• No evidence of apoptosis in salvaged myocardium in the cooling arm.  Well-
preserved cardiac output during the cooling process. 
Of particular relevance, Gotberg et al reported in 2008 that hypothermia achieved before 
reperfusion decreased infarct size, while hypothermia initiated at the time of reperfusion 
prevented microvascular obstruction, but did not decrease myocardial infarct size. 16 
 
Human Clinical Studies   
5.2.1 COOL MI Trial  
The COOL MI Trial19 was conducted from September 2001 through April 2003. A total 
of 421 patients were enrolled (199 Control, 193 Intervention, 29 Roll-In) at 27 
investigational sites in the US, Germany and Australia.  The primary analysis population 
included 357 patients (180 Control, 177 Intervention) who received the assigned 
treatment.  The COOL MI Trial evaluated the safety and effectiveness of cooling as an 
adjunctive therapy to percutaneous coronary intervention (PCI) in patients with acute 
myocardial infarction.  Table 2 below displays enrollment characteristics. 
Table 2: COOL MI Trial Enrollment Characteristics 
 
Control  
(N=180) 
Intervention 
(N=177) 
p-value 
Anterior Myocardial 
Infarction 
77 (44%) 
74 (42%) 
0.77 
Inferior Myocardial 
Infarction 
99 (56%) 
103 (58%) 
0.77 
Failed thrombolytic therapy 
prior to enrollment 
23 (12.8%) 
18 (10.3%) 
0.67 
Time in minutes – median (interquartile range) 
From symptom onset to 
hospital presentation 
123 (69 – 201) 
114 (60 – 190) 
0.08 
From hospital presentation to 
PCI 
88 (61 – 114) 
104 (80 – 134) 
<0.0001 

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5.2.1.1 
Procedural and Angiographic Results COOL MI Trial 
The Trial demonstrated that endovascular cooling using the Radiant Medical’s (now 
ZOLL’s) Reprieve System TM in the setting of myocardial infarction was safe, well 
tolerated, and readily integrated into the existing treatment pathway.  While the primary 
effectiveness endpoint of the study was not achieved, the data provided a strong signal 
indicating that when patients were sufficiently cooled prior to reperfusion, myocardial 
damage was reduced19. 
The Control and Intervention groups were well matched in terms of culprit vessels, 
percutaneous coronary intervention (PCI) procedures and treatment success.  As expected, 
cooling did not affect the angiographic success of PCI procedures.  Of the 357 patients 
who underwent primary PCI, the majority were treated with stent implantation and a 
platelet glycoprotein receptor inhibitor.  Approximately 20% of study subjects were 
determined to have Thrombolysis in Myocardial Infarction (TIMI 3) flow prior to PCI.  
TIMI Grade Flow is a scoring system from 0-3 referring to levels of coronary blood flow 
assessed during percutaneous coronary angioplasty: 
• TIMI 0 flow (no perfusion) refers to the absence of any antegrade flow beyond a 
coronary occlusion. 
• TIMI 1 flow (penetration without perfusion) is faint antegrade coronary flow 
beyond the occlusion, with incomplete filling of the distal coronary bed. 
• TIMI 2 flow (partial reperfusion) is delayed or sluggish antegrade flow with 
complete filling of the distal territory. 
• TIMI 3 flow (complete perfusion) is normal flow which fills the distal coronary 
bed completely 
After PCI, TIMI 3 flow was achieved in approximately 92% of patients. Only about 30% 
of patients had TIMI myocardial perfusion grade 3; however the percentage was similar 
in both treatment groups and is consistent with literature reports of myocardial perfusion. 
Procedural and angiographic data are presented in Table 3 below. 
Table 3: COOL MI Trial - Procedural and Angiographic Data 
 
Control  
(N=180) 
Intervention 
(N=177) 
p-value 
Infarct related artery, Stent implantation, Glycoprotein & Stenosis Diameter 
Left anterior descending coronary 
artery 
70 (39%) 
69 (39%) 
0.91 
Circumflex artery 
13 (7%) 
14 (8%) 
0.87 
Right coronary artery 
77 (43%) 
74 (42%) 
0.93 
Stent implanted 
153 (92%) 
157 (94%) 
0.59 
Glycoprotein IIb/IIIa receptor inhibitor 140 (78%) 
142 (80%) 
0.74 

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*Thrombolysis in Myocardial Infarction 
5.2.1.2 
COOL MI Trial Results 
Of the 177 Intervention patients, 11 (6.2%) patients had the Reprieve Catheter placed in 
the emergency room (ER), one (0.6%) patient had the catheter placed in the cath lab 
holding area, and 165 (93.2%) patients had the catheter placed in the cath lab.  Overall, 
patients in the Intervention group received a median of 17 minutes (interquartile range 
(IQR): 10-27) of cooling prior to PCI.  During that time, patient temperature was 
decreased from a median of 36.2°C (IQR: 35.8-36.5) at the initiation of cooling to 35.1°C 
(IQR: 34.5-35.6) at the time of PCI (Figure 1).  The median of the minimum temperature 
reached by each patient was 33.1°C (IQR: 33.0-33.4), which was achieved in 75 minutes 
(IQR: 50-108).  Target patient temperature was set at a 33°C for 3 hours post-PCI.  Patients 
were then re-warmed at 1°C/hr until Investigator-determined normothermia was reached 
[median=36.5 (IQR: 36.2-36.8]).  Figure 5 below shows patient temperature over time 
with cooling and time to PCI.  The goal to reach target temperature of 33°C at PCI was 
not achieved in the trial, due to the inadequate cooling power of the Reprieve System.  As 
noted above, target temperature of 33°C was reached after 75 minutes of cooling, long 
after PCI had occurred. 
Initial diameter stenosis  
(mean ± std dev) 
92 ± 14% 
92 ± 12% 
0.93 
Initial TIMI flow 
Grade 0/1 
126 (71%) 
122 (69%) 
0.77 
Grade 2 
14 (8%) 
21 (12%) 
0.28 
Grade 3 
38 (21%) 
34 (19%) 
0.74 
Final diameter stenosis 
7 ± 9% 
8 ± 10% 
1.00 
Final TIMI* flow 
Grade 0/1 
2 (1%) 
5 (3%) 
0.33 
Grade 2 
7 (4%) 
12 (7%) 
0.31 
Grade 3 
170 (95%) 
160 (90%) 
0.11 
Final myocardial perfusion grade 
 
 
 
Grade 0/1 
63 (43%) 
76 (53%) 
0.11 
Grade 2 
35 (24%) 
26 (18%) 
0.27 
Grade 3 
49 (33%) 
41 (29%) 
0.54 

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Figure 5: Median Temperature and Elapsed Times for Intervention Patients 
 
5.2.1.3 
COOL MI Trial Tolerability of Cooling 
Shivering was managed according to the shivering suppression guidelines recommended 
for this study by Dr. Daniel Sessler, Chairman of the Department of Anesthesiology at the 
University of Louisville.  The recommended baseline combination of Pethidine, buspirone 
and skin warming using a forced-air blanket could be supplemented incrementally in the 
event of shivering or patient discomfort, by additional Pethidine, or by slightly increasing 
the target temperature.  If these steps were unsuccessful, patients could be actively 
rewarmed to normothermia. 
This protocol proved to be quite effective at maintaining patient comfort.  Intervention 
patients received an average of 56 mg of oral buspirone and an average of 267 mg of 
intravenous Pethidine over the course of the cooling procedure.  Of 177 patients in the 
treatment group, only one patient (0.6%) required premature warming due to intolerability 
of cooling.  Nine patients (5.1%) required a slight increase in target temperature (0.2°C – 
0.5°C) to maintain patient comfort.  Ninety-eight patients (55.7%) required supplementary 
dosing of Pethidine, but 60 of these 98 patients (61.2%) had not received the 
recommended loading dose of the anti-shivering drugs. 
COOL MI Trial Safety Results: The primary safety endpoint of the COOL MI study was 
the incidence, through 30 days, of Major Adverse Cardiac Events (MACE), defined as the 
composite of death, recurrent myocardial infarction of the target vessel and the need for 
urgent revascularization of the target vessel.  As shown in Table 4 below, there was no 
statistical difference in the incidence of MACE in the Intervention group as compared to 
the Control group.  All MACE were adjudicated by an independent Clinical Events 
Committee and none were attributed to cooling or use of the Reprieve System. Table 4 
1        2        3        4        5        6        7        8        9        10
Elapsed Time (hours)
37
36
35
34
33
Onset 
to 
Door
115 min
Door 
to 
PCI
104 min
Start Temp
= 36.2°C
Median Minimum Temp = 33.1°C
Time to Minimum Temp = 75 min
Temperature ºC
Temp at PCI = 35.1 °C
Cooling Prior to PCI = 17 min
1        2        3        4        5        6        7        8        9        10
Elapsed Time (hours)
37
36
35
34
33
Onset 
to 
Door
115 min
Door 
to 
PCI
104 min
Start Temp
= 36.2°C
Median Minimum Temp = 33.1°C
Time to Minimum Temp = 75 min
Temperature ºC
Temp at PCI = 35.1 °C
Cooling Prior to PCI = 17 min

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below demonstrates the results of the study with regard to the incidence of Major Adverse 
Cardiac Events. 
Table 4: COOL MI Trial Incidence of MACE 
 
These MACE rates observed in COOL MI compare favorably with those reported for 
similar patients in recent AMI trials, such as ADMIRAL, CADILLAC, DANAMI and 
RAPID MI-ICE (Table 5). 
Table 5 Incidence of MACE for Comparable Patients in Recent AMI Trials  
Trial 
Death 
Reinfarction 
Revascularizatio
n 
COOL MI (Treatment Group) 
(n=177) 
3.4% 
0.6% 
2.3% 
ADMIRAL (n=149)17 
3.4% 
1.3% 
4.7% 
CADILLAC (n=524)18 
2.7% 
0.8% 
1.6% 
DANAMI-2 (n=790)19 
6.6% 
1.6% 
NA 
RAPID MI-ICE (n=20)1 
0% 
0% 
0% 
5.2.1.4 
COOL MI Trial Adverse Events Related to Cooling 
Potential adverse events related to cooling (e.g., arrhythmia or hemodynamic 
complications) and to placement and/or use of the Reprieve Catheter (e.g., vascular or 
thrombogenic complications) were also evaluated as a secondary endpoint.  The incidence 
of these types of events is presented.  It is important to note that these complications are 
also risks of myocardial infarction and coronary intervention themselves. Table 6 below 
reports the incidence of non-MACE complications. 
Events through 30 days 
Control  
(N=180) 
Intervention 
(N=177) 
p-value 
MACE 
7 (3.9%) 
11 (6.2%) 
0.45 
 
Death 
4 (2.2%) 
6 (3.4%) 
0.71 
 
Recurrent MI 
3 (1.7%) 
1 (0.6%) 
0.63 
 
Urgent Revascularization 
0 (0%) 
4 (2.3%) 
0.12 

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Table 6: Incidence of Other Complications 
Events through 30 days 
Control  
(N=180) 
Intervention 
(N=177) 
p-value 
Bradyarrhythmia 
41 (22.8%) 
46 (26.0%) 
0.56 
Ventricular Tachycardia/Fibrillation 
36 (20.0%) 
31 (17.5%) 
0.64 
Cardiogenic Shock 
11 (6.1%) 
22 (12.4%) 
0.06 
Pulmonary Edema 
3 (1.7%) 
6 (3.4%) 
0.49 
Vascular Complications  
      Retroperitoneal bleed 
      Hematoma >6cm 
      Pseudoaneurysm 
      AV fistula 
15 (8.3%) 
2 (1.1%) 
12 (6.7%) 
1 (0.6%) 
1 (0.6%) 
15 (8.5%) 
1 (0.6%) 
13 (7.3%) 
3 (1.7%) 
0 (0%) 
0.90 
0.95 
0.99 
0.63 
0.95 
Bleeding Requiring Transfusion  
14 (7.8%) 
20 (11.3%) 
0.34 
Deep Venous Thrombosis 
0 
3 (1.7%) 
0.24 
Pulmonary Embolism 
3 (1.7%) 
0 
0.24 
Stroke 
1 (0.6%) 
0 
0.95 
Arrhythmias are a known risk of moderate to severe hypothermia.  In the COOL MI trial, 
with its mild hypothermia target temperature, arrhythmias were not more common and 
appeared to be primarily related to ischemia and/or the coronary intervention.  
Cardiogenic shock requiring treatment with an intra-aortic balloon pump trended toward 
a higher incidence in the hypothermic group.  However, the majority of shock cases 
appeared to be more related to complicated MIs and/or complex interventions than to 
cooling.  Other potential contributory factors (e.g., age, weight, Pethidine dose) were 
compared between shock and stable patients; however, no causal relationships were 
apparent.  The majority of the vascular complications reported in the Intervention group 
were related to the arterial access site for the PCI procedure rather than the venous access 
site for the cooling catheter.  Three cases of deep venous thrombosis (DVT) were reported 
in the Intervention group. 
5.2.1.5 
COOL MI Trial Effectiveness Results 
The primary effectiveness endpoint in the COOL MI study was infarct size, measured 
using SPECT imaging at 30 days.  Overall, there was no observed difference in infarct 
size (%LV) between study groups (Table 7).  The secondary effectiveness endpoints of 
LV ejection fraction, CK-MB release, and ST-segment resolution, likewise did not 
demonstrate a difference between the Intervention and Control groups. 

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Table 7: COOL MI Results 
 
Control  
Intervention 
p-value 
% LV Infarct Size  (N) 
     mean ± std dev 
     median 
157 
13.8 ± 15.1 
10 
168 
14.1 ± 14.3 
10 
0.83 
LV Ejection Fraction  (N) 
     mean ± std dev 
     median 
104 
55.2 ± 11.4 
54 
115 
53.0 ± 12.0 
53 
0.17 
Peak CK-MB  (N) 
     mean ± std dev 
     median 
167 
42.8 ± 48.1 
33.9 
168 
49.1 ± 50.7 
33.6 
0.25 
ST-segment resolution - 90 min. post-PCI 
(N) 
      < 30% 
      30 - 69% 
      ≥ 70% 
90 
11.1% 
27.8% 
53.3% 
82 
20.7% 
35.4% 
39.0% 
 
0.13 
0.36 
0.09 
ST-segment resolution - 180 min. post-PCI 
(N) 
      < 30% 
      30 - 69% 
      ≥ 70% 
79 
10.1% 
20.3% 
60.8% 
80 
16.3% 
27.5% 
51.3% 
 
0.36 
0.38 
0.30 
 
In addition, no statistically significant differences were demonstrated when the 
Intervention and Control patients were compared based on the following stratifications:  
infarct location, time from onset of symptoms to PCI, prior MI, or TIMI flow prior to PCI.  
However, subsequent analysis revealed a strong relationship between final infarct size and 
patient temperature at the time of reperfusion. 
The mean temperature at the time of reperfusion, or more specifically, at the time of first 
balloon inflation, was 35.1°C.  As shown in Figure 6, in the population of patients with 
anterior myocardial infarction, those patients who had a temperature <35°C at the time of 
reperfusion had a statistically significant reduction in final infarct size as compared to 
both the control group (9.3% vs. 18.2%, p=0.05) and those with a temperature ≥35°C 
(9.3% vs. 21.9%, p=0.01). 

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5: Mean Infarct Sizes (%LV) of Patients with Anterior Infarctions 
  
 
 
 
 
 
 
 
 
 
This effect has a strong basis in physiology and was consistent across other clinical 
measures, i.e., there was a trend toward decreased CK-MB release and increased LV 
Ejection Fraction in the cooled patients.  This effect is not attributable to differences in 
baseline clinical or angiographic variables.  In fact, those patients with a temperature 
<35°C were more likely to have occlusion of the proximal versus mid left anterior 
descending coronary artery and a longer time to reperfusion.  These factors would be 
expected to increase infarct size in this group, but the observed reduction in infarct size 
appears to be the result of cooling. 
5.2.2 COOL MI II Trial  
Because of the encouraging results in patients with anterior AMI’s in whom hypothermia 
had been achieved at the time of PCI, COOL MI II was initiated.  Additionally, COOL 
MI II Trial was intended to verify the feasibility of initiating cooling earlier in the 
treatment pathway (e.g., in the emergency department).  Only a fraction of the anticipated 
sample size were enrolled before the trial was ended early because the sponsor became 
financially insolvent after only 41 patients were enrolled. The study data were submitted 
by the sites to a Data Management CRO.  As a result, the final report is not currently 
available because the data was not released to ZOLL by the Data Management CRO upon 
ZOLL acquisition of Radiant Medical.   
In COOL MI II, all cooling was initiated in the Cath Lab even though the focus was on 
earlier cooling.  Since earlier initiation of cooling was not accomplished, reaching the goal 
of a core temperature of 35° C before PCI was dependent on the more powerful GTO 
System.  This was accomplished in 26 of the 27 patients without the intentional delay of 
PCI.  Pivotal data for 23 patients were available and the mean time to reach 35°C was 6.1 
17.9 
9.3 
21.9 
18.2 
0 
10 
20 
30 
All Treatment < 35°C 
≥ 35°C Control 
%LV 
p=0.92 
p=0.05 
p=0.30 
(n=61) 
(n=16) 
(n=38) 
(n=59) 
Subject groups: 
i)   All Intervention patients 
regardless of temperature at PCI 
ii)  Intervention patients cooled 
to      < 35°C at PCI 
iii) Intervention patients > 35°C 
at PCI 
iv) Control patients 
Subject groups: 
i)   All Intervention patients 
regardless of temperature at PCI 
ii)  Intervention patients cooled 
to      < 35°C at PCI 
iii) Intervention patients > 35°C 
at PCI 
iv) Control patients 
Figure 6: Mean Infarct Sizes (%LV) of Patients with Anterior Infarction 

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minutes (± 3.0), 34°C was 14.5 minutes (± 7.9) and 33°C was 31.3 minutes (± 29.9).  Data 
showed 15 of the patients were cooled to 32°C; the mean time was 36.1 minutes (± 14.0).  
Efforts to initiate cooling as early as possible resulted in a median of 39 minutes of cooling 
time prior to PCI, a significant improvement over the median of 18 minutes of cooling 
time achieved in the previous study.  In addition, the median door-to-balloon time was 
106 minutes for these COOL MI II patients, compared to a median of 104 minutes for 
Test patients in the previous study, indicating that PCI was not delayed by the introduction 
of cooling.  By focusing on cooling earlier in the treatment pathway, additional cooling 
time can be achieved without significant adverse impact on time to reperfusion. 
5.2.2.1 
COOL MI II Trial Adverse Events 
As with COOL MI, the primary safety endpoint of the COOL MI II study was the 
incidence, through 30 days, of MACE. Shown below are the adverse events in the COOL 
MI II trial in the intent to treat (ITT) population.  Table 8 combines the Feasibility and 
Pilot hypothermia groups for a total of 41 patients (12 Feasibility and 29 Pivotal). 

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Table 8:  Incidence of MACE and Other Complications 
Events through 30 Days 
Normothermia 
Hypothermia 
Enrollment 
10 
41 
UADE 
0 
0 
Cardiac 
  
  
     Death 
0 
1 (2.4%) 
     Repeat MI 
0 
1 (2.4%) 
     Repeat PCI 
1 (10%) 
3 (7.3%) 
     CABG 
0 
2 (4.9%) 
     Hypotension / Shock 
1 (10%) 
6 (14.6%) 
     CHF 
0 
2 (4.9%) 
     Pericardial Effusion 
0 
1 (2.4%) 
     Pericarditis 
0 
1 (2.4%) 
     HTN 
0 
1 (2.4%) 
Arrhythmias  
  
  
     Ventricular Fibrillation 
0 
4 (9.8%) 
     Vent. Tachycardia 
1 (10%) 
7 (17.1%) 
     Frequent PACs 
1 (10%) 
0 
     SVT 
0 
1 (2.4%) 
     Atrial Fibrillation 
0 
11 (26.8%) 
Vascular Events 
  
  
     Bleeding requiring transfusion 
0 
3 (7.3%) 
     Thrombocytopenia 
0 
2 (4.9%) 
     Anemia 
0 
2 (4.9%) 
     Hematoma > 6cm 
0 
2 (4.9%) 
     DVT   
0 
1 (2.4%) 
     Local Tissue Trauma 
0 
1 (2.4%) 
     Epistaxis 
1 (10%) 
0 
     Hemoptysis 
0 
1 (2.4%) 
     Stroke 
0 
0 
Respiratory Events 
  
  
     Pulmonary Edema 
0 
8 (19.5%) 
     Pulmonary Embolism 
0 
0 
     Hypoxia 
0 
1 (2.4%) 
     Respiratory Failure 
0 
1 (2.4%) 
     Plural Effusion 
0 
3 (7.3%) 
     Increased Pulmonary HTN 
1 (10%) 
0 
     Pneumonia 
1 (10%) 
0 

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Renal 
  
  
     Renal requiring Treatment 
1 (10%) 
2 (4.9%) 
     Hemodialysis 
0 
0 
     UTI 
0 
2 (4.9%) 
     Hematuria 
1 (10%) 
0 
Other 
  
  
     Nausea / Vomiting 
1 (10%) 
15 (36.6%) 
     Systemic Infection 
0 
3 (7.3%) 
     Fever 
0 
3 (7.3%) 
     Muscular Pain 
1 (10%) 
3 (7.3%) 
     Rhabdomyolysis 
1 (10%) 
0 
     Mental Status Changes 
0 
2 (4.9%) 
     Hypokalemia 
0 
1 (2.4%) 
     Vaginal Infection 
0 
1 (2.4%) 
5.2.3 COOL RCN Trial 
The COOL RCN (Radio-Contrast nephropathy) trial was undertaken to evaluate whether 
endovascular cooling provides more effective protection for patients at high risk of 
experiencing RCN.  The trial was designed as an international, multicenter, 1:1 
randomized controlled trial of up to 400 subjects at up to 35 investigational sites.  Subjects 
with a calculated Creatinine clearance of 20 – 50 mL/min and scheduled for a diagnostic 
or interventional catheterization procedure were enrolled. The trial utilized Radiant 
Medical’s Reprieve System. The study was commenced in March 2006 and was 
terminated after enrolling only 136 subjects due to the financial insolvency of Radiant 
Medical. 
Table 9: COOL RCN Trial: Adverse Events Incidence of Complications In-
Hospital  
  
Normothermia  Hypothermia 
P Value 
Enrollment 
70 
58 
  
Nausea/Vomiting 
6 / 70 (8.6%) 
26 / 58 
(44.8%) 
<0.01 
Bradycardia 
2 / 70 (2.9%) 
7 / 58 (12.1%) 0.04 
Bleeding Requiring 
Transfusion 
7 / 70 (10.0%) 
1 / 58 (1.7%) 
0.05 
Atrial Fibrillation 
2 / 70 (2.9%) 
3 / 58 (5.2%) 
0.5 
CABG 
4 / 70 (5.7%) 
1 / 58 (1.7%) 
0.25 
Pulmonary Edema 
4 / 70 (5.7%) 
1 / 58 (1.7%) 
0.25 
Renal Complication 
2 / 70 (2.9%) 
3 / 58 (5.2%) 
0.5 

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Normothermia  Hypothermia 
P Value 
     Acute Renal Failure 
2 / 70 (2.9%) 
2 / 58 (3.4%) 
0.85 
     Elevated Serum Creatinine 
0 / 70 (0%) 
1 / 58 (1.7%) 
-- 
     Hemodialysis 
2 / 70 (2.9%) 
0 / 58 (0%) 
-- 
     Urinary Tract Infection 
3 / 70 (0.4%) 
1 / 58 (1.7%) 
0.41 
Hypotension/Shock 
1 / 70 (1.4%) 
3 / 58 (5.2%) 
0.22 
Hematoma >6cm 
0 / 70 (0%) 
3 / 58 (5.2%) 
-- 
SVT 
0 / 70 (0%) 
2 / 58 (3.4%) 
-- 
MI 
0 / 70 (0%) 
1 / 58 (1.7%) 
-- 
Ventricular Tachycardia 
1 / 70 (1.4%) 
1 / 58 (1.7%) 
0.89 
Death 
0 / 70 (0%) 
1 / 58 (1.7%) 
-- 
Repeat PCI 
1 / 70 (1.4%) 
1 / 58 (1.7%) 
0.89 
Stroke 
0 / 70 (0%) 
1 / 58 (1.7%) 
-- 
 
Table 10: COOL RCN Trial: Incidence of Complications to 30 Days  
  
Normothermia 
Hypothermia 
P Value 
Enrollment 
70 
58 
  
Renal 
7 
2 
0.15 
     Acute Renal Failure 
5 
1 
0.15 
     Renal Stent 
2 
0 
-- 
     Kidney Infection 
0 
1 
-- 
Cardiac 
8 
14 
0.1 
     MI 
1 
1 
0.89 
     CABG 
2 
3 
0.5 
     PCI 
1 
3 
0.22 
 
 

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Normothermia 
Hypothermia 
P Value 
     PCI or CABG 
3 
6 
0.18 
     Death - Cardiac 
1 
2 
0.45 
     Shock 
0 
3 
-- 
     CHF 
2 
1 
0.67 
     Angina 
1 
0 
-- 
     Hypertension 
0 
1 
-- 
Arrhythmia 
3 
3 
0.81 
     Atrial Fibrillation 
2 
1 
0.67 
     Bradycardia 
0 
2 
-- 
     SVT 
1 
0 
-- 
     Ventricular Fibrillation 
0 
0 
-- 
Non-Cardiac 
3 
3 
0.81 
     Stroke 
1 
0 
-- 
     Bleed/Transfusion 
2 
3 
0.5 
     Dialysis  
0 
0 
-- 
Vascular Complications Requiring  Surgery  
0 
0 
-- 
Rehospitalization 
13 
13 
0.59 
Other 
9 
12 
0.23 
     Anasarca 
1 
  
-- 
     Fatigue 
1 
  
-- 
     Ischemic Bowel 
1 
1 
0.89 
     Hypoglycemia 
1 
  
-- 
     Lesion Excision 
1 
  
-- 
     Anemia 
1 
  
-- 
     Hiatal Hernia 
1 
1 
0.89 
     Pulmonary Edema 
1 
  
-- 
     Knee Injury 
1 
  
-- 
     Rash 
  
1 
-- 
     Debridement of Sternal Wound 
  
1 
-- 
     Leg Weakness 
  
1 
-- 
     Nausea/Vomiting 
  
2 
-- 
     Dehydration 
  
1 
-- 
     Acute Respiratory Failure 
  
1 
-- 
     Metabolic Acidosis 
  
1 
-- 
     Back Pain 
  
1 
-- 
     Systemic Infection 
  
1 
-- 

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5.2.3.1 
Unanticipated Adverse Events 
(i) 
COOL MI Trial – Unanticipated Adverse Events 
There was one Unanticipated Adverse Device Effect (UADE) in the COOL MI Trial; A 
patient experienced nasopharyngeal trauma and bleeding potentially caused by the 
nasoesophageal temperature probe used as part of the Reprieve System. This resulted in a 
modification to the Informed Consent Form to explain the risk of nasal trauma and/or 
bleeding due to the nasoesophageal probe.  
(ii) 
COOL MI II Trial – Unanticipated Adverse Events 
There were no UADE’s in the COOL MI II Trial. 
(iii) 
COOL RCN Trial – Unanticipated Adverse Events 
There was one UADE in the COOL-RCN Trial.  A 73 year old male with chronic renal 
insufficiency and a history of aortobifemoral bypass scheduled for cardiac catheterization.  
The patient was randomized to the Hypothermia arm. The Reprieve catheter was placed 
via the left femoral vein.  The angiogram and stenting procedures were performed via 
right radial arterial access.  After approximately 1 hour of cooling, the patient complained 
that his feet were itching and it was noted that the patient’s left foot and leg were cyanotic 
up to mid-thigh, with no left DP pulse, and  the right foot was slightly discolored.  He was 
subsequently rewarmed at the maximum rate for approximately 40 minutes.  It was 
observed that the cyanosis lightened as the patient rewarmed and was apparently resolved 
with no further sequelae after discontinuation of treatment with the Reprieve catheter, 
indicating that cooling with the device contributed to the reduced peripheral circulation.  
The already compromised peripheral vascular circulation is suspected to have been 
exacerbated by hypothermia induced vasoconstriction. It is known that hypothermia 
induces superficial vasoconstriction, but this degree of cyanosis had not been observed 
with previous use of the device.  Additionally, after the patient had received Pethidine and 
versed as part of the anti-shivering protocol, his respiration became depressed, requiring 
assisted ventilation, Romazicon and Narcan. It is possible that this transient hypoxic event 
may have also contributed to the cyanosis. 
 
Lower extremity cyanosis in the presence of peripheral vascular insufficiency had 
not been identified in the protocol or informed consent document as a potential risk of 
mild hypothermia or use of the Reprieve catheter. The resolution of the cyanosis upon 
rewarming and removal of the catheter indicated that these may have contributed to the 
event. The risk section of the protocol and informed consent were subsequently revised.  
5.2.4 ICE- IT Trial 
The Intravascular Cooling Adjunctive to Percutaneous Coronary Intervention for Acute 
Myocardial Infarction Trial (ICE-IT) 23 randomized 228 patients presenting with an acute 

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MI within 6 hours of symptom onset to endovascular cooling concomitant with PCI versus 
routine PCI. The primary endpoint of infarct size at 30 days as measured by SPECT 
imaging was similar between the 2 groups (10% for the hypothermia group versus 13% 
for the control group, p = 0.14). Like the COOL MI trial, ICE-IT was also an overall 
negative trial. But while TH did not demonstrate any significant decrease in infarct size 
overall, a trend towards benefit was again observed on post-hoc analysis of the subgroup 
with anterior infarction who were sufficiently cooled to a temperature of < 35°C at the 
time of revascularization (infarct size of 12.9% of the left ventricle in the TH population 
compared to 22.7% in the control group, p = 0.09).23 
5.2.5 RAPID-MI ICE Trial 
Recently, Lund University presented a preliminary report of their RAPID-MI ICE Trial.1 
This trial enrolled 20 patients presenting with acute myocardial infarction, and 10 patients 
each were randomized to TH by intravascular cooling or a control group.  Cooling was 
accomplished with a combination of 2L of cold saline infusion and the Phillips InnerCool 
catheter-based cooling system.  The endpoint was infarct size normalized to myocardium 
at risk assessed by cardiac magnetic resonance using T2 weighted imaging and late 
gadolinium enhancement.  Although the sample size is relatively small, the trial produced 
a number of potentially important results: 
• Core body temperature less than for 35°C was achievable before reperfusion without 
significant delay in the door to balloon time. 
• Infarct size normalized to myocardium at risk was reduced by a remarkable 38% in 
patients receiving hypothermia. 
• There were also significant decreases in peak and cumulative Troponin I or T in the 
hypothermia group. 
5.2.6 CHILL-MI Trial 
Lund University recently reported the results of the CHILL-MI trial37, which was a multi-
center study of 120 patients with STEMI (< 6 hours) planned to undergo PCI who were 
randomized to hypothermia induced by rapid infusion of 600 – 2000 ml of cold saline and 
endovascular cooling, or standard of care.  Hypothermia was initiated before PCI and 
continued for 1 hour after reperfusion.  The primary endpoint was infarct size as a 
percentage of the myocardium at risk (IS/MaR), assessed by cardiac MRI at 4±2 days.  
The goal to reach target temperature of 33°C at reperfusion was also not achieved in the 
CHILL-MI trial, due to the inadequate cooling power of the cooling device.  Patients 
randomized to cooling achieved a core body temperature at reperfusion of 34.7°C with a 
9 minute longer door-to-balloon time.  Hypothermia induced by cold saline infusion and 
endovascular cooling was feasible and safe, however, there was no significant difference 
in IS/MaR between the groups.  Exploratory analysis of early anterior infarctions (0-4 hrs) 
showed a significant reduction in IS/AAR of 33% (p<0.05).  Further, the incidence of 

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heart failure was lower with hypothermia at 45 days (3% vs 14%, p<0.05).  This trial, as 
the others cited above, shows potential efficacy of cooling in patients with anterior 
STEMI, supporting further research for confirmation. 
5.2.7 Induction of Mild Systemic Hypothermia With Endovascular Cooling 
During Primary Percutaneous Coronary Intervention for Acute 
Myocardial Infarction 
 
This multi-center study included 42 patients with acute myocardial infarction (AMI) 
(onset less than 6hrs) and evaluated the safety and feasibility of endovascular cooling 
during primary PCI for AMI. 39 Subjects were randomized to PCI with or without 
endovascular cooling (target core temperature 33°C). Cooling was maintained for 3 h after 
reperfusion. Skin warming, oral buspirone, and intravenous meperidine were used to 
reduce the shivering threshold. The primary end point was major adverse cardiac events 
at 30 days. Infarct size at 30 days was measured using SPECT imaging. All patients 
successfully cooled did achieved a core temperature below 34°C (mean target temp 33.2 
± 0.9°C). MACE events occurred in 0% vs. 10% (p = NS) of treated versus control 
patients. The median infarct size was not significantly smaller in patients who received 
cooling compared with the control group (2% vs. 8% of the left ventricle, p = 0.80). 
5.2.8 VELOCITY Trial 
The VELOCITY trial38 randomized 54 STEMI patients at 7 centers in the United States 
and Canada to emergent PCI with (n = 28) or without (n = 26) hypothermia induced by 
the Velomedix Automated Peritoneal Lavage System (Velomedix; Menlo Park, CA) 
between January 2013 and January 2014. Baseline characteristics were similar between 
the 2 groups, and 46.3% of all infarcts were anterior. 
Hypothermia (core temperature at or below 34.9°C) was achieved in 96.3% of patients 
and PCI was performed in all but 1 patient in each treatment group. Median door-to-
balloon time was shorter in the control vs hypothermia group (47 vs 62 minutes; P = 
.007). Among the 46 PCI patients who underwent MRI 3 to 5 days post procedure, the 
median myocardial infarct size was similar in the control vs hypothermia group (16.1% 
vs 17.2% of LV mass; P = .54). 
VELOCITY Investigators observed that prolonged door-to-balloon time in the 
hypothermia group may have attenuated the effect of hypothermia on infarct size though 
it is unlikely have been totally responsible for absence of effect as DTB times were short 
in both groups and within the range wherein further reductions in mortality may not be 
realized. 

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At 30-day follow-up, no patients in the control group had a primary composite safety 
endpoint event, compared with 6 (21.4%) of the patients who underwent hypothermia 
(P = .01). Further details in Section 5.2.8.1. 
In conclusion, the VELOCITY study found that controlled systemic hypothermia through 
automated peritoneal lavage may be safely and rapidly established in patients with 
evolving STEMI undergoing primary PCI at the expense of a modest increase in door-to-
balloon time. In the VELOCITY randomized trial, peritoneal hypothermia was associated 
with an increased rate of adverse events (including stent thrombosis) without reducing 
infarct size. Adequately powered randomized trials (likely limited to patients with anterior 
MI) are needed to assess the effect of rapidly induced hypothermia on myocardial salvage 
and clinical outcomes after primary PCI. 
5.2.8.1 VELOCITY Trial Adverse Events at 30 Days 
At 30-day follow-up, no patients in the control group had a primary composite safety 
endpoint event (death, reinfarction, ischemia-driven TLR, major bleeding, sepsis, 
pneumonia, peritonitis, severe arrhythmias, or renal failure), compared with 6 (21.4%) 
of the patients who underwent hypothermia (P = .01). Four patients (14.3%) experienced 
MACE (cardiac death, reinfarction, or ischemia-driven TVR), and 3 (11.0%)—all in the 
hypothermia arm—developed definite stent thrombosis. 

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Table 11: VELOCITY Trial Clinical Event Rates Within 30 Days 
 
5.2.9 EU AMI Case Series 
ZOLL is currently enrolling patients in the COOL-AMI EU Case Series Trials to assess 
the ability to integrate hypothermia into the current pathway for patients receiving PCI for 
ST elevation MI.  To date, 308 patients have been enrolled at 36 sites in the EU.  Both 
anterior and non-anterior STEMI patients have been enrolled, and cooling is performed 
using the ZOLL Thermogard XP (TGXP) System or Proteus IVTM system. .  A series of 
six standards has been developed and monitored to enable consistency in the execution of 
the protocol.  The standards include delivery of the antishivering regimen correctly, 
delivery of 1 L of iced saline before PCI, and at least 18 minutes of cooling delivered prior 
to wire crossing the lesion.  Feedback in the form of a report card (Figure 7) is provided 
to the site after each case as indicated in the following diagram: 
Figure 7:  Report Card Standards 
 

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These six standards are consistently achieved at all sites.  The 18 minute duration of 
cooling matches the average duration of cooling in the previous EU COOL AMI trial.  
The ability to deliver 18 minutes of cooling prior to PCI is consistently achieved in the 
recent EU Case Series, where the door to balloon (DTB) times, at all sites, were less than 
60 minutes (ranging from 38 minutes to 58 minutes).  This is far less than the maximum 
door to balloon time of 90 minutes recommended by the current guidelines for PCI, 2011 
ACCF/AHA/SCAI PCI Guideline24,50).  The experience of one of the sites has been 
published26, and notes that the average DTB time for the first 11 patients enrolled in the 
trial was 38 minutes, compared to a mean DTB time of 37 minutes for all patients 
presenting with STEMI without cooling.  In view of the validation that implementation of 
hypothermia in the treatment pathway for PCI of STEMI patients is feasible, ZOLL has 
also conducted the COOL-AMI EU PILOT Trial, following the same standards of 
implementation, with cooling done by the more powerful Proteus device.  The goal is to 
maximize the dose of cooling prior to PCI. 
5.2.10 COOL-AMI EU PILOT Trial 
ZOLL has completed enrollment in the COOL-AMI EU PILOT Trial that evaluated the 
retention of subjects after integrating therapeutic hypothermia using the ZOLL Proteus 
IVTM System into existing STEMI treatment protocols for subjects who presented with 
acute anterior myocardial infarction.  50 subjects were randomized at 16 sites in the EU. 
22 patients (88%; 95% confidence interval [CI]: 69-97%) in the hypothermia group and 
23 patients (92%; 95% CI: 74-99) in the control group completed cardiac magnetic 
resonance imaging at four to six days and 30-day follow-up. A series of three standards 
were monitored to enable consistency in the execution of the protocol.  The standards 
included delivery of the antishivering regimen correctly, delivery of up to 1 L of iced 
saline, and 18 minutes of cooling delivered prior to wire crossing the lesion. Patients with 

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anterior STEMI were rapidly and safely cooled. Intravascular temperature at coronary 
guidewire crossing after 20.5 minutes of endovascular cooling decreased to 33.6°C 
(range 31.9-35.5°C), which is ≥1.1°C lower than in previous cooling studies. There 
was a 17-minute (95% CI: 4.6-29.8 min) cooling-related delay to reperfusion. In the “per 
protocol” analysis, median infarct size/left ventricular mass was 16.7% in the hypothermia 
group versus 23.8% in the control group (absolute reduction 7.1%, relative reduction 30%; 
p=0.31) and median left ventricular ejection fraction (LVEF) was 42% in the hypothermia 
group and 40% in the control group (absolute reduction 2.4%, relative reduction 6%; 
p=0.36). There were no statistically significant differences between the groups, in adverse 
events or serious adverse events49. 
 
Summary and Clinical Trial Rationale 
Previous clinical trials in patients experiencing acute myocardial infarction (AMI) have 
demonstrated that therapeutic hypothermia is safe, well tolerated and showed reductions 
in infarct size. Additionally, recent preclinical results (Stanford-ZOLL data) have shown 
that temperature at reperfusion of 32 °C is superior to 35 °C for reducing infarct size, 
confirming a dose response. Future clinical trials will require more powerful cooling 
devices, and more consistency in implementing 18 minutes of cooling before reperfusion 
across all study sites in order anterior infarctions. It is therefore the objective of the 
COOL-AMI EU PIVOTAL Trial to evaluate the actual effectiveness of therapeutic 
hypothermia as a protection strategy. 
Further clinical trials are needed to evaluate more powerful cooling devices, along with a 
refined therapeutic hypothermia protocol (target temperature of 32°C + 18 minutes of 
cooling prior to PCI). It will also be important to understand whether adequate cooling to 
32°C + 18 minutes of cooling prior to PCI can be implemented into existing STEMI 
treatment protocols with no significant delay in door-to-balloon times. This trial aims to 
address the need for a powered clinical evaluation assessing the safety and effectiveness 
the Proteus IVTM for this refined therapeutic hypothermia protocol as an adjunct therapy 
for AMI patients undergoing PCI. Among these refinements are: 1) A larger dose of 
cooling was achieved with the Proteus System (temp at PCI was 33.6°C as opposed to 
35°C for COOL MI), 2) Delivery of at least 18 minutes of cooling prior to PCI was 
possible (mean 20 minutes in the EU Pilot Study), 3) the anti-shivering protocol was 
refined and worked successfully, and 4) the use of report cards for every case to track : a) 
anti-shivering protocol impementation, b) infusion of 1 liter of cold saline prior to PCI, c) 
18 minutes of cooling prior to PCI, d) door to balloon time less than 90 minutes, e) total 
ischemic time less than 6 hours, and f) proper administration of dual antiplatelet therapy 
(DAPT) are all refinements ready to be implemented. 
  

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CLINICAL TRIAL PLAN 
 
Trial Objective 
The objective of this randomized clinical trial is to evaluate the safety and effectiveness 
of therapeutic hypothermia, using the ZOLL Proteus IVTM System, as an adjunctive 
therapy for patients presenting with acute anterior myocardial infarction and undergoing 
PCI. in comparison with patients with acute anterior myocardial infarction and undergoing 
PCI only. 
 
Trial Endpoints 
6.2.1 Primary Effectiveness Endpoint 
Relative reduction of 20% in mean anterior myocardial infarct size (IS), as determined by 
Cardiac Magnetic Resonance (cMR) imaging at 4-6 days post infarct in the Test Arm 
(cooling + PCI) compared to the Control Arm (PCI only). Infarction Size (IS) is defined 
as % Left Ventricular Mass as measured by Cardiac Magnetic Resonance (cMR) imaging. 
Infarct Size (IS) will be assessed by Cardiac Magnetic Resonance (cMR) at 4 – 6 days 
following the index procedure.  
The trial is considered to have met the primary efficacy endpoint if the Test Arm 
demonstrates a 20% relative reduction in infarct size compared to the Control Arm. 
The ITT analysis set will be used for primary statistical analyses and summaries. The ITT 
population includes those subjects who have signed an informed consent and have been 
randomized to the Test Arm or the Control Arm of the trial. ITT subjects will be evaluated 
according to the group to which they were randomized. 
The PP analysis set will also be evaluated. The PP population includes those subjects who 
met inclusion and exclusion criteria, were randomized to either the Test or Control arm, 
received the treatment to which they were randomized, and complied substantially with 
the treatment timeline and steps of this protocol without major protocol violations. 
6.2.2 Primary Safety Endpoint 
Per-patient rate of composite Major Adverse Cardiac Events (MACE) subjects, defined 
as Cardiac Death (CD), All Myocardial Infarction (All MI) and Clinically-Indicated 
Target Lesion Revascularization (CI-TLR) at 30 day follow-up; non-inferiority to the 
control. 
6.2.3 Additional Assessments: Demographics and Other Parameters 
Subject demographics and various baseline characteristics will also be collected. 
Additional clinical data collected and evaluated will include the number of patients who 
can successfully be enrolled and randomized, the timing of subject presentation to 
hospital, the timing of therapeutic and adjunctive interventions, the timing of reaching the 

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target temperature zone, temperature at PCI, subsequent maintenance of hypothermia and 
temperature data from the IVTM System. Observations will be evaluated relating to the 
use of the ZOLL Proteus IVTM System and how it performs in relation to the induction 
of therapeutic cooling and follow-up cMR imaging. New York Health Association24 
(NYHA) Functional Class and Kansas City Cardiomyopathy Questionnaire25 (KCCQ) 
will be evaluated at12 month follow-up.  
 
 
Trial Design 
This clinical trial is a multicenter, prospective, interventional, randomized-controlled trial. 
Randomization will be in a 1:1 ratio, Test Arm (PCI + Cooling) or Control Arm (PCI 
alone) in up to a total of 500 patients (250 subjects in each arm), at up to 70 clinical sites. 
 
Patient Population 
Subjects will include those who present to the Emergency Department (ED) and / or Cath 
lab, who meet the trial eligibility requirements and who can provide informed consent for 
cooling treatment. Subjects considered for enrollment in this trial will include adult 
patients presenting with an acute anterior myocardial infarction. To qualify, patients must 
have symptoms consistent with AMI (i.e., chest pain, arm pain, etc.) unresponsive to 
nitroglycerin, qualifying ST-segment elevation of ≥ 0.2 mV in two or more anterior 
contiguous precordial leads (V1-V4), with symptom onset greater than 30 minutes, but 
less than 4.5 hours prior to presentation at hospital, and be eligible for PCI. This ensures 
that the overall ischemic time from symptom onset to time of wire crossing is less than 6 
hours.   
Subjects randomized to the Test Arm will receive intravascular cooling with the Proteus 
IVTM device.  While undergoing temperature management, the Anti-shivering Protocol 
must be followed (see Attachment II).  
 
Selection Criteria 
Patients shall be screened to the following inclusion and exclusion criteria. Patients are 
qualified for participation only if all Inclusion Criteria have been met and all Exclusion 
Criteria have been confirmed not present. 
 
Inclusion Criteria 
All Inclusion Criteria must be answered YES for subject to satisfy Inclusion Criteria: 
 
1. The patient is ≥ 18 years of age. 
2. The patient has symptoms consistent with AMI (i.e. chest pain, arm pain, etc.) and 
unresponsive to nitroglycerin, with symptoms beginning greater than 30 minutes but 
less than 4.5 hours prior to presentation at hospital. 

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3. Qualifying Infarct Location: Evidence of Acute Anterior MI with ST- segment 
elevation of ≥ 0.2 mV in two or more anterior contiguous precordial leads (V1 –V4). 
4. The patient is eligible for PCI. 
5. The patient is willing to provide written informed consent to participate in this clinical 
trial (V1 –V4).. 
 
Exclusion Criteria 
All Exclusion Criteria must be answered NO for subject to satisfy Exclusion Criteria: 
 
1. The patient has had a previous Myocardial Infarction. 
2. The patient is experiencing cardiogenic shock (systolic blood pressure [SBP] <100 
mmHg, HR > 100 bpm and arterial oxygen saturation (pulse oximetry) <92% without 
additional oxygen.  The patient is presenting with resuscitated Cardiac Arrest, Atrial 
Fibrillation, or Killip risk stratification class II through IV. 
3. The patient has an aortic dissection or requires an immediate surgical or procedural 
intervention other than PCI. 
4. The patient has known history of Congestive Heart Failure (CHF), Hepatic Failure, 
end-stage kidney disease or severe Renal Failure (clearance < 30ml/min/1.73m²).  
5. The patient is febrile (temperature > 37.5 °C) or has experienced an Infection with 
Fever in the last 5 days. 
6. The patient has a known previous CABG. 
7. The patient has a known recent Stroke within 90 days of admission.  
8. Cardio-Pulmonary Decompensation that has occurred en route to the hospital or, in 
the opinion of the physician, that is imminent or likely to occur following presentation 
to the clinical site. 
9. Contraindications to hypothermia, such as patients with known Hematologic 
Dyscrasias which affect thrombosis (e.g., cryoglobulinemia, sickle cell disease, serum 
cold agglutinins) or Vasospastic Disorders (such as Raynaud’s or thromboangitis 
obliterans). 
10. Any contraindication to cardiac MRI, or any implants in the upper body which may 
cause artifacts on cardiac MRI imaging. 
11. The patient has a known hypersensitivity or contraindication to aspirin, heparin, or 
sensitivity to contrast media, which cannot be adequately pre-medicated. 
12. The patient has a known history of Bleeding Diathesis, Coagulopathy, 
Cryoglobulinemia, Sickle Cell Anemia, or will refuse blood transfusions. 
13. The patient has a height of <1.5 meters (4 feet 11 inches). 
14. The patient has a known hypersensitivity or contraindication to buspirone 
hydrochloride or Pethidine (Meperidine) and/or has been treated with a monoamine 
oxidase inhibitor in the past 14 days. 

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15. Patient has a known history of severe hepatic or renal impairment, untreated 
hypothyroidism, Addison’s disease, benign prostatic hypertrophy, or urethral stricture 
that in the opinion of the physician would be incompatible with Pethidine 
administration. 
16. The patient has an Inferior Vena Cava filter in place (IVC). 
17. The patient has a pre-MI life expectancy of <1 year due to underlying medical 
conditions or pre-existing co-morbidities. 
18. The patient has a known, unresolved history of drug use or alcohol dependency, or 
lacks the ability to comprehend or follow instructions. 
19. The patient is currently enrolled in another investigational drug or device trial. 
20. The patient is apprehensive about or unwilling to undergo the required MRI imaging 
at follow-up, has a documented or suspected diagnosis of claustrophobia, or has 
Gadolinium allergy, or is in permanent Atrial Fibrillation. 
21. The patient has received thrombolytic therapy en route to the hospital 
22. The patient shows clinical evidence of spontaneous reperfusion as observed 
symptomatically and/or from baseline ECG findings (partial or complete ST 
resolution in ECG prior to informed consent and randomization). 
23. The patient is a vulnerable subject, for instance, a person in detention (i.e., prisoner or 
ward of the state). 
24. The patient is a female who is known to be pregnant. 
 
Clinical Trial Procedures 
6.8.1 Patient Screening 
Patients presenting at participating centers with clinical signs and symptoms of AMI will 
be expeditiously triaged and offered the opportunity to participate in this clinical trial 
without regard to age, gender or ethnicity.  To ensure that patients are approached for 
potential trial participation without bias, patient screening information will be maintained 
on a patient screening log at each site.  This log will track patients that were enrolled in 
the trial as well as patients who were excluded from participation and the reason(s) for 
their exclusion. The use of a patient screening log assures that all eligible subjects are 
given an opportunity to participate or decline participation in the trial. 
The subject’s eligibility for treatment with the Proteus IVTM System will be evaluated 
based on the medical and anatomical criteria outlined above in the inclusion/exclusion 
criteria section.  The Investigator will explain the elements of this clinical trial, including 
the risks, potential benefits and required interventional and follow-up procedures, to each 
subject prior to obtaining informed consent. 
If a subject is found to be ineligible during baseline screening and routine diagnostic tests, 
the subject shall be considered a screen failure and will be documented on the patient 
screening log.  Randomized subjects are considered enrolled in the trial when all inclusion 

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and exclusion criteria have been satisfied, informed consent has been signed, and the 
patient is randomized to either Test or Control Arm of the trial. 
6.8.2 Informed Consent 
The reviewing Medical Ethics Committee (MEC) must review and approve an Informed 
Consent Form (ICF) specific to this study. The Sponsor will provide each study center 
with an example ICF. The study center, to meet specific requirements, may modify this 
example ICF; however, the ICF to be used for subject consent under this protocol must 
contain all of the elements required by the study Sponsor and the governing regulatory 
requirements for informed consent (21 CFR Part 50). Therefore, each investigational site 
will provide the Sponsor with a copy of the MEC approved ICF - as well as any 
amendments - for the duration of the study.  
Informed consent will be required from each subject.  The MEC approved Informed 
Consent document must be signed by the patient or by the  legal authorized representative 
(LAR) prior to any related procedures (or according to the MEC’s approved guidelines), 
including the collection of data on case report forms (CRFs). Only subjects that have the 
appropriate informed consent form will be included in the trial. 
The informed consent process (including time and date of discussion), should be 
documented in the subject’s medical record and signed/dated by the individual 
(investigator or designee) who recorded it.  The original signed consent form must be filed 
in the subject’s medical record and a copy of the signed informed consent documentation 
given to the subject.  
All subjects must sign, date and note the time on the Institutional Medical Ethics 
Committee (MEC) approved informed consent prior to any clinical trial/investigation-
specific procedures. Obtaining the consent with the documented date and time, and the 
provision of a copy to the subject will be documented in the subject’s medical record.  
Due to the emergent nature of treating acute myocardial infarction, patients who have been 
enrolled in the study may receive a subsequent consent which provides more detailed 
information about their participation in the trial (based on MEC requirements), which may 
be reviewed and signed after the acute phase of their treatment has been completed.  If the 
patient decides they no longer want to be included in the study, they will be withdrawn 
and their data will be included in the analysis up until the time of withdrawal. 
If in the course of the pre-study evaluations prior to consent, the patient is found not to be 
eligible for inclusion in the study, the patient should be notified and the reason for 
ineligibility documented on the appropriate Screening Log. 
 
All information pertinent to this clinical investigation (including at a minimum the 
description and purpose of the study, potential benefits, potential risks and 

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inconveniences, active procedures, confidentiality, compensation, circumstances for 
termination and site contact persons) will be provided to the subjects in writing and in 
their native, non-technical, language by Investigator or designee, who has been trained on 
the protocol.   
If new information becomes available that can significantly affect a subject's future health 
and medical care, this information shall be provided to the affected subject(s) in written 
form. If relevant, all affected subjects shall be asked to confirm their continuing informed 
consent in writing. 
6.8.3 Simulated Training Program (German centers only) 
Germany sites will participate in a simulation training program prior to randomization. 
The training will include a training mannequin and functional devices (catheters, cassettes, 
controller, Bair Hugger warming blankets, medication infusion devices).  ZOLL will train, 
test and monitor the sites for times to completion of the various steps to implement 
cooling, including time to consent, administration of anti-shivering medications, infusion 
of cold saline, insertion of the cooling catheter, and time of onset of endovascular cooling.  
Metrics for the successful completion of each step will be developed to provide feedback 
to the sites.  The goal is to ensure the highest level of quality in the execution of the trial 
protocol and minimize the time from patient contact to institution of cooling. 
6.8.4 Approval to Randomize in the Trial 
It will be at the discretion of the sponsor to advance a site to Randomization.  Based on 
the site’s performance with the Simulated Training Program, as determined by the 
Sponsor, the site will be notified of authorization to randomize patients in the trial. 
6.8.5 Randomization 
In the randomization phase, patients who meet eligibility criteria for participation will be 
randomly assigned to either the Test Arm (PCI + Cooling) or Control Arm (PCI alone) in 
a 1:1 ratio. 
Randomization will be applied using an internet based Interactive Web Response Systems 
(IWRS). In the trial, randomization will be done using random permuted blocks (based on 
procedure outlined in Pocock SJ. Clinical Trials: A Practical Approach. Wiley, 
Chichester, 1983), stratified by site, with 1:1 allocation ratio using a randomization list. 
At randomization, inclusion and exclusion criteria will be verified, and confirmation of 
informed consent signature will be done. 
Subjects will be considered to be enrolled in the Test Arm and Control Arms of the trial 
when all inclusion and exclusion criteria have been met, the informed consent form has 
been signed, and randomization assignment has been completed. 

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6.8.6 Acute Care and Emergency Room Triage  
Prior to the initiation of this trial at each participating institution, training will be 
conducted by the Sponsor targeted toward the integrated care of each trial subject and 
emphasizing the shared responsibility between the Departments of Emergency Medicine 
and Interventional Cardiology, where applicable at each center, with the goal of rapid 
screening, enrollment and treatment of appropriate patients. 
Each center will clearly delineate departmental responsibilities for the following: 
• Assessment of patient clinical features, signs and symptoms 
• Administration of Informed Consent 
• Review of Inclusion/Exclusion Criteria 
• Assurance that diagnostic procedures mandated by the protocol are completed 
prior to randomization into this trial and are appropriately documented 
• Patient Randomization 
• Administration of pre-treatment medication(s) 
• Administration of Anti-shivering medications to subjects randomized to the Test 
Arm of the trial 
• Consensus on location in hospital where cooling using the Proteus IVTM System 
will be initiated 
• Set-up of Proteus IVTM System, including insertion of the Proteus Catheter into 
the femoral vein induction of cooling, initiation of re-warming, Proteus IVTM 
System shutdown and catheter extraction for Test Subjects. 
6.8.7 Standardized Care Prior to the Cooling Procedure 
It is anticipated that subjects may receive one or more of the following therapies as part 
of current clinical practice in the treatment of acute myocardial infarction: 
• Intravenous fluids and electrolytes 
• Oxygen  
• Antiplatelets and/or antithrombotics  
• Vasoactive agents and diuretics 
 
Clinicians will be encouraged to manage the subject in a standardized manner with respect 
to oxygenation, anti-coagulation and/or anti-platelet medications.  
6.8.8 Documentation Procedures 
Trial procedures and treatment data will be documented on standardized Case Report 
Forms (CRFs) which may be on paper or via an electronic data capture system (EDC). 
The completion of the CRFs may be delegated to a member of the study team (e.g., the 
study coordinator) as long as that person is listed on the Delegation of Authority Log.  
However, the Principal Investigator retains responsibility for the accuracy and integrity of 

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the data entered on the CRF.  The CRF will be monitored for accuracy and completeness 
per the source documents (medical records, charts, interventional systems, worksheets as 
applicable, etc.) at each clinical center.  Temperature data from the Proteus IVTM System 
will be downloaded and sent to Sponsor.  A flow diagram for the Test Arm is represented 
in Figure 10.  
It is anticipated that technology and/or techniques such as edit checks and double entry 
of data may be utilized to minimize the rate of error.  Additionally, ZOLL or its 
assignees may ask for data clarification or re-check of data for accuracy.  Monitoring 
visits and CRF completion logs will be used to track data entry in accordance with trial 
logistics and expectations.  
Any source documentation (procedure reports, imaging studies, lab reports, death 
certificates, etc.) that is sent to the Sponsor should have all patient identifiers removed 
and replaced with the subject’s trial ID, and processes ensuring patient privacy and 
clinical data confidentiality will be followed in accordance with local regulations and 
applicable laws.

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6.8.9 Study Flow and Procedures 
Figure 8 Screening and Enrollment Flow 
Admission to Hospital
Patient Screening
Eligible?
Patient Screening Log
(If Patient doesn’t qualify, document 
Reason for Screen Failure)
Complete Informed Consent Procedure
No
Yes
Turn Proteus 
Console ON
1:1 Randomization
TEST ARM
Cooling + PCI
CONTROL ARM
PCI Only
Approved by Sponsor to 
Randomize?
Yes
 
 
 
 

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Figure 9 Control Arm Flow 
1:1 Randomization
CONTROL ARM
PCI Only
Perform PCI 
Procedure
Obtain Vital Signs 
and Core Body Temp 
at Baseline
Perform 12-lead ECG 
at Baseline
Record Troponin I or 
T at Baseline and 
until peak identified
Document All 
Medications and All 
Adverse Events
Post PCI
 
 

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Figure 10 Test Arm Flow 

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Figure 11 All Patient Procedures 
 
  
 
 
 
 
 
 

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6.8.10  
Pre-Cooling Assessment Procedures 
All required procedures and data collection from the time of subject screening (presentation at 
hospital) through the pre-cooling assessment period are given below in Table 11. 
 
Table 11:  Baseline / Screening and Enrollment Procedures/Evaluations and Data 
Collection for the Test & Control Arms of the Trial 
Procedures/ 
Evaluations  
Data 
Trial 
Eligibility 
At admission to the hospital 
Informed 
Consent  
Obtain Consent from patient before any trial-related procedure is initiated. 
Trial 
Enrollment  
- 
Follow randomization process to assign patient to Test or Control Arms 
of the trial 
- 
Complete Enrollment Form, document randomization, and FAX  or 
email to ZOLL at 
 
+1 800.243.0360 or ami-eu@zoll.com to enter in the eCRF 
Temperature 
Document subject’s temperature using a tympanic thermometer 
Vital Signs 
Blood Pressure, Heart Rate, Respiratory Rate, BSAS measurement 
Physical Exam  
Complete Physical Examination 
Blood Studies 
RBC’s, WBC’s, Hct, Hgb, Platelets,  
Lab Studies 
BUN, Creatinine, sodium, potassium, calcium, phosphate, magnesium, 
chloride, lactic acid, glucose, amylase, lipase 
Cardiac 
Markers  
Baseline and peak Troponin I or Troponin T including upper limit of normal 
ECG 
12-lead baseline 
Medications 
Document as indicated on Case Report Form since STEMI onset 
Adverse 
Events 
Collect all adverse events as soon as patients are enrolled in the trial 
 

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6.8.11 Initiation, Maintenance, and Reversal of Cooling with Proteus IVTM System 
Procedures / Evaluations and Data Collection for Subjects Enrolled in the 
Test Arm 
6.8.12 Test Arm: Temperature Management Protocol and Data Collection Time 
Points 
Treatment with therapeutic hypothermia will begin with a forced infusion of up to 1 L of cold 
saline (4°C) (according to the guideline) using pressure bags, and at the time of administration of 
the anti-shivering medication according to the anti-shivering guidelines, then will continue with 
the Proteus IVTM System as soon as possible.  Cooling will be initiated with the Proteus IVTM 
System set at a temperature of 32.0 °C, and the subject’s temperature will be measured with the 
Proteus IVTM System immediately before PCI has occurred (measured as time the wire crosses 
the target lesion). Cooling will be maintained for 3 hours and will be followed with active 
rewarming to attain normothermia 36.0 °C (96.8°F).  
Cooling induction, maintenance of hypothermia, and rewarming are described in the following 
Table 12. The data collection schedule for Test Arm subjects is summarized in Section 6.8.13. 
Table 12:  Initiation, Maintenance, and Reversal of Cooling with Proteus IVTM System 
Procedures / Evaluations and Data Collection for Subjects Enrolled in the Test Arm 
 
Phase 
Task 
Immediately Upon 
Arrival to the 
Hospital 
1. Turn the Proteus Console on (in preparation for cooling with the 
device) 
2. Document time of occurrence of STEMI and ECG 
3. Document time of arrival of Emergency Medical Service EMS 
(Paramedics) 

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Phase 
Task 
Baseline / 
Enrollment 
4. Immediately after informed consent is obtained and patient is 
randomized to the Test Arm of the trial, initiate anti-shivering 
medication protocol using Guidelines outlined in Attachment 
II. 
5. Begin cooling induction by forced infusion with 25mL/kg of 4°C 
cold saline using pressure bags up to 1 L of cold saline (4°C) 
(according to the guideline) at the physician’s discretion. Use Bair 
Hugger TM (CE marked device)  for patient comfort. 
6. Document the time the Proteus console is turned on. The 
device will begin cooling the patient immediately; however, 
optimal cooling is achieved in 5-10 minutes after it is turned on. 
7. Perform Physical Examination and obtain Vital Signs. 
8. Obtain Blood and Lab studies. 
9. Obtain Troponin I or Troponin T . 
10. Obtain 12-lead baseline ECG. 
11. Document all medication use since STEMI onset. 
12. Measure body temperature using an independent tympanic 
thermometer.  The independent measurement is to be used in 
addition to the core body temperature collected by the Proteus 
Temperature Probe (X-Probe). 
13. Document all Adverse Events. 

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Phase 
Task 
Initiation of 
Cooling  
14. Document the volume of cold saline, the time the cold saline 
infusion is started and the time the cold saline infusion is finished. 
15. Following the ZOLL Proteus IVTM System Instructions for Use 
(IFU), insert the Proteus Catheter into the Inferior Vena Cava via 
either femoral vein.  The Proteus Catheter is then connected to the 
Cassette that has been inserted into the Proteus Console. 
16. Following insertion of the Proteus Catheter, insert the Proteus 
Temperature Probe (X-Probe). 
Access site selection may vary by both operator preference and 
anatomical considerations; however, the function of the system is not 
dependent on which femoral vein is chosen. 
17. Once the Proteus System Catheter & Proteus Temperature Probe 
(X-Probe) have been inserted, enter set point temperature to 
32.0°C on the Proteus Console and perform cooling at maximum 
power as soon as the console is ready to cool.  
18. Document the time of Proteus Catheter & X-Probe 
(temperature probe) insertion. 
19. Document the time cooling is initiated with the Proteus IVTM 
System. 
20. Document vital signs (BP, HR, RR), and temperature 
measurements (Tympanic and Proteus Console measurements). 
21. Document all medication use. 
22. Document all adverse events since the time of enrollment. 
23. Use Bair HuggerTM warming blankets for counter-warming. 
If choosing to use low dose anticoagulation during the cooling phase, 
follow hospital’s guidelines for venous thromboembolism 
prophylaxis. 

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Phase 
Task 
Immediately Prior 
to Reperfusion 
24. If clinically relevant shivering (Bedside Shivering Assessment 
Scale (BSAS) of 2 or greater) occurs at 32° (see Anti-Shivering 
Guidelines, Attachment II, and BSAS Attachment III), increase 
the dose of Pethidine (Meperdine) as indicated in shivering 
protocol and increase set point temperature on the Proteus IVTM 
System to 32.5°C. If clinically relevant shivering continues (BSAS 
≥2), once again increase dose of Pethidine as indicated in Anti-
Shivering Protocol and increase set point temperature on the 
Proteus IVTM System to 33°C.  Continue this process until a 
temperature is reached where there is no shivering. Follow 
sedation procedures using Anti-Shivering Guidelines, 
Attachment II, and the BSAS Attachment III. 
25. Perform *angiogram after the induction of hypothermia has been 
initiated and just prior to PCI. 
26. Obtain vital signs (BP, HR, RR), BSAS and temperature 
measurements (Tympanic and Proteus Console 
measurements) just prior to PCI. 
27. Document all medication use since the initiation of cooling. 
28. Document all adverse events since the initiation of cooling. 
CAUTION: Anticipate changes in electrolytes and laboratories 
values secondary to hypothermia. 
29. Document core body temperature at the time of PCI. 
30. If subject has not reached 32.0 ± 1.0°C (or temperature where 
shivering does not occur, as indicated above) at the time of PCI, 
continue cooling induction until target temperature has been 
reached. 
31. Document the time wire crossed the target lesion. 

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Phase 
Task 
Maintenance of 
Hypothermia 
Target 
Temperature 32 
±1°C 
32. Maintain the patient at the set target temperature of 32.0 (or 
temperature where shivering does not occur, as indicated above) 
for 3 hours ± 15 minutes from the initiation of cooling with the 
Proteus System.  
33. Obtain vital signs (BP, HR, RR), BSAS and temperature 
measurements (Tympanic and Proteus Console 
measurements) every 30 minutes during the 3 hours of cooling. 
34. Document all medication use since the angiogram/ PCI procedure. 
35. Document all adverse events since the angiogram/ PCI procedure. 
36. If clinically relevant shivering [Bedside Shivering Assessment 
Scale  (BSAS) of 2 or greater] occurs at 32.0°C (See Anti-
Shivering Guidelines, Attachment II, and BSAS, Attachment 
III), increase dose of Pethidine (Meperidine) as indicated in 
shivering protocol and increase temperature on the Proteus IVTM 
System console to 32.5°C. 
37. If clinically relevant shivering continues (BSAS ≥ 2), once again 
increase dose of Pethidine as indicated in shivering protocol and 
increase temperature on the Proteus IVTM System to 33°C.  
Continue this process until a temperature is reached where there is 
no shivering.  Follow sedation procedures using Anti-Shivering 
Guidelines outlined in Attachment II and BSAS assessment in 
Attachment III. 

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Phase 
Task 
Rewarming 
38. After 3 hours of cooling with the Proteus IVTM System, begin 
active rewarming to normothermia.  Palliative care such as 
blankets, Bair Hugger patient warming systems, and warm liquids 
may be used. 
39. Using the Proteus System Console, press STOP and Increase 
target temperature to 36.0°C using the arrow touch buttons and 
then press Continue.  
40. Set rewarming rate to 1.0°C/hr using the arrow touch buttons and 
press Continue to start rewarming. 
41. Maintain the Pethidine infusion during rewarming using the Anti-
Shivering Protocol outlined in Attachment II. 
42. Obtain vital signs (BP, HR, RR), BSAS and temperature 
measurements (Tympanic and Proteus Console measurements) 
every hour until normothermia is achieved 
43. Obtain blood studies, lab studies and record peak Troponin I or 
Troponin T including upper limit of normal for site.  
44. Document all medication use during the rewarming phase. 
45. Document all adverse events during the rewarming phase.  
CAUTION: Anticipate changes in electrolytes and laboratories 
secondary to re-warming 

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Phase 
Task 
Catheter Removal  
46. Document core body temperature at time of Proteus Catheter 
removal. 
47. Remove Proteus Catheter and X-Probe per IFU and document 
time of removal. 
48. Dispose of the Proteus Catheter, X-Probe and Proteus Cassette per 
institution’s guidelines (single-use). 
49. Assess catheter access site for signs of bleeding, access vessel 
trauma, or hematoma formation. 
50. Download temperature data from the Proteus Console after 
the cooling phase has been completed. Send downloaded data 
to amidatadownload@zoll.com immediately upon 
downloading.  Device data must be saved according to Section 
16.1, Investigator Records.  
51. Document all medication use during the hypothermic phase. 
52. Document all adverse events during the hypothermic phase. 
DO NOT DISCARD SPLITTER CABLE (MULTI–USE  
TEMPERATURE CABLE) 
Normothermia 
53. Document all adverse events until patient is discharged from the 
hospital. 
Post-Procedure 
54. If required, provide additional Informed Consent document to 
patients who were consented with the short consent form (if 
required by MEC or country-specific regulations). 
NOTE:  All post-PCI times will be measured from the start of PCI, defined as time the wire 
crosses the target lesion. In the event that PCI is not performed, the time of the first 
cineangiogram of the infarct related artery will be referenced. If PCI is staged for the non-
culprit lesion, then the PCI will be performed after the 4-6 day cMR 
*Angiograms are to be uploaded for all adjudicable events.  
 

 
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6.8.13 Trial Schedule for Test Arm Subjects 
Procedure/ Interval 
Baseline / 
Enrollment 
Initiation of 
Cooling  
Immediate
ly prior to 
reperfusio
n (PCI) 
Maintenance of 
Target Temp  
32 ±1°C 
Rewarming to 
36°C 
Catheter 
Removal 
Discharge 
Follow-Up 
@ 4-6 Days  
Follow-Up 
@ 30 Days 
(±7 days) 
Follow-Up 
@ 12 
months 
(±14 days) 
Unscheduled 
Visit 
Trial Eligibility & Informed 
Consent 
upon arrival to 
hospital 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
X 
 
 
 
 
Anti-Shivering Protocol 
X 
 
 
X∞ 
 
 
 
 
 
 
 
Cold Saline Infusion 
 
X 
 
 
 
 
 
 
 
 
 
Catheter Insertion Time 
 
X 
 
 
 
 
 
 
 
 
 
Catheter Removal Time 
 
 
 
 
 
X 
 
 
 
 
 
Temperature Documented 
X 
X 
X 
every 60 min 
during 3 hr 
cooling 
every 60 min 
during 
rewarming 
 
 
 
 
 
 
Temperature Data Download   
 
 
 
 
 
X 
 
 
 
 
 
Vital Signs 
X 
X 
X 
every 60 min 
every 60 min  
 
 
 
 
 
 
Blood Studies  
RBC’s, WBC’s, Hct, Hgb, 
Platelets,  
X 
 
 
 
upon reaching 
normothermia 
 
 
 
 
 
 
NT-pro BNP 
 
 
 
 
 
 
 
 
 
X 
 
Lab Studies  
BUN, Creatinine, Na, K, Ca, 
Mg, Cl, P, lactic acid, 
glucose, amylase, lipase 
X 
 
 
 
upon reaching 
normothermia 
 
 
 
 
 
 
Any Medication Use 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Troponin I or T(including 
ULN) during hospitalization 
X 
Perform Troponin until peak value identified 
 
 
 
 
 
 
12 lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Catheter Access Site 
Assessment  
 
 
 
 
 
X 
X 
X 
 
 
 
Cardiac Magnetic Resonance 
(cMR) imaging 
 
 
 
 
 
 
 
X 
 
 
 
NYHA Assessment 
 
 
 
 
 
 
 
 
 
X 
 
KCCQ  
 
 
 
 
 
 
 
 
 
X 
 
∞For persistent clinically relevant shivering (BSAS ≥ 2), increase dose of Pethidine as indicated in shivering protocol and increase temperature on Proteus IVTM System console by 0.5°C.  Continue this process until a temperature is reached 
where there is no shivering.  Follow sedation procedure using Anti-Shivering Guidelines outlined in Attachment II and BSAS assessment in Attachment III Include BSAS measurement and temperatures from independent method. 

 
 
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6.8.14 Trial Schedule for Control Arm Subjects 
Procedure/ Interval 
Baseline / 
Enrollment 
Immediately 
prior to 
reperfusion 
(PCI)Post-PCI 
Discharge* 
Follow-Up 
@ 4-6 Days  
Follow-Up 
@ 30 Days 
(±7 days) 
Follow-Up @ 
12 months 
(±14 days) 
Unscheduled 
Visit 
Trial Eligibility & 
Informed Consent 
upon 
arrival to 
hospital 
 
 
 
 
 
 
Physical Exam 
X 
 
X 
 
 
 
 
Catheter Insertion Time 
X 
 
 
 
 
 
 
Catheter Removal Time 
 
 
 
 
 
 
 
Temperature Documented 
X 
 
 
 
 
 
 
Vital Signs 
X 
 
 
 
 
 
 
Blood Studies  
RBC’s, WBC’s, Hct, Hgb, 
Platelets,  
X 
 
 
 
 
 
 
 
NT-pro BNP 
 
 
 
 
 
X 
 
Lab Studies  
BUN, Creatinine, Na, K, 
Ca, Mg, Cl, P, lactic acid, 
glucose, amylase, lipase 
X 
 
 
 
 
 
 
 
Any Medication Use 
X 
X 
X 
X 
X 
X 
X 
Troponin I or T(including 
ULN) 
X  
Perform 
Troponine 
until peak 
value 
identified  
 
 
 
 
 
12 lead ECG 
X 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
Cardiac Magnetic 
Resonance (cMR) 
 
 
 
X 
 
 
 
NYHA Assessment 
 
 
 
 
 
X 
 
KCCQ 
 
 
 
 
 
X 
 
6.8.15 Control Arm Protocol and Data Collection Time Points 
The data collection schedule for Control Arm subjects is summarized in Section 6.8.14. For 
patients randomized to the Control Arm, i.e., PCI alone, the following procedures will be 
performed: 
i. 
Document time of occurrence of the STEMI & ECG results 
ii. 
Document time of arrival of Emergency Medical Service EMS (Paramedics) & 
time of arrival at hospital 
iii. 
Collect all adverse events as soon as patients are enrolled in the trial 
iv. 
Perform Blood Studies, Labs, and record Baseline and peak Troponin I or T  

 
 
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v. 
Perform PCI. If PCI is staged for the non-culprit lesion, then the PCI will be 
performed after the 4-6 day cMR 
vi. 
Monitor and record the patient’s vital signs, temperature, blood pressure, heart 
rate and respiratory rate at baseline. 
vii. 
Obtain 12-lead baseline ECG . 
viii. Monitor and record all pharmacological agents 
ix. 
 Measure and record Baseline Troponin I or T, including upper limit of normal, 
and when a peak is identified. 
x. Monitor and record all adverse events for the duration of 12 month follow-up.  
xi. 
Complete physical exam prior to discharge.  
6.8.16 Follow-up at 4-6 days and at 30 days following the PCI Procedure 
Subjects enrolled in the Test and Control Arms will undergo Cardiac Magnetic Resonance 
(cMR) to assess infarct size at 4-6 days.  
In addition, the following procedures are to be performed at 4 - 6 days and at 30 days after the 
index procedure (PCI) for both Test Arm and Control Arm patients: 
i. 
Monitor and record all adverse events for the duration of 12 month follow-up. 
ii. 
Review and record all medication changes since index. 
6.8.17 Follow-up at 12 months following PCI 
Following completion of the 30 day follow-up, all subjects will be followed through 12 months 
for the incidence of Adverse Events, Serious Adverse Events, Death and Heart Failure (as assessed 
by NYHA and Kansas City Cardiomyopathy Questionnaire (KCCQ) 
i. 
 Monitor and record all adverse events for the duration of 12 month follow-up. 
ii. 
Collect NT-pro BNP value to assess clinical prognosis of Heart Failure. 
iii. 
Review and record all medication changes 
iv. 
Perform blinded NYHA Assessment andadminister Kansas City Cardiomyopathy 
Questionnaire (KCCQ). 
6.8.18 Use of other Cooling Methods 
For the purposes of this trial, no other cooling methods may be used. 

 
 
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6.8.19 Transferring Subject during Cooling 
Although interruption during the induction phase of hypothermia is not recommended, if subject 
transfer is required during any phase of the cooling, follow relevant instructions in the device 
Instructions for Use.   
 
For additional detail, refer to the Proteus IVTM System Instructions for Use. The console screen 
also provides prompts for entry of user-defined parameters and system start-up.  
 
6.8.20 Patient Withdrawal and Discontinuation 
The term “patient withdrawal” refers to the patient deciding to terminate their participation in the 
trial.  The term “discontinuation” refers to the physician deciding that the patient will not continue 
trial participation as defined below.   
A subject has the right to withdraw from the trial at any time and for any reason without prejudice 
to his or her future medical care by the physician or the institution. Trial withdrawal by a subject 
specifically means withdrawal of consent from further participation in the trial. Subjects who 
withdraw consent after enrollment will be evaluated to the time of withdrawal, and withdrawal of 
consent precludes any further trial related treatment or data collection. If possible, a complete, 
final physical examination should be performed on all subjects who withdraw from the trial. At a 
minimum, every effort should be made to document subject outcome at the time of trial 
withdrawal.   
A subject may withdraw from the clinical investigation for the following reason:  
o 
Subjects may choose to withdraw from the clinical investigation under the terms 
of the Declaration of Helsinki and their consent documentation without having to 
give a reason;  
A subject may be discontinued from the clinical investigation for the following reasons: 
o 
Any unanticipated adverse reaction which is, in the opinion of the Investigator, 
related to the treatment and will endanger the well-being of the patient if treatment 
is continued;  
o 
Development of any illness(es), infection or condition(s) that might interfere with 
the Clinical Investigational Plan;  
o 
Non-compliance with the clinical investigation procedures deemed by the 
Investigator to be sufficient to cause discontinuation;  
o 
Any problem deemed by the Investigator to be sufficient to cause discontinuation.  

 
 
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- Investigator will treat all subjects discontinued from the investigation due to an 
unanticipated adverse reaction, directly related to the investigation, until the reaction 
resolves.  
- Investigator will not replace subjects who have withdrawn from the clinical 
investigation if they have received the investigational device. If possible, Investigator 
will perform any procedures or assessments planned for the subject at the time of 
withdrawal.  
All subjects are expected to continue in the trial through the final follow-up assessment or until 
ZOLL notifies the Investigator in writing that further follow-up is no longer required, except in 
the event of death or upon the subject's request for early withdrawal from the clinical trial.  
6.8.21 Patient Lost to Follow-up  
The investigator will attempt to contact a subject at least three times prior to designating them as 
lost-to-follow-up subjects. The investigator will document the date and type of attempted 
communication. The investigator will complete and sign the Study Exit Form when a subject is 
lost to follow-up.  
6.8.22 Early Termination of a Clinical Investigation 
Both the Sponsor and Investigator reserve the right to terminate the clinical investigation at any 
time. If necessary, and after review and consultation with Principal Investigator, Sponsor will 
make a final determination on whether to terminate the study. 
A clinical investigation or Investigator may be terminated at a clinical center for any of the 
following reasons, or for reasons not listed that affect patient safety or integrity of the trial: 
• Unsatisfactory rate of patient enrollment or compliance to eligibility criteria. 
• Repeated noncompliance with the investigational plan. 
• Inaccurate, incomplete, and/or untimely submission of data. 
• Inadequate accountability of the investigational device. 
 
The sponsor may terminate this trial if there are new, previously unknown adverse events related 
to device or cooling procedure, deaths, SAEs/AEs exceeding those reported as related to 
device/cooling procedures in previous trials, and/or if recommended by DMC (Data Monitoring 
Committee) to stop the trial. The sponsor will make the final determination on whether to terminate 
the study. 
The sponsor may terminate the trial for any other unforeseen circumstances. In case of premature 
termination/suspension, ZOLL will stop the enrollment, inform all investigators at all sites and all 

 
 
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regulatory agencies governing the study. ZOLL will perform complete device accountability of all 
investigational devices and retrieve them from the clinical sites. All study subjects will be followed 
through the specified follow-up periods. ZOLL will issue a final report of the clinical study. 
6.8.23 Amendments and Protocol Deviations 
Investigator will not deviate from the CIP without prior written confirmation by Sponsor, or their 
designee, except as required in a medical emergency. In medical emergencies, Sponsor does not 
require prior confirmation for protocol deviations, but Investigator will notify Sponsor within 5 
days of the incident and will notify the EC according to local requirements. Investigator, or 
designee, will record deviations with an explanation for the deviation. Investigator will report to 
Sponsor who will analyze them and assess their significance.  Significant deviations from the CIP 
will be reported to the Competent Authority. 
 
Examples of protocol deviations may include those relating to: 
• Eligibility 
• Enrollment and randomization 
• Informed consent 
• Protocol adherence (e.g., tests and assessments done as required in Trial Schedule, etc.) 
 
Routine monitoring will assess Investigator compliance to the protocol.  
 
Investigator must not modify the CIP without the prior and written permission from Sponsor. All 
modifications to the clinical protocol must be submitted to the Competent Authority (where 
required) to allow the Competent Authority review and approval.  
 
The Sponsor is responsible for management, processing and approval of any amendment to the 
Investigational Plan. Should the site consider an amendment necessary, the Sponsor will work with 
the site to make the appropriate changes. The Sponsor will manage documentation of such changes 
through the existing document control system. A history of changes and a redline version of the 
documentation will be maintained per the applicable quality system procedures. The proposed 
amendment will be submitted to the reviewing MEC and government agency as applicable. Any 
necessary approvals will be received in writing before the requested change is implemented. 
 
This study will be conducted in compliance with ISO 14155, ICH E6 Consolidated Good Clinical 
Practice Guidance, 21 CFR 812, 21 CFR Part 50, and any requirements imposed by countries with 
participating clinical sites. The study will not commence until the necessary government and MEC 
approvals have been obtained. 

 
 
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6.8.24 Trial Exit 
The Trial Exit Form (CRF) should be completed at the time a subject is exited from the trial.  A 
subject will be considered to have exited from the trial for any of the following reasons. 
• Subject completes follow-ups required by the investigational plan. 
• Subject dies. 
• Subject requests to be withdrawn. 
• Physician requests that patient be withdrawn to protect the welfare of the patient. 
• Patient is lost to follow-up. 
• Other (specify) 
6.8.25 Subject Confidentiality 
Subject confidentiality will be maintained throughout the clinical trial to the extent permitted by 
law.  That is, every attempt will be made to remove patient identifiers from clinical trial documents.  
For this purpose, a unique subject identification code (site number, subject number and subject 
initials) will be assigned and used to allow identification of all data reported for each subject.  This 
will also ensure that the information can be traced back to the source data.  
Trial data may be made available to third parties, e.g., in the case of an audit performed by 
regulatory authorities, provided the data are treated confidentially and that the subject’s privacy is 
guaranteed.  The identity of a subject will never be disclosed in the event that trial data are 
published. 
Security and Unique usernames and passwords will be utilized by data entry, data verification and 
other personnel who have database access to insure confidentiality and protection of data. 
Trial sites must comply with Health Insurance Portability and Accountability Act (HIPPA) and/or 
the subject confidentiality provisions and privacy laws of each participating country, local 
regulations, and institutional requirements, whichever is stricter. 
6.8.26 Device Accountability 
ZOLL is responsible for the availability and traceability of all investigational products.  
Documentation is required at each step of the process via a device accountability log.  
Investigational product will be reconciled on a regular basis. 
The investigator also is required to maintain adequate records of the receipt and disposition of all 
investigational devices.  A device accountability log will be provided for this purpose. 
All unused product must be returned to ZOLL prior to the close of the trial. 

 
 
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6.8.27 Return of Materials upon Trial Termination 
Sponsor will ship investigational devices only to qualified Investigators participating in this 
clinical investigation. Sponsor will not ship investigational devices to any site until evidence of 
EC approval has been provided to Sponsor, or designee.  
Investigator will control access to investigational devices, and will only use investigational devices 
in the clinical investigation and according to the CIP.  
Sponsor will keep investigational device records to document the physical location of each device. 
Record(s) will include information documenting devices shipped, devices at investigation sites, 
devices disposed of, and devices returned.  
Investigator, or designee, will keep records documenting the receipt, use, return and disposal of 
the investigational devices, which will include:  
• Date of receipt,  
• Identification of each investigational device (serial number or unique code),  
• Expiry date, if applicable,  
• Date or dates of use,  
• Subject identification,  
• Date on which the investigational device was returned, or explanted from subject, if 
applicable, and  
• Date of return of unused, expired or malfunctioning investigational devices, if applicable.  
 
After the trial procedures have been completed, all unused devices must be accounted for and 
returned to ZOLL.  Instructions for device return to ZOLL will be reviewed at the site initiation 
visit. 
6.8.28 Trial Closure 
Trial closure can occur under the following circumstances: 
a. termination of site participation in the trial (i.e., closure that occurs prior to meeting 
defined endpoints) of the trial 
b. upon completion of the trial (i.e., when all patients enrolled have completed the 
follow-up visits or previously exited the trial, and the CRFs and queries have been 
completed)  
Under any circumstance for closure of the trial at the site, ZOLL and/or its designees will notify 
the site of this occurrence in writing.  Trial closeout visits will be performed once a 
determination has been made that the trial is closed.  All unused trial devices and any unused 
trial materials and equipment will be collected and returned to ZOLL and/or its designees.  The 
monitors will ensure that the investigator’s regulatory files are current and complete and that any 
outstanding issues from previous visits have been resolved.  Other issues that will be reviewed at 

 
 
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this visit include:  discussing record retention requirements (refer to Section 14.1—Investigator 
Records), device accountability, possibility of site audits, publication policy, and notifying the 
Medical Ethics Committee and Competent Authorities of trial closure, etc., as applicable. 
 
Cardiac Magnetic Resonance (cMR) imaging Core Laboratory 
Cardiac Magnetic Resonance (cMR) imaging must be collected per the Manual of Operations 
provided by the sponsor. Images must be submitted to the core laboratory designated by the 
sponsor for analysis. 
 
ADVERSE EVENTS & DEVICE DEFICIENCIES 
 
Definitions 
7.1.1 Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in subjects, users or other persons, whether or not 
related to the investigational medical device. 
NOTE 1 This definition includes events related to the investigational medical device or the 
comparator. 
NOTE 2 This definition includes events related to the procedures involved. 
NOTE 3 For users or other persons, this definition is restricted to events related to investigational 
medical devices.  
7.1.2 Serious Adverse Event (SAE) 
Adverse event that:  
a) led to a death, injury or permanent impairment to a body structure or a body 
function.  
b) led to a serious deterioration in health of the subject, that either resulted in:  
- a life-threatening illness or injury, or  
- a permanent impairment of a body structure or a body function, or  
- in-patient hospitalization or prolongation of existing hospitalization, or  
- in medical or surgical intervention to prevent life threatening illness  
c) led to foetal distress, foetal death or a congenital abnormality or birth defect.  

 
 
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NOTE 1: Planned hospitalization for pre-existing condition, or a procedure required by the 
Clinical Investigation Plan, without a serious deterioration in health, is not considered a serious 
adverse event. 
7.1.3 Device Deficiency (DD) 
Inadequacy of an investigational medical device related to its identity, quality, durability, 
reliability, safety or performance. This may include malfunctions, use error, or inadequacy in the 
information supplied by the manufacturer. 
7.1.4 Adverse Device Effect (ADE) 
Adverse event related to the use of an investigational medical device. 
NOTE 1- This includes any adverse event resulting from insufficiencies or inadequacies in the 
instructions for use, the deployment, the implantation, the installation, the operation, or any 
malfunction of the investigational medical device. 
NOTE 2- This includes any event that is a result of a use error or intentional abnormal use of the 
investigational medical device. 
7.1.5 Serious Adverse Device Effect (SADE) 
A adverse device effect that has resulted in any of the consequences characteristic of a serious 
adverse event. 
7.1.6 Unanticipated Serious Adverse Device Effect (USADE) 
Serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report. 
NOTE: Anticipated SADE (ASADE): an effect which by its nature, incidence, severity or 
outcome has been previously identified in the risk analysis report. 
 
Adverse Event Reporting 
7.2.1 Adverse Event Reporting from Site to Sponsor and MEC 
The collection of AEs will begin after the informed consent is signed. All AEs that occur through 
completion of the final follow-up visit, whether observed by the investigator or by the subject, and 
whether or not thought to be device related, will be reported in detail on the appropriate CRF and 
followed to resolution or the end of trial participation. 
The description of the AE will include the date and time of onset, seriousness, relationship to the 
device or procedure, the results of any diagnostic procedures or laboratory tests, any treatment 
recommended, and the outcome of the event.  In the circumstance that an AE has not resolved by 

 
 
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the time of the subject’s completion of the trial, an explanation will be entered on the appropriate 
CRF. 
ZOLL will implement and maintain a system to ensure that the reporting of the reportable events 
by the investigator to ZOLL occur immediately, but no later than 3 calendar days after 
investigational site study personnel awareness of the event. 
7.2.2 Serious Adverse Event Reporting to Sponsor and MEC 
Serious adverse events (SAEs) and device deficiencies should be reported as soon as possible. 
Serious adverse events and device deficiencies must be reported no later than 3 calendar days from 
the site becoming aware of the event or as per the investigative site’s local requirements if the 
requirement is more stringent than those outlined. 
The date the site staff became aware of the SAE must be recorded in the source document. The 
Investigator will further report the event to the IRB/EC according to the institution’s IRB/EC 
reporting requirements. 
Serious adverse events that do not occur in the study subject but occur in the user or other persons 
need to be reported on the fax notification form titled SAE Notification Form. Serious adverse 
events that occur in the user or other persons other than the study subject should not be entered 
into the clinical database. 
Serious adverse events should be reported on the SAE Notification Form in the occurrence that 
the clinical database is not available. This does not replace the electronic clinical database. All 
information must still be entered in the clinical database once the system is back to normal 
function. 
7.2.3 UADE/USADE Reporting to Sponsor and MEC 
ZOLL requires the Investigator to report any USADE to the sponsor within 3 calendar days of the 
investigator’s knowledge of the event and to the EC per EC requirements. 
7.2.4 Sponsor Reporting to NCAs  (National Competent Authority) when European 
Sites Participate in the Trial 
7.2.4.1 What to Report 
The following events are considered reportable events: 
• any SAE, 
• any Device Deficiency that might have led to a SAE if: 
o suitable action had not been taken or 

 
 
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o intervention had not been made or 
o if circumstances had been less fortunate 
• new findings/updates in relation to already reported events. 
7.2.4.2 Report to Whom 
Reportable events must be reported at the same time to all NCAs where the clinical investigation 
has commenced using the summary tabulation featured in the of MEDDEV 2.7/3. 
7.2.4.3 Reporting Timelines 
ZOLL must report to the NCAs where the clinical investigation has commenced: 
- for all reportable events as described in section 7.2.4.1 which indicate an imminent risk of death, 
serious injury, or serious illness and that requires prompt remedial action for other 
patients/subjects, users or other persons or a new finding to it: immediately, but not later than 2 
calendar days after awareness by ZOLL of a new reportable event or of new information in relation 
with an already reported event. 
- any other reportable events as described in section 7.2.4.1 or a new finding/update to it: 
immediately, but not later than 7 calendar days following the date of awareness by the ZOLL of 
the new reportable event or of new information in relation with an already reported event. 
 
Device Relationship 
Determination of whether there is a reasonable possibility that an investigational product or device 
caused or contributed to an AE is to be determined by the Investigator and recorded on the 
appropriate CRF form. Determination should be based on assessment of temporal relationships, 
biologic plausibility, association (or lack of association) with underlying disease and presence (or 
absence) of a more likely cause. 
7.3.1.1 Causality Assessment 
The relationship between the use of the medical device (including the medical - surgical procedure) 
and the occurrence of each adverse event shall be assessed and categorized. 
The above considerations apply also to the serious adverse events occurring in the comparison 
group. 
The following definitions are used to assess the relationship of the serious adverse event to the 
investigational medical device or procedures. 
1) Not related: relationship to the device or procedures can be excluded when: 

 
 
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• the event is not a known side effect of the product category the device belongs to or of 
similar devices and procedures; 
• the event has no temporal relationship with the use of the investigational device or the 
procedures; 
• the serious event does not follow a known response pattern to the medical device (if the 
response pattern is previously known) and is biologically implausible; 
• the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible – and reintroduction of its use (or increase 
of the level of activation/exposure), do not impact on the serious event; 
• the event involves a body-site or an organ not expected to be affected by the device or 
procedure; 
• the serious event can be attributed to another cause (e.g. an underlying or concurrent 
illness/ clinical condition, an effect of another device, drug, treatment or other risk factors); 
• the event does not depend on a false result given by the investigational device used for 
diagnosis, when applicable; 
• harms to the subject are not clearly due to use error; 
• In order to establish the non-relatedness, not all the criteria listed above might be met at 
the same time, depending on the type of device/procedures and the serious event. 
2) Unlikely: the relationship with the use of the device seems not relevant and/or the event can be 
reasonably explained by another cause, but additional information may be obtained. 
3) Possible the relationship with the use of the investigational device is weak but cannot be ruled 
out completely. Alternative causes are also possible (e.g. an underlying or concurrent illness/ 
clinical condition or/and an effect of another device, drug or treatment). Cases were relatedness 
cannot be assessed or no information has been obtained should also be classified as possible. 
4) Probable the relationship with the use of the investigational device seems relevant and/or the 
event cannot reasonably explained by another cause, but additional information may be obtained. 
5) Causal relationship: the serious event is associated with the investigational device or with 
procedures beyond reasonable doubt when: 
• the event is a known side effect of the product category the device belongs to or of similar 
devices and procedures; 
• the event has a temporal relationship with investigational device use/application or 
procedures; 
• the event involves a body-site or organ that 
• the investigational device or procedures are applied to; 

 
 
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• the investigational device or procedures have an effect on; 
• the serious event follows a known response pattern to the medical device (if the response 
pattern is previously known); 
• the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible); 
• other possible causes (e.g. an underlying or concurrent illness/ clinical condition or/and an 
effect of another device, drug or treatment) have been adequately ruled out; 
• harm to the subject is due to error in use; 
• the event depends on a false result given by the investigational device used for diagnosis 
17, when applicable; 
• In order to establish the relatedness, not all the criteria listed above might be met at the 
same time, depending on the type of device/procedures and the serious event. 
ZOLL and the investigators will distinguish between the serious adverse events related to the 
investigational device and those related to the procedures (any procedure specific to the clinical 
investigation). An adverse event can be related both to procedures and the investigational device. 
Complications of procedures are considered not related if the said procedures would have been 
applied to the patients also in the absence of investigational device use or application. 
In some particular cases the event may be not adequately assessed because information is 
insufficient or contradictory or the data cannot be verified or supplemented. The ZOLL and the 
Investigators will make the maximum effort to define and categorize the event and avoid these 
situations. 
Particular attention shall be given to the causality evaluation of unanticipated serious adverse 
(device) events. The occurrence of unanticipated events related to the use of the device (USADE) 
could suggest that the clinical investigation places subjects at increased risk of harm than was to 
be expected beforehand. 
 
MONITORING BY DATA MONITORING COMMITTEE 
The Data Monitoring Committee (DMC) is used to ensure safety by reviewing cumulative data 
from the clinical trial at pre-defined intervals for the purpose of safe-guarding the interest of trial 
participants. The DMC will serve in an advisory role in this trial. The composition, guiding 
policies, and operating procedures governing the DMC are described in a separate DMC charter. 
Based on safety data, the DMC may recommend a modification to the protocol or that the sponsor 

 
 
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stops the clinical trial/investigation. All final decisions regarding clinical trial/investigation 
modifications, however, rest with the Sponsor. 
 
ADJUDICATION OF EVENTS 
The Clinical Events Committee (CEC) is comprised of qualified physicians who are not 
investigators in the trial. The Clinical Events Committee is responsible for adjudicating specified 
clinical endpoints based on the specific criteria used for the categorization of clinical events in the 
trial. 
Periprocedural MI will be adjudicated according to the Clinically Relevant Myocardial Infarction 
After Coronary Revascularization (CRMI) definition.40 Death, Stent Thrombosis, Spontaneous 
MI, and Revascularization will be adjudicated per ARC definitions.27 
Hospitalization due to Heart Failure will be adjudicated per ACC/AHA definition.48 
The composition, guiding policies, and operating procedures governing the CEC are described in 
a separate CEC Manual of Operations. 
When applicable, sites will provide patients’ source documentation per request from the Sponsor 
and will aploade angiograms into AMBRA website through software service Dicom Grid, Inc., 
which will de-identify angiograms. 
 RECOMMENDATION FOR DAPT AND STENTS 
Control and intervention group patients should receive dual antiplatelet therapy (DAPT) and 
anticoagulation medication as recommended by the ESC Guideline for the management of acute 
myocardial infarction in patients presenting with ST-segment elevation. 
• This includes aspirin 162 or 325 mg po chewed as soon as feasible. 
• This should be followed by loading dose of ticagrelor (preferably crushed or chewed) 180 
mg before PCI. If ticagrelor not available, loading dose of prasugrel (60 mg) can be used. 
o Clopidogrel can be used only if the patient cannot take ticagrelor or prasugrel. 
• This also includes unfractionated heparin (UFH) given as an intravenous bolus as soon as 
feasible with subsequent boluses targeted to an activated clotting time of 200 to 250 
seconds. If Bivalirudin is used, the infusion should continue after finished PCI for 1-2 
hours. 
• Use of an intravenous GP IIb/IIIa inhibitor should be used according to the decision of 
interventional cardiologist. 

 
 
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• In patients with STEMI in whom clopidogrel was initiated before coronary angiography, 
it is recommended to switch to either ticagrelor or prasugrel before, or during, or at latest 
immediately after PCI, if ticagrelor or prasugrel are not contraindicated. 
o Switching from clopidogrel to ticagrelor or prasugrel should include a loading dose 
of ticagrelor 180 mg (preferably crushed or chewed if before or during PCI) or 
prasugrel 60 mg if the patient is not at high risk of bleeding, irrespective of the prior 
dose of clopidogrel. 
• Recommended maintenance therapy consists of aspirin 81 mg once daily (or per local 
practice); ticagrelor 90 mg twice daily for at least 12 months. If ticagrelor not available, 
prasugrel 5 or 10 mg according to label recommendation can be used. 
• If needed, transition to clopidogrel can take place after 30 days post index PCI. 
o The recommended first dose of clopidogrel is 600 mg po 12 h after the last dose of 
ticagrelor or prasugrel. If maintenance therapy consists of aspirin and clopidogrel, 
the recommended doses are aspirin 81 mg once daily (or per local practice) and 
clopidogrel 75 mg once daily. 
• Use second or third generation DES. Do not use BMS or BVS or BRS such as Absorb in 
study patients. 
 
 RISK ANALYSIS 
 Risk Assessment Process 
 
ZOLL has a documented EN ISO 14971:2012 compliant Risk Management process, which 
includes the identification of risks, risk assessment, identification, implementation and verification 
of adequate controls (mitigations) to ensure that identified risks have been reduced as low as 
possible and to ensure the benefits of the intended use as compared to any residual risk is 
acceptable. 
The intent of the Risk Management process is to identify potential hazardous situations related to 
the design, manufacture, and use of the Proteus IVTM System, evaluate each risk and implement 
controls to reduce the risks as low as possible. 
Risks related to the IVTM System and Sub-Systems (Console, Catheter, Cassette and Temperature 
Probe) have been evaluated in a number of ways: 
• Hazard Analysis – The purpose of the Hazards Analysis is to identify, evaluate and 
control potential hazards to the patient, user and the environment. 

 
 
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• Software Hazards Analysis - The Software Hazards Analysis is used to investigate 
potential device Software related hazards and control the potential hazards.  
• Design FMECA - The purpose of the Design FMECA is to evaluate failure modes 
of the device components, or subsystems to identify potential design failure risk, 
then evaluate and control potential hazards. 
• Process FMECA - The purpose of the Process FMECA is to evaluate failure modes 
of the device manufacturing process steps to identify process failure risks, then 
evaluate and control potential hazards. 
The results of the Proteus IVTM System Risk Management process was reviewed, and concluded 
that the risk controls are effective to reduce the risks as low as possible. The ZOLL Proteus IVTM 
System presents an acceptable risk benefit ratio when used in accordance with its labeling for its 
proposed intended use: The Proteus IVTM System is intended for use in adult subjects with acute 
anterior myocardial infarction to induce and maintain hypothermia prior to percutaneous coronary 
intervention as an adjunctive therapy to reduce anterior infarct size.  
Note: See the Investigator Brochure for additional information on the Proteus IVTM System, as 
applicable. 
 Expected Clinical Observations 
In subjects who have been treated for myocardial infarction, there are many sequelae of such an 
event that may be thought to be “normal” effects and not due to the treatment provided.  These 
events may be outside the range of what is considered to be “normal” (e.g., a high lab value such 
as a shift in potassium), but do not put the patient at risk for harm.  These events are therefore 
expected physiological responses to treatment with therapeutic hypothermia in all patients.  
Prospectively, these observations may include but are not limited to the following: 
• Shift in Potassium levels 
• High or low levels of glucose 
 
The expected clinical sequelae of patients treated with hypothermia include, but are not limited to, 
the following28: 
• Shivering 
• Prolonged ECG intervals 
• Bradycardia defined as a heart rate of 40 beats per minute and not requiring treatment 
(e.g., pacemaker, medications, etc.) 

 
 
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• J wave (also called Osborne wave) can occur at any temperature < 32.3°C 
• Blood electrolyte shifts: Calcium, Phosphorus, Magnesium, Chloride 
• High or low levels of glucose: Decreased insulin sensitivity and insulin secretion 
• Asymptomatic shifts in serum amylase and lipase levels 
• Peripheral pulses may be difficult to detect 
Cold Diuresis: Increased resistance to ADH or Vasopressin resulting in decreased water or solute 
reabsorption. 
 Potential Clinical Risks 
Adverse events that are inherent to a PCI procedure and expected to occur in most subjects for a 
projected duration according to the opinion of the investigator may be considered unavoidable.  
Such events include, but are not limited to, those listed in Table 14.  These adverse events should 
not be reported during this trial. 
Table 14 Expected and unavoidable adverse events related to the PCI procedure 
Description of the Event 
Time Frame from the Index Procedure (PCI) 
Back pain related to laying on Cathlab table 
Within 48 hours 
Peripheral vasoconstriction  
Within 24 hours 
Thermal discomfort  
Within 24 hours 
Incisional pain (pain at access site) 
Within 72 hours 
Sleep problems or insomnia 
Within 72 hours 
Mild to moderate bruising or ecchymosis 
Within 168 hours 
 
A list of potential (expected) risks that may be associated with use of the Proteus IVTM System is 
provided below.  Since this clinical study utilizes an investigational device, all risks may not be 
known.   However, they are believed to be similar to those associated with the existing intra-
vascular temperature management devices in clinical use or commercially available. 
The following potential adverse events may occur during the course of the clinical trial. 
11.3.1 Potential Adverse Events associated with the Proteus Catheter and Cooling 
System: 
Potential risks related to the Proteus Catheter are reasonably believed to be consistent with the 
common, known risks of central venous catheters and/or venous introducer sheaths.  Potential risks 
related to cooling, re-warming, and/or the Proteus IVTM System include but are not limited to the 
following: 

 
 
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• Catheter related injury [embolism (air, thrombus, catheter fragment), clinically significant 
hematoma, vascular perforation or dissection, arteriovenous fistula, nerve injury, excessive 
bleeding, pseudoaneurysm 
• Deep vein thrombosis (DVT) requiring treatment 
• Infection [local or systemic (pneumonia, sepsis, meningitis, visceral organ)] 
11.3.2 Potential Adverse Events associated with the cooling procedure include but 
are not limited to the following:   
• Acute renal failure  
• Acute renal insufficiency 
• Adverse drug reaction 
• Angina 
• Blood lysis 
• Congestive Heart Failure  
• Clinically relevant shivering (BSAS ≥ 2) that cannot be controlled by the antishivering 
medication regimen 
• Dysrhythmia [ventricular tachycardia, ventricular fibrillation or atrial fibrillation 
requiring intervention, bradycardia (HR ≤ 40 bpm, block)] 
• Hyperglycemia / Hypoglycemia 
• Hyperkalemia / Hypokalemia 
• Hyperphosphatemia / Hypophosphatemia 
• Hypotension  
• Infection (local, systemic) 
• Liver Failure 
• Myocardial infarction 
• Multi-system organ failure 
• Overcooling (temperature <31.0°C for ≥ 20 continuous minutes) 
• Overwarming (temperature >38°C for ≥ 20 continuous minutes including dehydration, 
burns and neurological damage) 
• Pancreatitis 
• Pulmonary edema  
• Peripheral vascular insufficiency  
• Thrombocytopenia 
• Rebound hyperthermia 
• Respiratory failure during cooling or rewarming 
• Seizures 

 
 
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• Stroke [Cerebral vascular Accident (CVA)] 
• Transient Ischemic Attack (TIA) 
• Unstable angina 
11.3.3 Risks Associated with Anti-shivering Medications 
In order to preserve patient comfort and suppress the shivering response during cooling, a 
combination of recommended buspirone, where available (or equivalent alternative) and required 
Pethidine (Meperidine) should be used (see Attachment II).  As identified in their labeling, the 
risks associated with the use of these pharmacologic agents in this trial population include the 
following:  
Buspirone (or equivalent alternative) 
• Interaction with MAO Inhibitors  
• Dizziness  
• Nausea  
• Headache  
• Nervousness  
• Lightheadedness  
• Excitement 
 
Pethidine (Meperidine) 
• CNS Depression  
• Hypotension  
• Respiratory Depression  
• Circulatory Depression  
• Respiratory Arrest  
• Shock  
• Cardiac Arrest 
 
Other reported reactions:  
• Lightheadedness  
• Dizziness  
• Nausea  
• Vomiting  
• Sweating 

 
 
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 Additional investigations due to the trial 
Participation in the clinical trial will involve extra blood sampling for laboratory markers 
(electrolytes, complete blood count, baseline and peak troponin including upper limit of normal), 
additional ECGs, and the need for cardiac MRI imaging.  All of these are standard clinical 
procedures, and the risks to participants are low.  Sites will be carefully monitored for adherence 
to the protocol.  Patients will be screened for appropriateness for MRI prior to enrollment. 
11.4.1 Delay in PCI through the use of hypothermia therapy 
The probability for potential delay in PCI is considered Occasional.  In prior trials of hypothermia 
for STEMI, the increase in door to balloon time ranged from 9 minutes to 18 minutes.  It is 
noteworthy that this delay was not associated with an increase in infarct size hypothermia patients 
compared to controls.  In fact, patients with anterior STEMI with < 35°C at the time of reperfusion 
showed smaller infart size.  Sites will be trained to incorporate hypothermia into the cath lab 
workflow while minimizing delay.  Feedback will be provided for each case to help maintain 
efficiency. 
11.4.2 Implementation of PCI in patients undergoing hypothermia (patient-related 
risks). 
Potential risks related to the use of hypothermia therapy in patients are outlined in sections  11.2.1 
and 11.2.2 above. These risks include: potential adverse events associated with the Proteus 
Catheter and Cooling System, potential adverse events associated with cooling, and potential risks 
associated with the anti-shivering medications. 
11.4.3 Implementation of PCI with concurrent use of endovascular hypothermia. 
The addition of hypothermia as adjunctive treatment of STEMI will potentially lead to more 
difficult conditions for the Investigator and other users.  The ability to integrate hypothermia into 
the cath lab workflow has been demonstrated successfully in prior clinical trials.  Again, thorough 
training, frequent monitoring, and rapid feedback will help mitigate the challenges of incorporating 
hypothermia into treatment for STEMI. 
11.4.4 The concurrent medication. 
Patients who have received medications such as monoamine oxidase inhibitor within a 14 day 
period will be excluded from the trial to prevent potential interaction with the anti-shivering 
medications.  In patients that receive morphine prior to arrival to the hospital, the pethidine dose 
will be lowered to decrease the likelihood of respiratory depression. 

 
 
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11.4.5 The supply of 4°C cooled saline solution 
The amount of cooled saline solution is limited to 1,000 ml, an amount shown to be well tolerated 
in the CHILL-MI trial, where the average amount of cooled saline was 1475 ml.  Again, careful 
training and monitoring will help to avoid unnecessary exposure to larger volumes of saline. 
11.4.6 Other procedures within the clinical trial 
The risk of adverse interaction or influence of other procedures within the clinical trial are deemed 
to be low.  In prior hypothermia trials in STEMI, there was no interference with the stenting 
procedure, with resuscitation efforts for arrhythmias or cardiogenic shock.  Hypothermia does 
inhibit the absorption and metabolism of clopidogrel, a anti-platelet inhibitor, given to reduce the 
risk of stent thrombosis.  This risk will be mitigated by calling for adherence to ESC guidelines 
which recommend either prasugrel or ticagrelor, both of which are less affected by hypothermia. 
 Potential Clinical Benefits 
Although no assurances or guarantees can be made, there is a reasonable expectation that the use 
of this investigational device is safe within the context of the trial and may be beneficial.  Cooling 
using the device, for instance, may result in improved temperature control relative to the standard 
techniques already in use at the sites. 
The primary benefits of therapeutic hypothermia have been shown to be:  
• Improved patient survival 
• Improved heart tissue salvage after the ischemic event 
Additional potential benefits of therapeutic hypothermia with the Proteus System may include: 
• Faster cooling 
• More accurate control of the cooling procedure than with surface cooling 
• Further improved survival  
There is no guarantee that participation in this trial or use of hypothermia will benefit the trial 
subject.  However, collection of such trial data may provide added benefit for future myocardial 
infarction subjects. 
 Methods to Minimize Risk 
All efforts will be made to minimize risks by selecting investigators who are experienced and 
skilled in using minimally invasive catheter-based cardiovascular interventions and who have been 
adequately trained.  Also, risk minimization activities were performed during development and 
design verification tests of the device.  Activities intended to minimize risks include the following. 

 
 
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• Investigator and trial personnel training will be conducted to share information regarding 
the design of the Proteus IVTM System, its application, pre-clinical results, and clinical 
trials on comparable intra-vascular cooling devices. 
• Adherence to eligibility criteria and screening procedures will ensure that appropriate 
patients are enrolled.   
• Adherence to the Proteus IVTM System Instructions for Use packaged with the device.  
• 
Corrective and preventative actions will be implemented by ZOLL, as necessary, if 
deviations from recommendations in the protocol or IFU are observed.  
• 
Clinical support by ZOLL representative will be provided during the enrollment in the 
study and thereafter if needed.  ZOLL representatives will only have advisory role.  
• The subjects will be carefully monitored throughout the trial period.   
• The investigator will evaluate the subject adverse events during the course of the trial. 
• Data submitted from the investigative centers will be monitored during the course of the 
trial.   
• Monitoring visits will be conducted to evaluate protocol compliance and data quality. 
• Safety and effectiveness data obtained during the course of the trial will be shared with 
investigators in periodic reports to increase understanding of the device and potential 
adverse events. 
• An independent Data Safety Monitoring Board (DSMB) will monitor safety throughout 
the clinical trial. Stopping rules will be discussed with the DSMB and applied for subject 
safety through enrollment. 
 
Detailed trial procedures are provided in Section 6.8 - Clinical Trial Procedures. 
 Risk – Benefit Assessment 
To date, there have been five clinical trials that have reported on the safety and effectiveness of 
therapeutic hypothermia in AMI and one in Radio-Contrast nephropathy (COOL-RCN Trial), with 
a total of more than eleven hundred patients being enrolled in total with at least half of those treated 
with therapeutic hypothermia.  The rate of adverse events are well reported in these populations 
(see section 5, Prior Investigations), and the risks are clearly categorized for these trials.  In 
summary, the number of trials, patients enrolled, and low numbers of safety events reported 
indicate that therapeutic hypothermia in this patient population is at an acceptable risk level to 
engage in this trial. 
There is significant morbidity and mortality associated with the numerous clinical conditions 
outlined in this report, and therapeutic hypothermia has shown promise to greatly improve clinical 
outcomes in these patients.  In particular, patients with anterior STEMI have a higher incidence of 

 
 
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congestive heart failure, cardiogenic shock, and cardiac mortality.  A significant reduction in 
infarct size in these patients, with therapeutic hypothermia, has the promise to reduce these adverse 
clinical outcomes.  Risks associated with the use of the Proteus IVTM system have been reduced 
via the Risk Management Process, and are deemed acceptable, considering the potential benefits.  
We conclude that the use of the Proteus IVTM system for medical practice is justified and 
warranted. 
 
Risk assessment of the Proteus IVTM System has been performed in accordance with the ISO 
14971:2012.30  The Proteus IVTM System is safe and presents an acceptable risk benefit ratio to 
provide cooling or warming of patients when: 
• Used by and under the supervision of a qualified medical practitioner 
• In patients for whom the risks of a central line are acceptable 
• In intensive care environments equipped to handle clinical conditions warranting 
use of the device under this protocol 
• Used according to the Instructions For Use (IFU) 
 RECORDS AND REPORTS 
Throughout the course of this clinical trial, ZOLL, the investigators, and reviewing MEC are 
responsible for the records and reports detailed in the following sections.  
 Investigator Records 
Investigators must retain all trial records required by ZOLL and by the applicable regulations in a 
secure and safe facility.  The investigator must consult a ZOLL representative before disposal of 
any trial records and must notify ZOLL of any change in the location, disposition, or custody of 
the trial files. 
Trial records are those that individually and collectively permit evaluation of the conduct of the 
trial and the quality of the data produced.  ZOLL’s SOP requires that all clinical trial data be kept 
for a minimum of 15 years and all data used in submissions be kept for the life of the corporation.  
It is the site’s obligation to inform ZOLL if their own policy does not comply with the sponsor’s 
requirement so necessary arrangements can be negotiated.  It is ZOLL’s responsibility to inform 
the investigator/institution as to when these documents no longer need to be retained. 
The investigator is responsible for the preparation (review and signature) and retention of the 
records cited below. 

 
 
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• All correspondence with another investigator, MEC, ZOLL, a monitor, or FDA, including 
required reports and trial documents which pertain to the investigation. 
• Records of receipt, use, and final disposition of a device.    
• Records of each subject's case history and exposure to the device.  Case histories include 
the Case Report Forms (CRFs) and supporting source data (signed and dated informed 
consent forms, medical records, e.g., progress notes of the physician, patient’s hospital 
chart, nursing notes).   
• The clinical investigational plan, with documents showing the dates of and reasons for 
each deviation from the protocol.  
• Any other records that are required to be maintained by local regulations or by specific 
regulatory requirements for a category of investigations or a particular investigation. 
• Any other record that the reviewing MEC requires to be maintained for the subject 
investigation. 
 Investigator Responsibilities 
The participating investigator is responsible for adhering to this Clinical Investigational Plan 
(CIP), FDA CFR,  ISO 14155 and Declaration of Helsinki  (Regulatory requirements of his/her 
country local law). 
Specifically, the Principal Investigator at each site shall: 
a) indicate his/her acceptance of the CIP in writing, 
b) conduct the clinical investigation in compliance with the CIP, 
c) create and maintain source documents throughout the clinical investigation and make 
them available as requested during monitoring visits or audits, 
d) ensure that the investigational device is used solely by authorized users as specified in 
6.2, and in accordance with the CIP and instructions for use, 
e) propose to the sponsor any appropriate modification(s) of the CIP or investigational 
device or of the use of the investigational device, 
f) refrain from implementing any modifications to the CIP without agreement from the 
sponsor, EC and regulatory authorities, if required, 
g) document and explain any deviation from the approved CIP that occurred during the 
course of the clinical investigation, 
h) ensure that an adequate investigation site team and facilities exist and are maintained 
and documented during the clinical investigation, 
i) ensure that maintenance and calibration of the equipment relevant for the assessment of 
the clinical investigation is appropriately performed and documented, where applicable, 

 
 
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j) ensure the accuracy, completeness, legibility and timeliness of the data reported to the 
sponsor in the CRFs and in all required reports, 
k) maintain the device accountability records, 
l) allow and support the sponsor to perform monitoring and auditing activities, 
m) be accessible to the monitor and respond to questions during monitoring visits, 
n) allow and support regulatory authorities and the EC when performing auditing activities, 
o) ensure that all clinical-investigation-related records are retained as required by the 
applicable regulatory requirement(s), and 
p) sign the clinical investigation report, where applicable. 
 
The investigator is responsible for the preparation and submission of the reports cited in Table 15.  
Reports must be prepared in complete, accurate and timely manner.  These reports may be subject 
to regulatory inspection (and ZOLL) and copying, and the retention requirements described above 
for Investigator Records.  In addition to the reports listed in Table 15, the reviewing MEC may 
request reports pertaining to any aspect of the clinical trial. 
Written approval Medical Ethics Committee (MEC) with authority for the participating site will 
be obtained prior to the start of the study. The investigator or if applicable the Sponsor is 
responsible for submitting all required documents to the MEC. At a minimum the following 
documents will be submitted: 
• Clinical Investigational Plan (CIP) 
• Patient Informed Consent documents in the local language 
• Any other written information to be provided to the subjects in the local language 
• Investigator Brochure (IB) (as required) 
• Other documents will be submitted as per local requirements 
After obtaining MEC approval, the investigator will submit the approval letter indicating the 
approved version of the CIP, Patient Informed Consent, IB and any other reviewed documentation 
to ZOLL. 
 
 

 
 
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Table 15 Investigator Reporting Responsibilities to Sponsor and MEC 
REPORT 
SUBMIT TO 
DESCRIPTION/CONSTRAINTS 
Withdrawal of 
MEC Approval 
Sponsor 
The investigator must report a withdrawal of the reviewing 
authority within 5 working days.  
Case Report Form  
(CRF)  
Sponsor & 
Monitor 
CRFs should be completed as soon as possible after any trial 
related procedure takes place. 
Deviation from 
Investigation Plan 
(Emergency) 
Sponsor & 
MEC 
Notification must be made within 5 working days if the 
deviation was made to protect the life or physical well-being of 
a subject. 
Deviation from 
Investigation Plan 
(Other – Non 
Emergency) 
Sponsor & 
MEC 
If the deviation may affect the scientific soundness of the plan 
or the rights, safety and welfare of the subjects (and is not an 
emergency), then the deviation must be approved by ZOLL, 
the MEC, and the reviewing authority prior to its 
implementation.  If the deviation does not affect these issues 
(trial soundness, rights, safety, etc.) then only ZOLL must 
approve it, (except in cases which are beyond the control of the 
investigator—see section on Protocol Deviations). 
Failure to Obtain 
Informed Consent 
Sponsor & 
MEC 
The Investigator must notify ZOLL and the reviewing authority 
within 5 working days after device use The investigator must 
submit notification after device use or after the investigator 
first learns of the absence of informed consent. The report must 
include a brief description of the circumstances surrounding the 
failure to obtain informed consent and include written 
concurrence by a licensed physician not involved in the 
investigation. Failure to obtain informed consent must be 
reported to the MEC as required by local regulations. 
Final Report 
Sponsor & 
MEC 
This report must be submitted within 3 months after 
termination or completion of the investigation. 
 
 Sponsor Records  
All Sponsor documents and records shall be maintained as indicated by ZOLL’s Quality System. 
ZOLL will maintain the following trial -related records in accordance with ZOLL record retention 
policies and procedures following the completion of this investigational plan. Clinical data for 
regulatory submissions and publications will be retained for the life of the corporation. 
• All correspondence pertaining to the investigation with the sponsor, a monitor, an 
investigator, an MEC, regulatory agencies, including required reports.    

 
 
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• Records of shipment and disposition of the investigational device.  
• Signed investigator agreements including the financial disclosure information required to 
be collected and current signed and dated curriculum vitae.  
• Records of adverse events and device deficiencies.  
• List of participating institutions 
• Investigational product accountability reports including record of receipt, use, or 
disposition of the device(s) that relate to type, quantity, serial numbers of devices, and date 
of receipt, names of persons who received, used, or disposed of each device and why and 
how many devices have been returned to ZOLL or otherwise disposed 
• All signed and dated case report forms submitted by investigator, samples of patient 
informed consents, and other information provided to the subjects 
• Copies of all MEC approval letters and relevant MEC correspondence 
• Names and evidence of the institutions in which the clinical investigation will be conducted 
• Insurance certificates 
• Forms for reporting adverse events and device deficiencies  
• Names/contact addresses of monitors 
• Statistical analyses and underlying supporting data 
• Final report of the clinical investigation 
• The Clinical Investigational Plan, Clinical Monitoring Plan (CMP), Investigator Brochure 
(as applicable), and study related reports 
• Study training records for center personnel and ZOLL personnel participating in the trial 
• Any other records that MEC and /or competent authority requires to be maintained by 
regulation or by specific requirement for a category of investigation or a particular 
investigation. 
 Sponsor Reports 
ZOLL Circulation, Inc. is responsible for the classification and reporting of reportable adverse 
events and device deficiencies and ongoing safety evaluation of the clinical investigation in line 
with local regulatory requirements. 
ZOLL Circulation, Inc. will assure that all Serious Adverse Events and reportable Device 
Deficiencies are reported to the Competent Authorities in accordance with European Medical 
Devices directives and all applicable national regulations. 
ZOLL Circulation, Inc. is responsible for the reports cited in Table 16.  These reports are subject 
to regulatory retention and inspection requirements.  Governing Regulatory Agencies or the 
reviewing MEC may request reports pertaining to any aspect of the clinical trial. 

 
 
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Table 16:  ZOLL Reporting Responsibilities 
REPORT 
SUBMIT TO 
DESCRIPTION 
Unanticipated 
Adverse Device 
Effects; SAEs and 
Reportable DDs 
Relevant 
authorities and 
MECs 
Reporting timeframe as per local regulatory 
requirements. 
Investigators 
Notification throughout the course of the trial 
when appropriate (based on perceived risk) 
Premature 
termination or 
suspension of the 
Clinical 
investigation 
Investigators, 
MECs, Relevant 
Authorities 
Provide prompt notification of termination or 
suspension and reason(s). 
Subject 
enrollment 
Completed 
Investigators. 
MEC and 
Relevant 
regulatory 
Authorities upon 
request 
ZOLL will notify the investigators within 30 
working days of the completion of 
enrollment. Investigators will, in turn, inform 
their MECs, when required. 
Withdrawal of 
MEC approval 
Investigators, 
MECs 
Notification within five working days. 
Final Report 
Investigators, 
MECs, BfArM 
(and other 
relevant 
Authorities upon 
request) 
A final report will be submitted within six 
months after completion or termination of 
this study. The investigators shall have the 
opportunity to review and comment on the 
final report. If a clinical investigator does not 
agree with the final report, his/her comments 
shall be communicated to the other 
investigators. The principal clinical 
investigator in each center shall sign the 
report. 
 MONITORING AND AUDITING PROCEDURES 
 Clinical Trial Sponsor and Monitors 
ZOLL is the Sponsor of the clinical trial.  It is the responsibility of the sponsor to ensure that 
proper monitoring of the investigation is conducted.  Clinical trial monitoring and auditing will 

 
 
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be done by appropriately trained personnel appointed by the trial sponsor to ensure that the 
investigation is conducted in accordance with ZOLL’s requirements and applicable laws and 
regulations. 
A monitor is an individual designated by a sponsor or contract research organization to oversee 
the progress of an investigation.  The monitor may be an employee of a sponsor or a consultant 
to the sponsor, or an employee of or consultant to a contract research organization.  The monitor 
will be trained on the device, investigational plan, informed consent, instructions for use, 
applicable ZOLL procedures, electronic data capture system, and regulatory requirements.  The 
monitor will periodically check and report on the progress of the clinical trial at an 
investigational site or other data gathering organization or ZOLL facility.   
 Monitoring Methods 
Monitoring of the clinical trial will be a continuous, interactive process to ensure that high-
quality data is obtained in compliance with the clinical investigational plan and regulatory 
requirements.  Monitoring functions will be conducted by ZOLL, and/ or a contract research 
organization and/or other designees. Specific monitoring requirements are detailed in the Trial 
Monitoring Plan (maintained in the ZOLL COOL-AMI clinical trial project files).  Frequent 
communication will be maintained with each investigational site to keep both the clinical center 
and ZOLL up-to-date and aware of the trial progress.  Case Report Forms will be reviewed for 
completeness and accuracy.   
ZOLL will monitor sites in accordance with the monitor’s tasks set under Section 8.2.4 of 
Standard DIN EN ISO 14155:2012-01. These include visits to the clinical trial sites before the 
start of, during and at the end of the clinical trial. On-site monitoring of all trial centers will be 
frequent enough (at a minimum annually) to assure continued integrity and acceptability of the 
data.  Accuracy of data reported on case report forms will be verified by comparison to source 
documents.  Reports of monitoring visits will be provided to the clinical trial personnel at each 
site.  Corrective action will be taken to resolve any issues of noncompliance.  If ZOLL finds that 
an investigator is not complying with the executed trial agreements, the investigational plan, the 
applicable national regulations, or the requirements of the reviewing MEC, then prompt action 
will be taken to secure compliance.  In addition, shipment of the device may be stopped or the 
participation of the investigator may be terminated.  Additional information is provided in 
Section 6.30 – Trial Closure. 
 Monitoring Visits 
Scheduled visits to the clinical investigational site will occur at the following times:  prior to the 
start of the clinical trial (pre- trial qualification visit), at initiation of the trial (during first index 

 
 
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procedure or shortly thereafter), interim visits throughout the clinical trial as required, annually, 
and upon completion of the clinical trial. 
 Pre-trial Qualification Visit 
A pre- trial visit will be conducted by ZOLL personnel (or designees) to review the clinical 
investigational plan and regulatory requirements with the investigator and the trial personnel to 
assure that they:  
• Understand the investigational status of the device and the requirements for its use and 
accountability. 
• Understand the clinical investigational plan. 
• Understand the requirements for an adequate and well-controlled clinical trial. 
• Understand and accept the obligation to conduct the clinical investigation in accordance 
with the national regulations. 
• Understand and accept the obligation to obtain informed consent in accordance with the 
national regulations. 
• Understand and accept the obligation to obtain MEC approval before the clinical trial is 
initiated, ensure continuing review of the trial by the MEC, and keep ZOLL informed of 
MEC approval and actions concerning the clinical trial. 
• Have access to an adequate number of eligible patients to participate in the trial (at a 
minimum: 1 patient/center/month). 
• Have adequate facilities and resources to conduct the trial.  This includes resources 
appropriate for use of electronic data capture systems. 
• Have sufficient time from other obligations to carry out the responsibilities of the clinical 
trial. 
• Sign the Investigator Agreement and trial contracts (prior to enrollment of patients). 
A report of the pre- trial qualification visit will be completed.  Resolution of any concerns or 
completion of any appropriate follow-up activities stemming from the pre- trial visit also will be 
documented. 
 Initiation Visit 
ZOLL clinical personnel (or designees) will provide assistance for both technical concerns and 
trial management issues during the initiation visit.  Enrollment of the first patient at each clinical 
site may or may not coincide with this visit.  Any observations will be documented and issues 
requiring follow-up will be identified on a monitoring report.  Training of trial personnel also will 
be documented. 

 
 
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 On-Site Interim Monitoring Visits 
On-site monitoring visits will be made on an as-required basis (and at least annually) to assess 
adherence to the clinical investigation plan, MEC review of trial progress, maintenance of records 
and reports, and selected review of source documents for accuracy, completeness, legibility, and 
omissions.  The monitors will acquire information to assess the progress of the trial (toward 
meeting trial objective) and identify any concerns that stem from observation of device 
performance and/or review of the investigator's patient records, trial management documents, and 
patient informed consent documents.  Monitoring reports will be generated along with 
communications to the investigator, which document the result of the monitoring visit and any 
recommended actions.  Resolution of concerns and completion of assigned tasks will be 
documented. 
 Audits 
An on-site audit may be completed periodically throughout the trial at each clinical site by an 
independent group.  The purpose of the audit will be to ensure compliance to the investigational 
plan and regulatory requirements, e.g., written informed consent was documented, information 
recorded on the case report forms is complete and accurate as compared to source documentation, 
protocol deviations are noted, and device accountability is accurate and complete.  A randomly 
selected number of patient records and other supporting documents will be compared to the case 
report forms.  A record of the findings and recommended actions to correct deficiencies will be 
documented on the audit report. 
 Final Monitoring Review 
Depending upon the status of the trial at each center, a close-out or final visit may be conducted.  
Any ongoing responsibilities will be discussed with the investigator and the trial center 
coordinator.  A final monitoring report, which includes, at a minimum, disposition of any unused 
devices, will be completed. 
 DATA MANAGEMENT PROCEDURES 
 
ZOLL will oversee all data management functions.  ZOLL will be responsible for database 
development, system maintenance, user training, data queries, and report generation. 

 
 
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 Case Report Forms 
ZOLL will use an electronic data capture (EDC) system to collect patient data.  The electronic case 
report forms (eCRFs) are the primary component of EDC and are based on the sample forms that 
will be provided in a separate document.  Training on use of the system will be provided to the 
trial site personnel.  Instructions for completion of the eCRFs also will be provided. 
The eCRFs must be completed, saved, and locked via electronic signature by the Investigator using 
a unique ID and password.  This ID and password are for the use of the investigator only and may 
not be used by any other person.  Because of the potential for errors or inaccuracies in transcribing 
data into eCRFs, source documentation must be maintained in each subject’s hospital chart and/or 
electronic medical record.  The eCRFs and source documentation must be available at all times for 
inspection by the trial monitors or regulatory inspectors. 
Changes made to eCRFs will be electronically recorded in a complete audit trail that cannot be 
changed, but can be accessed by authorized personnel at any time.  All data are transmitted via the 
Internet in an encrypted fashion.  When received at the server site, the data are decrypted and 
stored.  Data can be extracted for ZOLL review and analysis at any time. 
 Source Documentation 
Regulations require that an investigator maintain information in the trial subject’s medical records 
to corroborate data collected on the eCRF.  To comply with these regulatory requirements, the 
following information will be maintained and made available as required by ZOLL and/or its 
designees and/or regulatory inspectors.  Shadow charts are not appropriate or adequate source 
documentation.  Complete medical (clinical and hospital) records include the following 
documentation.   
• Medical history/physical condition of the patient before involvement in the trial sufficient 
to verify clinical protocol eligibility criteria. 
• Description of cooling procedure (material used, drugs administered during the procedure, 
device identification information and disposition, date, time, angiographic and clinical 
findings, etc.).  
• Electronic data downloaded from the ZOLL Proteus IVTM System. 
• Signed notes in the subject’s medical record on the enrollment day that identify and 
include:  the subject’s date of enrollment, procedure date, the trial sponsor (ZOLL), clinical 
site name, the subject-assigned identification number, the subject- assigned enrollment 
number, and documentation and confirmation that the appropriate informed consent was 
obtained. 
• Dated and signed notes for each subject’s trial visit. 

 
 
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• Lab results.   
• Baseline ECG, angiogram, and MRI reports, etc.   
• Dated printouts or reports of special assessments (ECG baseline report, imaging report, 
etc.). 
• Adverse event reporting and follow-up of the adverse events.  Information in the medical 
chart should include at a minimum the following:  event description, severity, seriousness, 
onset date, date site became aware of event, duration, relation to trial device, treatment, 
and outcome of the adverse event. 
• Trial subject’s condition upon completion of or withdrawal from the trial. 
• Trial subject’s medical status, including all SAEs out to 1 year following trial enrollment. 
• All notes related to trial subject’s KCCQ and the New York Heart Association Functional 
Class questionnaires. 
 Transmission of Data 
Required data will be recorded on the appropriate eCRF at the time of or as soon as possible after 
the patient visit.  The eCRFs and any requested supporting source documents must be sent to ZOLL 
and/or retrieved from the investigator during monitoring visits.  Questions about completion of the 
eCRFs may be directed to the ZOLL COOL AMI clinical team at Clin-safety@zoll.com 
 Data Queries  
During monitoring visits, the Monitor will perform a 100% review of all variables, i.e., 
demography, inclusion/exclusion criteria, safety, effectiveness, on the eCRFs with each subject’s 
source documents. Any discrepancies will be queried by ZOLL or its designee and must be 
resolved by the investigational site staff and investigator in a timely manner.  Queries also will be 
generated by ZOLL data management personnel during routine review of the data on the electronic 
data capture system. 
 STATISTICAL ANALYSIS PLAN 
The objective of this trial is to evaluate the safety and effectiveness of therapeutic hypothermia, 
using the ZOLL Proteus IVTM System, as an adjunctive therapy for patients presenting with acute 
anterior myocardial infarction (AMI) and undergoing percutaneous coronary intervention (PCI). 
An analysis summarizing outcomes for the Primary Effectiveness Endpoint and the Primary Safety 
Endpoint will be created after the last randomized subject has completed the 30 day follow-up 
interval. The results of the primary endpoints will be summarized in the final clinical study report. 
Two interim analyses are planned to be performed at approximately 50% and 75% of 
randomization, once subjects have completed 4-6 day cMR follow-up. At the interim stage, the 

 
 
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trial will be stopped to reject the null hypothesis of no difference or continue enrolling. Another 
report will be issued summarizing all endpoints after all subjects have completed 12 month follow-
up. 
 Data Analysis 
Analysis Data Sets 
The Intention-to-Treat (ITT) analysis set will be used for primary statistical analyses and 
summaries. The ITT population includes subjects who have signed an informed consent and have 
been randomized to the Test Arm or the Control Arm of the trial. ITT subjects will be evaluated 
according to the group to which they were randomized. 
The Per-Protocol (PP) analysis set will also be evaluated. The PP population includes those 
subjects who met inclusion and exclusion criteria, were randomized to either the Test or Control 
arm, received the treatment to which they were randomized, and complied substantially with the 
treatment timeline and steps of this protocol without major protocol violations. 
The Safety Analysis Set will be used to evaluate safety endpoints. These will be all of the subjects 
included in the study as defined by the ITT analysis set and will include Roll-In subjects. For the 
safety analysis, subjects will be followed for all adverse events for 12 months post procedure. 
Additionally, all subjects will be followed for 12 months for the incidence of Adverse Events 
(AEs), Serious Adverse Events (SAEs), Death and Heart Failure (as assessed by NYHA and 
Kansas City Cardiomyopathy Questionnaire (KCCQ)). 
Infarction Size (IS) is defined as % Left Ventricular Mass as measured by Cardiac Magnetic 
Resonance (cMR) imaging. Infarct Size (IS) will be assessed by Cardiac Magnetic Resonance 
(cMR) at 4 – 6 days following the index procedure. Infarct Size will be assessed in subjects in the 
ITT analysis set and also in the Per-Protocol analysis set. 
The Safety Analysis Set will be used to evaluate safety endpoints. These will be all of the subjects 
included in the study as defined by the ITT analysis set and will include the following clinical 
components evaluated at 30 day follow-up visit (30 day ± 7 days): 
Secondary Endpoint Analysis: 
The following clinical components of MACE will be evaluated at 30 day follow-up visit (30 day 
± 7 days): 
o Death (Cardiac, Vascular, Non-Cardiovascular) 
o Myocardial Infarction (MI) 

 
 
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 Attributable to target vessel (TV-MI) 
 Not attributable to target vessel (NTV-MI) 
o Target Lesion Revascularization (TLR) 
 Clinically-indicated TLR (CI-TLR) 
 Not clinically-indicated TLR (NCI-TLR) 
o Target Vessel Revascularization (TVR non TLR,) 
 Clinically-indicated TVR non TLR 
 Not clinically-indicated TVR non TLR 
o Non-Target Vessel Revascularization (NTVR,) 
 Clinically-indicated NTVR 
 Not clinically-indicated NTVR 
o All coronary revascularization 
In addition, Stent Thrombosis will be evaluated at 30 day follow-up visit (30 day ± 7 days): 
 Evidence (Definite and Probable) 
o  
 Timing (Acute, Sub-acute) 
Additional Observational and Descriptive Analysis:  
In addition to the secondary endpoint, safety of the trial is also analyzed by the following 
observational and descriptive analysis.  These events are not endpoints for the study: 
o the following serious adverse events will be evaluated at 30 day follow-up visit (30 day 
± 7 days): 
 Stroke 
 Cardiogenic shock 
 Pulmonary embolism 
 Pulmonary edema 
 Atrial fibrillation 
 Ventricular fibrillation 
 Vascular complications requiring intervention 
 Bleeding requiring transfusion of 2 units or greater 
 Cooling catheter access site infection 
 Systemic infection 
 Deep Venous Thrombosis (DVT) 
 Bradycardia 
 Hypotension 
o The following serious adverse events will be evaluated at 12 month follow-up visit (12 
month ± 14 days): 

 
 
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 Death (Cardiac, Vascular, Non-Cardiovascular) 
 Stent Thrombosis 
• Timing (Acute, Sub-acute) 
• Evidence (Definite and Probable) 
 Hospitalizations due to Heart Failure 
 Statistical Methods 
Baseline demographic and clinical characteristics will be summarized for each arm using 
descriptive statistics. Continuous variables will be reported with mean, standard deviation, median, 
and range. Discrete variables will be reported as frequency and proportion. A χ2 test or Fisher 
exact test (for small frequencies) will be used to compare discrete variables; t-test or Wilcoxon test 
(for non-normal data) will be used to compare the 2 arms with continuous variables for randomized 
subjects in the trial. 
 
The primary effectiveness endpoint is to detect a 20% reduction of mean infarct size in the Test 
Arm compared to Control Arm where infarct size (%LV Mass) is measured by cMR at 4-6 days. 
The mean, median, standard deviation, and range will be presented for infarct size. A two sample 
t-test will be used to test the null-hypothesis of no difference in average infarct size test and control 
arm P-value will be reported with p<0.05 considered statistically significant. Infarct size will 
further be evaluated in subgroups and with ANOVA models. 
 
For the primary safety endpoint of MACE (as defined by CD, All MI, and CI-TLR) at 30 days, all 
events will be tabulated and reported. Per-patient rate of composite MACE will be compared 
between the two arms with 1-sided Fisher’s exact test. 
Two interim analyses are planned to be performed at approximately 50% and 75% of 
randomization, once subjects have completed 4-6 day cMR follow-up. At the interim stage, the 
trial will be stopped to reject the null hypothesis of no difference or will continue enrolling. Based 
on the Lan-DeMets method for group sequential trials using O’Brien-Fleming boundaries, the 
levels of significance for the interim analyses are alpha=0.00305 (50% information fraction), 
alpha=0.01832 (75% information fraction), and alpha=0.044 (final analysis).  
All analyses for effectiveness will be conducted in intent-to-treat and per-protocol analyses set. 
All analyses for safety will be conducted in the safety dataset. Imputation will be made for missing 
infarct size (LV%) in intent-to-treat analyses set per Intention-to-Treat principle; details are 
described in the Statistical Analysis Plan.  

 
 
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 Sample Size Justification 
The primary effectiveness analyses is designed to detect a relative reduction of 20% in mean 
anterior myocardial infarct size (IS), as determined by Cardiac Magnetic Resonance (cMR) 
imaging at 4-6 days post infarct in the Test Arm (cooling + PCI) compared to the Control Arm 
(PCI only). The absolute magnitude of a relative reduction of 20% depends on the mean IS in the 
control arm, which is assumed to be approximately 17 %LV.  Therefore, the treatment effect of 
interest is an absolute difference of 3.5 %LV.  
 
The hypothesis for the primary effectiveness endpoint is the following for patients randomized 1:1 
in Treatment Arm vs Control Arm: 
H0:  µT = µC   
HA: µT ≠ µC  
       
 
Null hypothesis:  
 
The null hypothesis is that the mean infarct sizein the Test Arm is equal to the mean IS in the 
Control Arm.   
 
Alternative hypothesis:  
 
The mean infarct size in the control arm is not equal to mean infarct size of control arm. 
This 20% relative reduction is defined as absolute value 3.5 %LV and accounted for in our sample 
size calculation as minimally detectable effect. This assumption is based on previous studies with 
anterior infarct size measured with cMR reporting between 17-20% absolute %LV in anterior 
infarct (Tables 17 & 18). Therefore, a relative reduction of 20% can vary depending on the mean 
infarct size of the control arm. Assuming a representative mean infarct size of ~17% in controls, 
we assume absolute difference of 3.5 %LV is equivalent to 20% mean anterior infarct size would 
be an adequate detection limit for effect. 
Based on these assumptions--standard deviation of 12.0 %LV, two-tailed t-test of difference 
between means, a normal distribution, 80% power (beta=0.2), with the final analysis will be 
conducted using a two-sided test at the alpha=0.044 level of significance (adjusted for the two 
interim analyses)-- the required total sample to detect a mean difference of 3.5 %LV with 80% 
power is 384 subjects (192 subjects per group).  Assuming 24% loss to follow-up, the trial plans 
for an enrolment up to 500 randomized subjects (250 in each arm) for 4-6 days cMR imaging 
follow-up. 
 
 

 
 
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Table 17: Clinical trials reporting anterior mean infarct size measured by cMR 4-6 days in 
PCI trials (Control Group Only) and calculated 20% relative reduction  
Study name 
Anterior n 
Mean 
infarct size 
Standard 
Deviation 
20% relative 
reduction 
APEX-AMI41 
60 
16.6 
10.7 
3.3 
LIPSIAABCIXIMAB42 
63 
25.3 
16.1 
5.1 
LIPSIA-STEMI43 
38 
18 
16.0 
3.6 
CRISP-AMI 44* 
142 
37.5 
20.1 
7.5 
INFUSE-AMI45 
172 
17.3 
10.2 
3.5 
RAPID-MI ICE1 
7 
19.7 
8.5 
3.9 
CHILL-MI37 
21 
26.5 
10.9 
5.3 
AMI EU PILOT  
21 
23.3 
12.0 
4 
*>60% are large proximal infarcts 
 
A range of standard deviation in the table expected is represented by anterior infarct data measured 
with cMR from separate and pooled analyses of previous hypothermia trials with AMI patients 
cooled below 35°C: RAPID-MI ICE (2009), CHILL-MI (2013), AMI EU Pilot (ongoing) as 
described below in Table 18. 
Table 18: Hypothermia trials using cMR measured infarct size as primary outcome 
RAPID-MI 
ICE (2009) 
CHILL-MI 
(2013) 
AMI EU 
Pilot (2017) 
Pooled  
AMI EU Pilot, RAPID-
MI-ICE, CHILL-MI 
n (Control vs 
Cooled) 
7 vs 5 
21 vs 15 
21 vs 19 
49 vs 39 
Control Mean 
LV% 
19.7 
26.5 
23.3 
24.5 

 
 
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RAPID-MI 
ICE (2009) 
CHILL-MI 
(2013) 
AMI EU 
Pilot (2017) 
Pooled  
AMI EU Pilot, RAPID-
MI-ICE, CHILL-MI 
20% reduction 
in infarct 
3.94 
5.3 
4.7 
4.9 
Std Dev 
(control) 
8.5 
10.9 
12.0 
10.5 
Std Dev (cooled) 
6.5 
9.3 
10.3 
11.0 
 
The potential impact of variations in control infarct size and variability is presented in Table 19.  

 
 
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Table 19: Sample size estimates with alternative standard deviation and detection limit 
Mean Difference 
in infarct size for 
detection (%) 
 Standard Deviation Estimated Sample Size 
Total Enrolment 
(with24% drop-out) 
3.0 
 
9 
288 
380 
3.0 
 
10 
355 
468 
3.0 
 
11 
430 
566 
3.0 
 
12 
506 
666 
3.5 
 
9 
212 
280 
3.5 
 
10 
260 
342 
3.5 
 
11 
314 
414 
3.5 
 
12 
374 
500 
4.0 
 
9 
162 
214 
4.0 
 
10 
200 
264 
4.0 
 
11 
240 
316 
4.0 
 
12 
286 
376 
The primary safety endpoint is a composite endpoint. For the sample size calculation, expected 
incidence is based on a literature review of acute MI hypothermia trials that combined six 
studies: Dixon et al, COOL MI, ICE-IT, RAPID MI-ICE, CHILL-MI, VELOCITY46 which 
resulted in a 30-day MACE rate of 6.6% in the Control patients and 7.5% in treatment patients. 
Previously, AMIHOT II trial defined 30-day MACE rate comprised of death, reinfarction, target 
vessel revascularization, and stroke used a non-inferiority hypothesis with a 6% equivalence 
delta and 7% in the Control patients47. 
The hypothesis for the primary safety endpoint is the following:  
H0: πT ≥ πC + 6%  

 
 
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HA: πT < πC + 6%  
πT and πC are the underlying proportion of patients having a MACE event.  
An enrollment of 500 patients would be able to demonstrate 91% power and 95% 1-sided 
significance. The safety endpoint will be considered to have been met if there is a high posterior 
probability of non-inferiority [i.e. P (πt < πc + 6% >95%)]. With a drop-out rate of 20%, the 
power is calculated to be 86%. 
 PUBLICATION 
At the conclusion of the trial, a multi-center manuscript will be prepared for publication. 
Publications will be managed by the Sponsor, its designee and the Advisory board. Additional 
publications from any single site will be considered but only after the multi-center publication. 
 INTELLECTUAL PROPERTY 
In all documents the company name of ZOLL Circulation® will be referred to in short hand as 
ZOLL.  ZOLL® is a registered trademark of ZOLL Medical Corporation.  The Proteus IVTM 
System is a trademark of ZOLL Circulation, Inc.  Proteus Catheters, Cassettes and Temperature 
Probes (X-Probe) are registered trademarks of ZOLL Circulation, Inc. 
 STATEMENT OF COMPLIANCE 
1. Sponsor and Investigator will conduct the clinical investigation in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki. 
2. Sponsor and Investigator will comply with ISO 14155:2011 and any regional or national 
regulations, as appropriate. 
3. Investigator will not begin the clinical investigation until Investigator obtains the required 
written approval or favorable opinion from the MEC or regulatory authority, if 
appropriate.  
4. Investigator will follow any additional requirements imposed by the MEC or regulatory 
authority, if appropriate. 

 
 
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radiologist and its effect on treatment. Radiology. 2012 Mar; 262(3):751-64. doi: 
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37. Erlinge, David MD PhD et al. “Rapid Endovascular Catheter Core Cooling Combined With 
Cold Saline as an Adjunct to Percutaneous Coronary Intervention for the Treatment of Acute 
Myocardial Infarction”, J Am Coll Cardiol 2014;63:1857–65 
38. Nichol, Graham, MD, MPH, et al.. Prospective, Multicenter, Randomized, Controlled Pilot 
Trial of Peritoneal Hypothermia in Patients With ST-Segment– Elevation Myocardial 
Infarction. Circ Cardiovasc Interv. 2015;8:e001965. DOI: 
10.1161/CIRCINTERVENTIONS.114.001965. 
39. Dixon, Simon R, MBCHB, FRACP, et al. Induction of Mild Systemic Hypothermia With 
Endovascular Cooling During Primary Percutaneous Coronary Intervention for Acute 
Myocardial Infarction J Am Coll Cardiol 2002;40:1928 –34) © 2002 by the American 
College of Cardiology Foundation. 
40. Issam D. Moussa, et al., 2013. Consideration of a New Definition of Clinically Relevant 
Myocardial Infarction After Coronary Revascularization, An Expert Consensus Document 

 
 
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From the Society for Cardiovascular Angiography and Interventions (SCAI), J Am Coll 
Cardiol. 2013 Oct 22; 62(17): 1563–1570. doi:  10.1016/j.jacc.2013.08.720. 
41. Patel MR, Worthley SG, Stebbins A, et al. Pexelizumab and infarct size in patients with 
acute myocardial infarction undergoing primary percutaneous coronary intervention: a 
delayed enhancement cardiac magnetic resonance substudy from the APEX-AMI trial. J Am 
Coll Cardiol Img 2010;3:52–60. 
42. Thiele H, Schindler K, Friedenberger J, et al. Intracoronary compared with intravenous bolus 
abciximab application in patients with STelevation myocardial infarction undergoing primary 
percutaneous coronary intervention: the randomized Leipzig immediate percutaneous 
coronary intervention abciximab IV versus IC in ST-elevation myocardial infarction trial. 
Circulation 2008;118:49–57. 
43. Thiele H, Eitel I, Meinberg C, et al. Randomized comparison of pre-hospital-initiated 
facilitated percutaneous coronary intervention versus primary percutaneous coronary 
intervention in acute myocardial infarction very early after symptom onset: the LIPSIA-
STEMI trial (Leipzig immediate prehospital facilitated angioplasty in ST-segment 
myocardial infarction). J Am Coll Cardiol Intv 2011;4:605–14. 
44. Patel MR, Smalling RW, Thiele H, et al. Intraaortic balloon counterpulsation and infarct size 
in patients with acute anterior myocardial infarction without shock: the CRISP AMI 
randomized trial. JAMA 2011;306:1329–37. 
45. Stone GW, Maehara A, Witzenbichler B, et al. Intracoronary abciximab and aspiration 
thrombectomy in patients with large anterior myocardial infarction: the INFUSE-AMI 
randomized trial. JAMA 2012;307:1817–26. 
46. Villablanca PA, Rao G, Briceno DF, et al. Therapeutic hypothermia in ST elevation 
myocardial infarction: a systematic review and meta-analysis of randomised control trials. 
Heart 2016;102:712-9. 10.1136/heartjnl-2015-308559 
47. Stone GW, Martin Jack L., de Boer Menko-Jan, et al. Effect of supersaturated oxygen 
delivery on infarct size after percutaneous coronary intervention in acute myocardial 
infarction. Circulation: Cardiovascular Interventions. 2009;2:366-375, originally published 
October 20, 2009 
48. Karen A.Hicks et all. 2014 ACC/AHA Key Data Elements and Definitions for 
Cardiovascular Endpoint Events in Clinical Trials. JACC, Vol  66, NO 4, 2015. 
49. Noc M1, Erlinge D, Neskovic AN,et al.(COOL AMI EU pilot trial: a multicentre, 
prospective, randomised controlled trial to assess cooling as an adjunctive therapy to 
percutaneous intervention in patients with acute myocardial infarction) 2017 May 17. Epub 
ahead of print  
50. 2017 ESC Guidelines for the management of acute myocardial infarction in patients 
presenting with ST-segment elevation. European Heart Journal (2017) 00, 1–66.  

 
 
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ATTACHMENT II – ANTI-SHIVERING PROTOCOL  
Shivering Suppression Guidelines 
Turn on IVTM System console to initiate system and begin cooling of coldwell 
↓ 
Obtain Informed Consent 
↓ 
Administer Buspirone 60 mg PO/NG x 1 immediately 
↓ 
Place Bair Hugger on upper body; set to “high”; forced-air cover should be adjacent to skin.   
Put one blanket on top. 
↓ 
Closer to the time of device deployment, Pethidine 1 mg/kg IV (up to 100 mg)  
 
***Morphine and/or other sedatives are often administered in the setting of an acute MI 
Morphine and Pethidine (Demerol) are both opiate narcotics and if possible, morphine should 
be held as the combination may cause over-sedation.  Consider 0.5 mg/kg Pethidine 
IV, if Morphine has been administered. 
↓ 
At 15 minutes, Pethidine 0.5mg/kg IV should be administered. 
 
Then a 25 mg/hr IV infusion of Pethidine (up to 80 kg patient) or 35mg/hr (> 80 kg 
patient) should be initiated and maintained for the duration of device deployment. 
***Make sure the patient has a respiratory rate ≥ 10 breaths/minute. 
 
What to do if shivering occurs: 
First, try repositioning the Bair Hugger or changing its settings to increase the heat delivered to 
the patient’s surface. 
 
Second, consider increasing dose of Pethidine.  Prior to giving additional Pethidine, look for 
signs of respiratory depression (i.e. decreased Respiratory Rate, decreased O2 Saturation by 
Pulse Ox.)  If it is decided that the patient can tolerate additional Pethidine the following may be 
tried: 
1. An IV dose of 25 mg x 1 may be given 
2. If Infusion rate is 25mg/hr, the rate may be increased to a maximum of 35 mg/hr 

 
 
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If the shivering persists following the above measures, consider raising the target temperature 
on the Proteus Console by 0.5°C (i.e. from 32.0°C to 32.5°C).  If this does not work after 5-10 
minutes at the new target temperature, then the process can be repeated until a temperature where 
no shivering is obtained. 
 

 
 
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ATTACHMENT III – BEDSIDE SHIVERING ASSESSMENT SCALE (BSAS) 
SCORE 
SEVERITY 
DEFINITION 
0 
None 
No shivering noted on palpation of the masseter, neck or chest 
wall 
1 
Mild 
Shivering localized to the neck and/or thorax only 
2 
Moderate 
Shivering involves gross movement of the upper extremities in 
addition to neck and thorax 
3 
Severe 
Shivering involves gross movements of the trunk, upper and lower 
extremities 
SCORE 
SEVERITY 
DEFINITION 
0 
None 
No shivering noted on palpation of the masseter, neck or chest 
wall 
1 
Mild 
Shivering localized to the neck and/or thorax only 
2 
Moderate 
Shivering involves gross movement of the upper extremities in 
addition to neck and thorax 
3 
Severe 
Shivering involves gross movements of the trunk, upper and lower 
extremities 

 
 
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ATTACHMENT IV – SPECIFIC NEW-ONSET ADVERSE EVENT DEFINITIONS 
SPECIFIC NEW-
ONSET ADVERSE 
EVENT  
DEFINITION 
1. All-Cause  
Mortality 
Deaths will be classified as cardiac, vascular or 
noncardiovascular as defined by the Academic Research 
Consortium.27 
 
All deaths are considered cardiac unless an unequivocal non-
cardiac cause can be established. Specifically, any 
unexpected death even in patients with coexisting potentially 
fatal non-cardiac disease (e.g. cancer, infection) should be 
classified as cardiac.  
 
Cardiac death (CD):  
Any death due to proximate cardiac cause (e.g. MI, low-
output failure, fatal arrhythmia), unwitnessed death and 
death of unknown cause, all procedure related deaths 
including those related to concomitant treatment.  
 
Vascular death:  
Death due to non-coronary vascular causes such as 
cerebrovascular disease, pulmonary embolism, ruptured 
aortic aneurysm, dissecting aneurysm, or other vascular 
cause.  
 
Non-cardiovascular death:  
Any death not covered by the above definitions such as 
death caused by infection, malignancy, sepsis, pulmonary 
causes, accident, suicide or trauma. 
2. Recurrent MI 27,31 
Recurrent MI or re-infarction may be diagnosed when 
cardiac biomarker levels are stable on 2 samples that are >6 
hours apart or are in decline if a subsequent value 3 to 6 
hours after the procedure is increased by > 20% from the 
baseline sample. If the baseline value is not stable, then 
insufficient data exist to recommend biomarker criteria for 
diagnosis, and the Academic Research Consortium27,31 
recommends that the event be considered as pre-procedure 
MI.  Periprocedural MI is that which occurs within the first 
48 hrs after PCI or within the first 72 hrs after coronary 
artery bypass grafting (CABG). 
 

 
 
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Q wave MI:  
Development of new, pathological Q wave on the baseline 
ECG (≥ 0.04 seconds in duration and ≥ 1 mm in depth) in ≥ 
2 contiguous precordial leads or ≥ 2 adjacent limb leads)  
 
Non-Q wave MI:  
Those MIs which are not Q-wave MI. 
3. Need for 
revascularization of 
the target vessel 
(TVR)27 
TVR is defined as any repeat percutaneous intervention or 
surgical bypass of any segment of the target vessel. The 
target vessel is defined as the entire major coronary vessel 
proximal and distal to the target lesion, which includes 
upstream and downstream branches and the target lesion 
itself.  
4. Stroke 
Development of a new neurological deficit that persists > 24 
hours, or worsening of previous neurological symptoms that 
persist > 24 hours. 
5. Cardiogenic shock 
Systolic blood pressure of less than 90 mmHg for at least 30 
minutes which is secondary to myocardial dysfunction, 
leading to decreased cardiac output and evidence of tissue 
hypoxia in the presence of adequate intravascular volume.  
6. Pulmonary 
embolism 
Sudden onset of pleuritic chest pain, cough, hemoptysis, 
hypoxia, tachycardia, and a positive ventilation/perfusion 
scan or a CT scan. 
7. Ventricular 
Fibrillation (V-  
Fib) 
Rapid uncoordinated fluttering contractions of the heart 
ventricles recognized by the occurrence on the 
electrocardiogram of coarse and irregular oscillations 
without discernible QRS complexes or T waves 
8. Vascular 
complications 
requiring intervention 
Complications arising from the use of the Proteus Catheter 
including the development of a vessel tear, hematoma, 
pseudoaneurysm, arteriovenous (AV) fistula, or 
retroperitoneal bleeding which require an additional surgical 
intervention for treatment. 
9. Bleeding requiring 
transfusion of 2 units 
or greater 
Any periprocedural bleeding which occurs as a result of the 
PCI and/ or cooling procedure which requires transfusing > 
2 units. 
10. Systemic Infection  Sepsis with confirmed positive blood cultures. 
11. Cooling Catheter 
Access Site Wound 
infection 
Infection and inflammation of the incision or puncture site 
requiring drainage and/or debridement in addition to 
antibiotic therapy, e.g., cellulitis. 
12. Pulmonary Edema Abnormal accumulation of fluid in the lungs 

 
 
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13. Deep Venous 
Thrombosis 
(DVT)32 
Formation of one or more blood clots in one of the body’s 
large veins, most commonly in the lower limbs. The clot(s) 
can cause partial or complete blocking of circulation in the 
vein, which in some patients leads to pain, swelling, 
tenderness, discoloration, or redness of the affected area, and 
skin that is warm to the touch.  As many patients enrolled in 
the trial will have pre-existing DVT, for the purposes of this 
trial DVT is defined as the de novo onset of DVT following 
enrollment which required treatment or worsening of pre-
existing DVT. 

 
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ATTACHMENT V – ADVERSE EVENT DEFINITIONS 
Adverse Event Definitions 
In addition to the definitions provided in Attachment IV– Specific New Onset Serious 
Adverse Event Definitions, the following definitions apply to expected adverse events 
that may occur and must be reported throughout this clinical trial.  Events reported should 
represent a new onset or increase in the severity of the condition from the time of 
enrollment. 
A. CARDIAC  
COMPLICATIONS 
DEFINITION 
Recurrent 
Myocardial 
ischemia 31  
Recurrent Myocardial Ischemia : is evidenced through baseline 
ECG changes identified during continuous multilead baseline 
ECG–ischemia monitoring (or Holter monitoring) which may 
be accompanied by the development of new clinical symptoms 
suggesting an ischemic cardiac episode.  
Arrhythmias 
The development of a new atrial and/or ventricular arrhythmia, 
significant increase in the severity of a preexisting arrhythmia, 
or any episode of cardiac arrest. 
Congestive Heart 
Failure34 
Defined as patients with defined or presumed cardiac disease 
and one of the following: Class I: without limitations of 
physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, or dyspnea. Class II: slight 
limitation of physical activity. They are comfortable at rest. 
Ordinary physical activity results in fatigue, palpitation, or 
dyspnea. Class III: marked limitation of physical activity. They 
are comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, or dyspnea. Class IV: inability to carry on 
any physical activity without discomfort. Symptoms are 
present even at rest or minimal exertion. 
 
B. PULMONARY 
COMPLICATIONS 
DEFINITION 
Pneumonia 
Clinical evidence as determined by physical, radiographic, and 
laboratory findings requiring treatment with antibiotics, 
inhalation therapy, intubation, or suctioning. 
Atelectasis 
Clinical evidence as determined by physical, radiographic, and 
laboratory findings requiring treatment with antibiotics, 
inhalation therapy, intubation, or suctioning. 

 
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Respiratory Failure 
Need for mechanical ventilation for > 24 hours 
postoperatively, or reintubation for any reason. 

 
 
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C. RENAL 
COMPLICATIONS 
DEFINITION 
Acute Kidney 
injury (AKI)35 
AKI is defined as any of the following:  
Increase in SCr by ≥.3 mg/dl (≥26.5 µmol/l) within 48 hours; 
or Increase in SCr to ≥ 1.5 times baseline, which is known or 
presumed to have occurred within the prior 7 days; or Urine 
volume < 0.5 ml/kg/h for 6 hours.  
 
D. VASCULAR 
COMPLICATIONS 
DEFINITION 
Arteriovenous 
Fistula 
Formation of an abnormal connection between the lumens of 
an artery and a vein as documented by CT, ultrasound, 
angiography, or direct observation. 
Embolism 
The obstruction of a blood vessel by a blood clot or foreign 
substance, e.g., air, fat, bacteria. 
Vessel perforation 
Defined as perforation of the access vessel wall or vena cava 
confirmed by extravasation of contrast under fluoroscopy, 
angiography, CT scan, and/ or direct observation at surgery or 
autopsy.  
Hematoma 
An abnormal localized collection of blood (clotted or partially 
clotted) and situated within an organ or a soft tissue space, 
such as within a muscle.  Development of an incisional or 
retroperitoneal hematoma requiring surgical intervention, 
evacuation, transfusion or prolonged hospitalization. 
Hemorrhage 
Post-procedural bleeding requiring transfusion of ≥ 2 units. 
Hypotension 
Abnormally low systolic blood pressure that is < 80 mm Hg 

 
 
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D. VASCULAR 
COMPLICATIONS 
DEFINITION 
Peripheral vascular 
insufficiency (PVI) 
Inadequate peripheral blood flow resulting from the occlusion 
of vessels by atherosclerotic plaques, thrombi, or emboli; 
damaged, diseased, or intrinsically weak vascular walls; 
arteriovenous fistulas; hematologic hypercoagulability; and 
heavy smoking. Signs of vascular insufficiency include pale, 
cyanotic, or mottled skin over the affected area; swelling of an 
extremity; absent or reduced tactile sensation; tingling; 
diminished sense of temperature; muscle pain, such as 
intermittent claudication in the calf; and, in advanced disease, 
ulcers and atrophy of muscles in the involved extremity.  
As many patients enrolled in the trial will have pre-existing 
Peripheral Vascular Insufficiency (PVI), for the purposes of 
this trial PVI is defined as the de novo onset of PVI following 
enrollment which requires treatment or worsening of pre-
existing PVI. 
Pseudoaneurysm 
Enlargement of the aorta, iliac, or femoral arteries, which 
contain some or all of the medial layer, the adventitia, and 
periaortic tissue most commonly associated with previous 
aortic operative procedures, trauma, and/or infection.  
Pseudoaneurysms typically present as a well-defined collection 
of blood outside the vessel wall from contained rupture.  
Stenosis 
A reduction in the diameter of the vessel lumen when 
compared to the reference diameter, as documented by 
angiography, which requires intervention and is related to the 
procedure, e.g., access vessel.  
Thrombosis  
Clotting within a blood vessel which may cause infarction of 
tissues supplied by the vessel; it may be occlusive or attached 
to the vessel or heart wall without obstructing the lumen. 
Transient Ischemic 
Attack (TIA) 
A brief episode of neurological dysfunction caused by focal 
brain or retinal ischemia with clinical symptoms typically 
lasting 1 - 24 hours and without evidence of acute infarction. 
 
E. WOUND 
COMPLICATIONS 
DEFINITION 
Hematoma 
An abnormal localized collection of blood (clotted or 
partially clotted) and situated within an organ or a soft tissue 

 
 
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space, such as within a muscle.  Development of an 
incisional or retroperitoneal hematoma requiring surgical 
intervention, evacuation, transfusion or prolonged 
hospitalization. 
Arteriovenous Fistula 
Formation of an abnormal connection between the lumens 
of an artery and a vein as documented by CT, ultrasound, 
angiography, or direct observation. 
Nerve 
Injury/Peripheral 
Neuropathy 
Direct damage to nerves surrounding the access site, 
operative field, or catheter deployment site, and the resultant 
signs and/or symptoms of such damage which may include 
pain and numbness in the affected area associated with 
muscle weakness and decreased patellar reflex lasting > 1 
month after treatment. 
 
F. SYSTEMIC 
COMPLICATIONS 
DEFINITION 
Coagulopathy 
The development of an abnormal bleeding disorder, e.g., 
disseminated intravascular coagulopathy or thrombocytopenia, 
documented by appropriate laboratory studies and requiring 
therapy with medication or transfusion. 
Anesthetic 
Complications 
Reaction or complication caused by administration of an 
anesthetic. 
Liver failure33 
Acute liver failure is defined as the rapid development of 
hepatocellular dysfunction, specifically coagulopathy and 
mental status changes (encephalopathy) in a patient without 
known prior liver disease.  
 
 
 
 
 
 

 
 
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F. SYSTEMIC 
COMPLICATIONS 
DEFINITION 
Pancreatitis36 
Evidenced on two of the following three conditions: 1) 
abdominal pain suggestive strongly of acute pancreatitis 
(epigastric pain often radiating to the back), 2) serum amylase 
and/or lipase activity at least 3 times greater than the upper 
limit of normal, (imaging is to be used if the elevated values 
are <3 times normal); and 3) characteristic findings of acute 
pancreatitis on transabdominal ultrasound or on Contrast 
Enhanced Computed Tomography (CECT) 32 
 
 
 
 
 
 
 

 
 
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ATTACHMENT VI – INVESTIGATOR LIST 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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ATTACHMENT VII – LIST OF ABBREVIATIONS 
AAR 
Area at Risk 
ACC 
American College of Cardiology 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AHA 
American Heart Assocation 
AKI 
Acute Kidney Injury 
AMI 
Acute Myocardial Infarction 
ASADE 
Anticipated Serious Adverse Device Effect 
AV 
Arteriovenous 
BSAS 
Bedside Shivering Assessment Scale 
CABG 
 Coronary Artery Bypass Grafting  
CD 
Cardiac Death 
CEC 
Clinical Events Committee 
CHF 
Congestive Heart Failure 
CIP 
Clinical Investigation Plan 
CI-TLR 
Clinically-Indicated Target Lesion Revascularization 
CMP 
Clinical Monitoring Plan 
cMR 
Cardiac Magnetic Resonance 
CNS 
Central Nervous System 
CRO 
Clinincal Research Organization 
CRF 
Case Report Form 

 
 
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CRMI 
Clinically Relevant Myocardial Infarction 
CVA 
Cerebral Vascular Accident 
CVP 
Central Venous Pressure 
DAPT 
Dual Antiplatelet Therapy 
DD 
Device Deficiency 
DES 
Drug Eluting Stent 
DMC 
Data Monitoring Committee 
DP 
Dorsalis Pedis        
DSMB 
Data Safety Monitoring Board 
DTB 
Door-to-Balloon 
DVT 
Deep Vein Thrombosis 
EC 
Ethics Committee 
ECG 
Electrocardiography 
EDC 
Electronic Data Capture 
ED 
Emergency Department 
ER 
Emergency Room 
ESC 
European Society of Cardiology 
EU 
European Union 
Fr 
French 
FMECA 
Failure Mode, Effects and Criticality Analysis 
FEP 
Fluorinated Ethylene Propylene 
GLP 
Good Laboratory Practice 

 
 
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HDPE 
High-density Polyethylene 
HIPPA 
Heath Insurance Portability and Accountability Act 
HTN 
Hypertension 
ICF 
Informed Consent Form 
IEC 
International Electrotechnical Commission 
IFU 
Instructions for Use 
IQR 
Interquartile Range 
IRB 
Institutional Review Board 
IRI 
Ischemia Reperfusion Injury 
IS 
Infarct Size 
ISO 
International Organization for Standardization 
ITT 
Intention-to-Treat 
IVC 
Inferior Vena Cava 
IVTM 
Intravascular Temperature Management 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LAL 
Limulus Amebocyte Lysate 
LED 
Light-emitting Diode 
LV 
Left Ventricular 
LVEF 
Left Ventricular Ejection Fraction 
MACE 
Major Adverse Cardiac Events 
MAO 
Monoamine Oxidase 
 

 
 
 
 
APPENDIX C 
 
COOL-AMI EU Pivotal Trial Clinical Investigational Plan 
 
Specific DAPT Protocol (For sites that require specific Dual 
Anti-Platelet Therapy details) (Rev. 6) 
                      
 
                   (124 pages) 
 
 
 
 
 
 
 
 
 
 
 

Page 1 of 124 
COOL-AMI EU Pivotal Trial EDC-3135 Rev 6  
CONFIDENTIAL & PROPRIETARY  
Clinical Investigation Plan 
 
COOL-AMI EU PIVOTAL TRIAL: A MULTICENTER, PROSPECTIVE, 
RANDOMIZED-CONTROLLED TRIAL TO ASSESS THE SAFETY AND 
EFFECTIVENESS OF COOLING AS AN ADJUNCTIVE THERAPY TO 
PERCUTANEOUS INTERVENTION IN PATIENTS WITH ACUTE 
MYOCARDIAL INFARCTION 
 
PROTOCOL NO.: EDC-3135 
 
Revision: 6 
 
EFFECTIVE DATE: JUNE 19, 2018 
 
 
 
 
 
CONFIDENTIAL & PROPRIETARY 
 
The information in this Protocol is confidential and proprietary and is to be used only in 
connection with matters authorized by ZOLL and no part is to be disclosed to others 
without prior written permission from ZOLL 
 
 
 
 

CLINICAL INVESTIGATION PLAN APPROVAL PAGE 
CLINICAL INVESTIGATION PLAN: 
COOL-AMI EU Pivotal Trial: A 
multicenter, prospective, randomized 
controlled Trial to assess the safety and 
effectiveness of cooling as an adjunctive 
therapy to percutaneous intervention in 
patients with acute myocardial infarction 
PROTOCOL No.: 
SPONSOR: 
EDC-3135 
ZOLL Circulation, Inc. 
2000 Ringwood A venue 
San Jose, CA 95131 
SPONSOR 
REPRESENTATIVE: 
ZOLL Medical Deutschland GmbH 
Emil-Hoffmann - StraBe 13 
CLINICAL TRIAL SPONSOR'S 
CONTACT: 
REVISION NUMBER: 
50996 KOln, Germany 
Philippa Hill 
6 
f Clinical Investigation Plan by Sponsor: 
Philippa Hill 
"' 
Date 
Senior Director, Clinical Affairs 
COOL-AMI EU Pivotal Trial EDC-3135 Rev 6 
CONFIDENTIAL & PROPRIETARY 
Page 2of124 

Page 3 of 124 
COOL-AMI EU Pivotal Trial EDC-3135 Rev 6  
CONFIDENTIAL & PROPRIETARY  
Signature Page 
 
Clinical Investigation Plan  
 
COOL-AMI EU PIVOTAL TRIAL: A MULTICENTER, PROSPECTIVE, RANDOMIZED-
CONTROLLED TRIAL TO ASSESS THE SAFETY AND EFFECTIVENESS OF COOLING AS 
AN ADJUNCTIVE THERAPY TO PERCUTANEOUS INTERVENTION IN PATIENTS WITH 
ACUTE MYOCARDIAL INFARCTION 
PROTOCOL NO.: EDC-3135 
Revision: 6 
Effective Date: JUNE 19, 2018 
 
Signatures of Investigator below constitute their approval of this clinical investigation 
plan (CIP) and provide necessary assurances that they have read the CIP, understand it, 
and will work according to all stipulations of it, and to the ethical principles stated in the 
latest version of the Declaration of Helsinki and the ISO 14155:2011 (Clinical 
Investigation of Medical Devices for Human Subjects – Good Clinical Practice). 
 
 
 
 
Investigator Name (Please Print) 
 
 
 
 
 
 
Investigator Signature 
 
Date 
 
 
 
 
 
 
Institution Name 
 
 
 
 
 
Institution Address 
 
 
 
 
 
ZOLL Circulation, Inc. 
 
 
Sponsor Name 
 
 
 
 
 
2000 Ringwood Avenue, San Jose CA 95131 
Sponsor Address 
 
 
 
 
 
ZOLL Medical Deutschland GmbH 
 
 
Sponsor Representative 
 
 
 

Page 4 of 124 
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CONFIDENTIAL & PROPRIETARY  
 
 
Table of Contents 
1 
SYNOPSIS .............................................................................................................. 9 
Inclusion Criteria ...................................................................................................... 10 
Exclusion Criteria ..................................................................................................... 11 
2 
INTRODUCTION ................................................................................................ 15 
3 
BACKGROUND .................................................................................................. 17 
4 
INTENDED USE, SYSTEM OVERVIEW, & DEVICE DESCRIPTION .......... 18 
 
Intended Use / Indication for Use ..................................................................... 18 
 
System Overview .............................................................................................. 18 
 
Device Description ............................................................................................ 19 
4.3.1 Proteus Catheter ................................................................................................ 19 
4.3.2 Proteus Temperature Probe ............................................................................... 19 
4.3.3 Proteus Cassette................................................................................................. 19 
4.3.4 Proteus Console ................................................................................................. 20 
4.3.5 Device Labeling ................................................................................................ 21 
5 
PRIOR INVESTIGATIONS ................................................................................. 21 
 
Pre-Clinical Studies ........................................................................................... 21 
 
Human Clinical Studies ..................................................................................... 22 
5.2.1 COOL MI Trial ................................................................................................. 22 
5.2.2 COOL MI II Trial .............................................................................................. 29 
5.2.3 COOL RCN Trial .............................................................................................. 32 
5.2.4 ICE- IT Trial...................................................................................................... 35 
5.2.5 RAPID-MI ICE Trial ........................................................................................ 36 
5.2.6 CHILL-MI Trial ................................................................................................ 36 
5.2.7 Induction of Mild Systemic Hypothermia With Endovascular Cooling During 
Primary Percutaneous Coronary Intervention for Acute Myocardial Infarction .......... 37 
5.2.8 VELOCITY Trial .............................................................................................. 37 
5.2.9 EU AMI Case Series ......................................................................................... 39 
5.2.10 COOL-AMI EU PILOT Trial ........................................................................... 40 
 
Summary and Clinical Trial Rationale .............................................................. 41 

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6 
CLINICAL TRIAL PLAN .................................................................................... 42 
 
Trial Objective................................................................................................... 42 
 
Trial Endpoints .................................................................................................. 42 
6.2.1 Primary Effectiveness Endpoint ........................................................................ 42 
6.2.2 Primary Safety Endpoint ................................................................................... 42 
6.2.3 Additional Assessments: Demographics and Other Parameters ....................... 42 
 
Trial Design ....................................................................................................... 43 
 
Patient Population ............................................................................................. 43 
 
Selection Criteria ............................................................................................... 43 
 
Inclusion Criteria ............................................................................................... 44 
 
Exclusion Criteria .............................................................................................. 44 
 
Clinical Trial Procedures ................................................................................... 45 
6.8.1 Patient Screening ............................................................................................... 45 
6.8.2 Informed Consent .............................................................................................. 46 
6.8.3 Roll-In Enrollment ............................................................................................ 47 
6.8.4 Approval to Randomize in the Trial .................................................................. 48 
6.8.5 Randomization .................................................................................................. 48 
6.8.6 Acute Care and Emergency Room Triage......................................................... 49 
6.8.7 Standardized Care Prior to the Cooling Procedure ........................................... 49 
6.8.8 Documentation Procedures ............................................................................... 50 
6.8.9 Study Flow and Procedures ............................................................................... 51 
6.8.10  Pre-Cooling Assessment Procedures ................................................................ 55 
6.8.11 Initiation, Maintenance, and Reversal of Cooling with Proteus IVTM System 
Procedures / Evaluations and Data Collection for Subjects Enrolled in the Test Arm 56 
6.8.12 Test Arm: Temperature Management Protocol and Data Collection Time 
Points 56 
6.8.13 Trial Schedule for Test Arm Subjects ............................................................... 63 
6.8.14 Trial Schedule for Control Arm Subjects .......................................................... 64 
6.8.15 Control Arm Protocol and Data Collection Time Points .................................. 65 
6.8.16 Follow-up at 4-6 days and at 30 days following the PCI Procedure ................. 65 
6.8.17 Follow-up at 12 months following PCI ............................................................. 66 

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6.8.18 Use of other Cooling Methods .......................................................................... 66 
6.8.19 Transferring Subject during Cooling................................................................. 66 
6.8.20 Patient Withdrawal and Discontinuation........................................................... 66 
6.8.21 Patient Lost to Follow-up .................................................................................. 67 
6.8.22 Early Termination of a Clinical Investigation ................................................... 67 
6.8.23 Amendments and Protocol Deviations .............................................................. 68 
6.8.24 Trial Exit ........................................................................................................... 69 
6.8.25 Subject Confidentiality ...................................................................................... 69 
6.8.26 Device Accountability ....................................................................................... 70 
6.8.27 Return of Materials upon Trial Termination ..................................................... 70 
6.8.28 Trial Closure ...................................................................................................... 70 
 
Cardiac Magnetic Resonance (cMR) imaging Core Laboratory ....................... 71 
7 
ADVERSE EVENTS & DEVICE DEFICIENCIES ............................................ 71 
 
Definitions ......................................................................................................... 71 
7.1.1 Adverse Event (AE) .......................................................................................... 71 
7.1.2 Serious Adverse Event (SAE) ........................................................................... 71 
7.1.3 Device Deficiency (DD).................................................................................... 72 
7.1.4 Adverse Device Effect (ADE)........................................................................... 72 
7.1.5 Serious Adverse Device Effect (SADE) ........................................................... 72 
7.1.6 Unanticipated Serious Adverse Device Effect (USADE) ................................. 72 
 
Adverse Event Reporting .................................................................................. 73 
7.2.1 Adverse Event Reporting from Site to Sponsor and MEC................................ 73 
7.2.2 Serious Adverse Event Reporting to Sponsor and MEC................................... 73 
7.2.3 UADE/USADE Reporting to Sponsor and MEC .............................................. 73 
7.2.4 Sponsor Reporting to National Competent Authorities (NCA) when European 
Sites Participate in the Trial ......................................................................................... 74 
 
Device Relationship .......................................................................................... 74 
8 
MONITORING BY DATA MONITORING COMMITTEE .............................. 76 
9 
ADJUDICATION OF EVENTS........................................................................... 76 
10 
RECOMMENDATION FOR DAPT AND STENTS........................................... 77 

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• 
Use second or third generation DES. Do not use BMS or BVS or BRS such as 
Absorb in study patients................................................................................................... 78 
11 
RISK ANALYSIS ................................................................................................. 78 
 
Risk Assessment Process .................................................................................. 78 
 
Expected Clinical Observations ........................................................................ 79 
Cold Diuresis: Increased resistance to ADH or Vasopressin resulting in decreased 
water or solute reabsorption. ........................................................................................ 80 
 
Potential Clinical Risks ..................................................................................... 80 
11.3.1 Potential Adverse Events associated with the Proteus Catheter and Cooling 
System: ......................................................................................................................... 80 
11.3.2 Potential Adverse Events associated with the cooling procedure include but are 
not limited to the following: ......................................................................................... 81 
11.3.3 Risks Associated with Anti-shivering Medications .......................................... 82 
 
Additional investigations due to the trial .......................................................... 83 
11.4.1 Delay in PCI through the use of hypothermia therapy ...................................... 83 
11.4.2 Implementation of PCI in patients undergoing hypothermia (patient-related 
risks)   83 
11.4.3 Implementation of PCI with concurrent use of endovascular hypothermia. ..... 83 
11.4.4 The concurrent medication. ............................................................................... 83 
11.4.5 The supply of 4°C cooled saline solution ......................................................... 84 
11.4.6 Other procedures within the clinical trial .......................................................... 84 
 
Potential Clinical Benefits ................................................................................. 84 
 
Methods to Minimize Risk ................................................................................ 84 
 
Risk – Benefit Assessment ................................................................................ 85 
12 
RECORDS AND REPORTS ................................................................................ 86 
 
Investigator Records .......................................................................................... 86 
 
Investigator Responsibilities ............................................................................. 87 
 
Sponsor Records ................................................................................................ 89 
 
Sponsor Reports ................................................................................................ 90 
13 
MONITORING AND AUDITING PROCEDURES............................................ 91 
 
Clinical Trial Sponsor and Monitors ................................................................. 91 
 
Monitoring Methods .......................................................................................... 92 

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Monitoring Visits .............................................................................................. 92 
 
Pre-trial Qualification Visit ............................................................................... 93 
 
Initiation Visit ................................................................................................... 93 
 
On-Site Interim Monitoring Visits .................................................................... 94 
 
Audits ................................................................................................................ 94 
 
Final Monitoring Review .................................................................................. 94 
14 
DATA MANAGEMENT PROCEDURES........................................................... 94 
 
Case Report Forms ............................................................................................ 94 
 
Source Documentation ...................................................................................... 95 
 
Transmission of Data ........................................................................................ 96 
 
Data Queries ...................................................................................................... 96 
15 
STATISTICAL ANALYSIS PLAN ..................................................................... 96 
 
Data Analysis .................................................................................................... 97 
 
Statistical Methods ............................................................................................ 99 
 
Sample Size Justification .................................................................................. 99 
16 
PUBLICATION .................................................................................................. 103 
17 
INTELLECTUAL PROPERTY ......................................................................... 103 
18 
STATEMENT OF COMPLIANCE .................................................................... 104 
ATTACHMENT I – REFERENCES ......................................................................... 105 
ATTACHMENT II – ANTI-SHIVERING PROTOCOL ........................................ 109 
ATTACHMENT III – BEDSIDE SHIVERING ASSESSMENT SCALE (BSAS) 111 
ATTACHMENT IV – SPECIFIC NEW-ONSET ADVERSE EVENT 
DEFINITIONS ............................................................................................................. 112 
ATTACHMENT V – ADVERSE EVENT DEFINITIONS ..................................... 115 
ATTACHMENT VI – INVESTIGATOR LIST ........................................................ 121 
ATTACHMENT VII – LIST OF ABBREVIATIONS ............................................. 121 
 
 
 

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1 
SYNOPSIS 
Clinical Trial 
Title 
COOL-AMI EU PIVOTAL TRIAL: A MULTICENTER, 
PROSPECTIVE, RANDOMIZED-CONTROLLED TRIAL TO 
ASSESS THE SAFETY AND EFFECTIVENESS OF COOLING 
AS AN ADJUNCTIVE THERAPY TO PERCUTANEOUS 
INTERVENTION IN PATIENTS WITH ACUTE 
MYOCARDIAL INFARCTION 
Clinical Trial 
Sponsor 
ZOLL® Circulation, Inc. 
Clinical Trial 
Sponsor’s 
Contact 
Philippa Hill 
Senior Director, Clinical Affairs 
ZOLL Circulation, Inc. 
2000 Ringwood Ave. 
San Jose, CA 95131 
Main:    +1 (408) 541-2140 
Fax:  +1 (408) 541-1030 
PHill@zoll.com@zoll.com 
Trial Number 
EDC-3135 
Investigational 
Device 
Proteus™ Intravascular Temperature Management (IVTM) 
System 
Trial Objective The objective of this trial is to evaluate the safety and effectiveness of 
therapeutic hypothermia, using the ZOLL Proteus IVTM System, as an 
adjunctive therapy for patients presenting with acute anterior 
myocardial infarction (AMI) and undergoing percutaneous coronary 
intervention (PCI)  in comparison with patients with acute anterior 
myocardial infarction and undergoing PCI only. 
Trial Design 
A multicenter, prospective, interventional, randomized-controlled trial. 
Randomization will be in a 1:1 ratio, Test Arm (PCI + Cooling) or 
Control Arm (PCI alone) in up to 500 randomized subjects (250 
subjects in each arm). 
 
Roll-In Subjects: To enhance each site’s ability to successfully 
integrate steps of the protocol and for training purposes prior to 
randomizing subjects in the trial, each site may enroll up to 4 Roll-In 
subjects in a non-randomized fashion. Roll-In subjects will be treated 
and followed in the same manner as subjects in the Test Arm of the 

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protocol (PCI + Cooling). Up to a total of 280 Roll-In subjects (up to 4  
per site) may be enrolled. Due to limited cMR data available in 
patients with inferior MI who received an adequate dose of cooling 
prior to revascularization, Inferior MI subjects will be allowed to be 
included as Roll-Ins to further evaluate inferior MI infarct size by 
cMR imaging. Evaluation of infarct size will be performed by cMR 
imaging at 4-6 days. 
Primary 
Effectiveness 
Endpoint  
Relative reduction of 20% in mean anterior myocardial infarct size as 
determined by Cardiac Magnetic Resonance (cMR) imaging at 4-6 
days post infarct in the Test Arm (cooling + PCI) relative to the 
Control Arm (PCI only). 
Primary Safety 
Endpoint 
Per-patient rate of composite Major Adverse Cardiac Events (MACE) 
in randomized subjects, defined as Cardiac Death (CD), All 
Myocardial Infarction (All MI) and Clinically-Indicated Target Lesion 
Revascularization (CI-TLR) at 30 day follow-up; non-inferiority to the 
control. 
Investigational 
Sites 
Up to 70 clinical sites in the Europe 
Inclusion & 
Exclusion 
Criteria 
Patients shall be screened to the following inclusion and exclusion 
criteria. Subjects are qualified for participation only if all Inclusion 
Criteria have been met and all Exclusion Criteria have been confirmed 
not present. 
 
Inclusion Criteria 
All Inclusion Criteria must be answered YES for subject to satisfy 
Inclusion Criteria: 
 
1. The patient is ≥ 18 years of age. 
2. The patient must have symptoms consistent with AMI (i.e. chest 
pain, arm pain, etc.) and unresponsive to nitroglycerin, with 
symptoms beginning greater than 30 minutes but less than 4.5 
hours prior to presentation at hospital. 
3. Qualifying Infarct location: 
a. Roll-In subjects:  Evidence of Acute Anterior or Inferior 
MI with ST-segment elevation of  ≥ 0.2 mV in two or more 
anterior or inferior contiguous precordial leads.(VI-V4) 

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b. Randomized subjects:  Evidence of Acute Anterior MI 
only with ST-segment elevation of  ≥ 0.2 mV in two or 
more anterior contiguous precordial leads. (V1-V4) 
4. The patient is eligible for PCI. 
5. The patient is willing to provide written informed consent to 
participate in this clinical trial. 
 
Exclusion Criteria 
All Exclusion Criteria must be answered NO for subject to satisfy 
Exclusion Criteria: 
The patient has had a previous myocardial infarction. 
1. The patient has had a previous Myocardial Infarction. 
2. The patient is experiencing cardiogenic shock, (systolic blood 
pressure [SBP] <100 mmHg, HR >100 bpm  and arterial oxygen 
saturation (pulse oximetry) <92% without additional oxygen.   
3. The patient is presenting with resuscitated cardiac arrest, atrial 
fibrillation, or Killip risk stratification class II through IV. 
4. The patient has an aortic dissection or requires an immediate 
surgical or procedural intervention other than PCI. 
5. The patient has known history of Congestive Heart Failure (CHF), 
hepatic failure, end-stage kidney disease or severe renal failure 
(clearance < 30ml/min/1.73m²).  
6. The patient is febrile (temperature > 37.5 °C) or has experienced 
an infection with fever in the last 5 days. 
7. The patient has a known previous CABG. 
8. The patient has a known recent stroke within 90 days of admission.  
9. Cardio-pulmonary decompensation that has occurred en route to 
the hospital or, in the opinion of the physician, that is imminent or 
likely to occur following presentation to the clinical site. 
10. Contraindications to hypothermia, such as patients with known 
hematologic dyscrasias which affect thrombosis (e.g., 
cryoglobulinemia, sickle cell disease, serum cold agglutinins) or 
vasospastic disorders (such as Raynaud’s or thromboangitis 
obliterans). 
11. Any contraindication to cardiac MRI, or any implant in the upper 
body which may cause artifacts on cardiac MRI imaging. 
12. The patient has a known hypersensitivity or contraindication to 
aspirin, heparin, or sensitivity to contrast media, which cannot be 
adequately pre-medicated. 

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13. The patient has a known history of bleeding diathesis, 
coagulopathy, cryoglobulinemia, sickle cell anemia, or will refuse 
blood transfusions. 
14. The patient has a height of <1.5 meters (4 feet 11 inches). 
15. The patient has a known hypersensitivity or contraindication to 
buspirone hydrochloride or Pethidine (Meperidine) and/or has 
been treated with a monoamine oxidase inhibitor in the past 14 
days. 
16. Patient has a known history of severe hepatic or renal impairment, 
untreated hypothyroidism, Addison’s disease, benign prostatic 
hypertrophy, or urethral stricture that in the opinion of the 
physician would be incompatible with Pethidine administration. 
17. The patient has an Inferior Vena Cava filter in place (IVC). 
18. The patient has a pre-MI life expectancy of <1 year due to 
underlying medical conditions or pre-existing co-morbidities. 
19. The patient has a known, unresolved history of drug use or alcohol 
dependency, or lacks the ability to comprehend or follow 
instructions. 
20. The patient is currently enrolled in another investigational drug or 
device trial. 
21. The patient is apprehensive about or unwilling to undergo the 
required MRI imaging at follow-up, has a documented or 
suspected diagnosis of claustrophobia, or has Gadolinium allergy, 
or is in permanent Atrial Fibrillation. 
22. The patient has received thrombolytic therapy en route to the 
hospital. 
23. The patient shows clinical evidence of spontaneous reperfusion as 
observed symptomatically and/ or from  baseline ECG findings 
(partial or complete ST resolution in  baseline  ECG prior to 
informed consent and randomization). 
24. The patient is a vulnerable subject, for instance, a person in 
detention (i.e., prisoner or ward of the state). 
25. The patient is a female who is known to be pregnant. 
Clinical Trial 
Population 
Adult male and female patients presenting with an acute myocardial 
infarction. To qualify, patients must have symptoms consistent with 
AMI (i.e. chest pain, arm pain, etc.) unresponsive to nitroglycerin, 
with symptom onset greater than 30 minutes but less than 4.5 hours 
prior to presentation at hospital and be eligible for PCI. 
 

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Randomized subjects must have evidence of Acute Anterior MI only 
with ST-segment elevation of ≥ 0.2 mV in two or more anterior 
contiguous precordial leads will be included. (V1-V4) 
 
Roll-In subjects with evidence of Acute Anterior or Inferior MI with 
ST-segment elevation of ≥ 0.2 mV in two or more anterior or inferior 
contiguous precordial leads will be included. (V1-V4) 
Intervention 
Intravascular permissive hypothermia as an adjunct to PCI.  Cooling 
will be initiated prior to PCI with infusion of up to 1 L of cold saline 
(4°C) (according to the guideline) and with the Proteus Console set at 
32.0 degrees Celsius.  Total cooling time will be 3 hours (± 15 
minutes) and will be followed with active rewarming with the Proteus 
IVTM System to attain normothermia [36 °C (96.8°F)]. 
Length of 
Follow Up 
12 months 
Enrollment 
Initiation of enrollment: January 2017 
Completion of Enrollment: June 2019 
Follow up completed: June 2020 
Summary of 
Statistical 
Analysis 
Primary efficacy endpoint of infarct size measured as percentage of 
total LV mass by cMR, the null hypothesis of equal infarct size 
between two arms will be tested with t-test for the study population. 
For the safety endpoint, comparison of per patient MACE rate for non-
inferiority will be made with Fisher’s exact Test. 
Planned 
Interim 
Analyses 
Two interim analyses are planned to be performed at approximately 
50% and 75% of randomization, once subjects have completed 4-6 day 
cMR follow-up. At the interim stage, the trial will be stopped to reject 
the null hypothesis of no difference or continue enrollment. 
Analysis Sets 
The Intention-to-Treat (ITT) population will be used for primary 
statistical analyses and summaries for all analyses except for Safety 
endpoints. The ITT population includes subjects who have signed an 
informed consent and have been randomized to the Test Arm or the 
Control Arm of the trial. ITT subjects will be evaluated according to 
the group to which they were randomized. 
The Per-Protocol (PP) population includes those subjects who met 
inclusion and exclusion criteria, were randomized to either the Test 
Arm or Control Arm, received the treatment to which they were 

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randomized, and complied substantially with the treatment timeline 
and steps of this protocol without major protocol violations. 
The Safety Analysis Set will be used to evaluate safety endpoints. 
These will be all subjects included in the study as defined by the ITT 
analysis set and Roll-In subjects. For the safety analysis subjects will 
be followed for all Adverse Events 30days post procedure. 
Additionally, all subjects will be followed through 12 months post 
procedure for the incidence of Serious Adverse Events (SAEs), Death 
and Heart Failure (as assessed by NYHA and Kansas City 
Cardiomyopathy Questionnaire (KCCQ),). 
Trial 
Oversight 
Each participating site will dedicate one Principal Investigator to 
oversee the execution of the clinical trial in accordance with the 
protocol. 

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2 
 INTRODUCTION 
Clinical investigations have shown that induction of hypothermia before reperfusion of 
acute coronary occlusion reduces infarct size.  A pilot study from Lund University 
demonstrated that the induction of mild hypothermia (<35°C) in ST Elevation 
Myocardial Infarction (STEMI) patients prior to performing Percutaneous Coronary 
Intervention (PCI) can save (preserve) 38% more cardiac tissue compared with the PCI 
alone.1 
Hypothermia has proven to be one of the most potent and consistent adjunctive therapies 
for infarct size reduction in numerous preclinical studies, when administered prior to 
reperfusion.  This is unlike the well accepted approach for therapeutic hypothermia for 
cardiac arrest, where cooling is applied after reperfusion. The mechanisms leading to 
protection are multifactorial.  However, unlike the consistent findings in preclinical 
studies, clinical trials (COOL -MI, ICE-IT, CHILL-MI) have failed to show a decrease 
in infarct size.  The major reason is likely due to the difficulty in achieving adequate 
cooling prior to reperfusion.  As shown in Table 1 below, none of the clinical trials to 
date has reached target temperature prior to reperfusion, as has been done in all of the 
animal studies. 
Table 1: Major Cooling Trials in STEMI. 
Major Cooling Trials in STEMI 
Trial 
Sample 
Size 
Target 
Temp 
(°C) 
Actual 
Temp at 
Reperfusion 
(°C) 
Temp Miss 
(°C) 
Cooling Time 
before 
Reperfusion 
(min) 
COOL -MI 168 – 
Hyp 
157 – 
Control 
33.0 
35.0 
2.0 
18 
ICE-IT 
105 – 
Hyp 
99 – 
Control 
33.0 
35 
2.0 
16 
CHILL-MI 61 – 
Hyp 
59 – 
Control 
33.0 
34.7 
1.7 
13 
 
The target temperature for each trial was 33.0 °C.  The actual temperature at the time of 
reperfusion was 1.7-2.0 °C higher than target.  This is a miss in temperature “dose” of 

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around 50% [normal temperature is 37.0 °C, target temperature was 33.0 °C, (37.0 – 
35.0) / (37.0 – 33.0) = 50%].     
Post hoc analysis of these trials showed that patients with anterior MI that were cooled 
to less than 35°C at the time of PCI showed a significant reduction in infarct size, 
supporting the idea of a dose response (See Figure 1).  Recent preclinical results 
(Stanford-ZOLL data) have shown that temperature at reperfusion of 32 °C is superior to 
35 °C for reducing infarct size, confirming a dose response.  Future clinical trials will 
require more powerful cooling devices, and more consistency in implementing 18 
minutes of cooling before reperfusion across all study sites in order to evaluate the 
actual effectiveness of therapeutic hypothermia as a protection strategy. 
 
Figure 1: Temperature at reperfusion for the Major Therapeutic Hypothermia in 
AMI Clinical trials. 
 
The Proteus device has a confirmed faster cooling rate.  With a duration of cooling of 18 
minutes prior to reperfusion, as occurred in the COOL -MI trial, the expected 
temperature at reperfusion is 33.3°C with the Proteus device.  This is significantly better 
than the 35°C achieved in COOL -MI and ICE-IT, and 34.7°C achieved in CHILL-MI. 
The relative effectiveness of the Proteus device for cooling, compared to the 
performance of the prior studies is shown in Figure 1 above. The addition of a bolus 

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infusion of 4°C cold saline is expected to further enhance the temperature achieved at 
reperfusion with the Proteus System.  
This Investigational Plan was developed in accordance with the requirements set forth in 
the Good Clinical Practices (E6)2, ISO 14155:2011 Clinical investigation of medical 
devices for human subjects3 - Good clinical practice, the Declaration of Helsinki, and 
the local regulatory requirements an adjunctive therapy to PCI. 
3 
BACKGROUND 
Coronary heart disease complicated by acute myocardial infarction (AMI) remains a 
leading cause of death and disability worldwide.  AMI most commonly occurs when a 
coronary artery becomes occluded by thrombus following the rupture of an 
atherosclerotic plaque. Factors that may affect the size of the subsequent infarction 
include duration of ischemia, size of ischemic territory, collateral blood flow, and 
myocardial metabolic rate. Long-term sequelae of AMI include ventricular remodeling, 
loss of ventricular function, congestive heart failure, dysrhythmias, and sudden death. 
Although major gains have been made in improving the outcome of patients suffering 
AMI, and early myocardial reperfusion with the use of thrombolytic therapy or primary 
percutaneous coronary intervention (PCI) are effective, morbidity and mortality remain 
substantial.  This may be because restoration of blood flow to the ischemic myocardium 
can itself induce injury through myocardial “ischemia reperfusion injury” (IRI), which 
can be defined as that portion of the ischemia-reperfusion continuum which is 
preventable by treatment initiated after restoration of blood flow.4 It has been proposed 
that 50% of the final infarct size may be a function of IRI. 4 
Ischemia reperfusion injury is protean in its components, likely including free radical 
and reactive oxygen species, disordered vasculature, inflammatory injury, programmed 
cell death, and pathologic remodeling among others.5   Unfortunately, the cascading 
nature of these events challenge and, in the end, may defeat the single molecular target 
pharmacologic model.  The long list of failed IRI pharmacologic agents includes 
antioxidants, calcium channel blockers, anti-inflammatory drugs, sodium hydrogen 
exchange inhibitors, among others, has led some to question the importance of 
reperfusion injury in the myocardium.6 Large infarctions still occur despite timely 
reperfusion, due to reperfusion injury.  Numerous treatments have been studied to 
reduce reperfusion injury, with little success to date. 7-9 
Therapeutic hypothermia (TH) has been studied for many years as a potential therapy 
for ischemia and reperfusion.10-16 The past few years have seen development of a broad 
literature reporting both laboratory and clinical trials of mild post-reperfusion TH in the 
treatment of disease entities as diverse as acute cardiac arrest, stroke, and myocardial 

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infarction, among others.  Unlike single pharmacologic agents, TH has the potential to 
modify and ameliorate multiple pathways of injury. 
4 
INTENDED USE, SYSTEM OVERVIEW, & DEVICE DESCRIPTION 
 
Intended Use / Indication for Use 
The ZOLL® Proteus™ Intravascular Temperature Management (IVTM) System is 
indicated for use in adult subjects with acute myocardial infarction to induce and 
maintain hypothermia prior to percutaneous coronary intervention as an adjunctive 
therapy to reduce anterior infarct size.  The Proteus IVTM System is to be used only as 
part of the clinical investigation. 
 
System Overview 
The Proteus Intravascular Temperature Management (IVTM) System consists of four 
primary components: a single-use heat exchange catheter; heat exchange cassette; a 
temperature probe and a reusable microprocessor-driven console.  The system is 
designed to achieve and maintain patient temperatures within the range of 32 - 37°C. Its 
performance profile includes: 
1. Rapid patient cooling and warming 
2. Precise achievement and maintenance of a desired patient target temperature 
3. Quick and simple deployment: See the catheterization lab, critical care unit, 
emergency department, and other hospital settings 
Reference the Investigator Brochure for additional information on the Proteus 
IVTM System. 
The Proteus IVTM System couples a heat exchange catheter with a dual microprocessor-
driven controller to manage patient temperature. The Proteus IVTM System is designed 
to rapidly cool and warm patients, achieve and precisely maintain a target patient 
temperature and to be quickly and easily deployed. 
Cool or warm sterile saline is continuously circulated through the catheter, thereby 
cooling or warming the blood as it flows over the catheter without perfusion of fluids 
into the body. The saline is transported from the catheter to the cassette (mounted in the 
console) via extension lines. The cassette has an integral heat exchange element and a 
pump that couples with the console to cool or warm the saline being pumped through the 
closed circuit comprised of the cassette and catheter. The Proteus IVTM Console 
continuously monitors the patient temperature and controls the catheter temperature to 
cool, warm or maintain the target temperature. 

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Device Description 
4.3.1 Proteus Catheter 
The Proteus Catheter (Figure 2) is a single-use, heparin coated, endovascular heat 
exchange catheter consisting of a triple lobed, helically wound balloon mounted on the 
distal portion of a multi-lumen shaft.  The catheter is designed for placement in the 
Inferior Vena Cava via the femoral vein using a 12Fr or a 14 Fr hemostatic introducer 
sheath.  The catheter has a fluid supply lumen, a fluid return lumen, a guidewire port at 
the proximal end of the catheter connecting to a guidewire lumen that accommodates 
guidewires with diameters up to 0.038”.  The expanded balloon portion of the catheter 
has an expanded diameter of 17 mm and a length of 26 cm during system operation.  
The catheter has a radiopaque marker mounted at the distal and proximal end of the 
balloon portion of the catheter.  The distal end of the catheter has a non-traumatic soft 
tip.  The fluid supply and fluid return lumens of the catheter are connected to the 
cassette via extension lines approximately 2 meters in length, which provide the closed 
heat transfer fluid circuit.  The 0.038”, 145-cm. stainless steel guidewire included in the 
package has a soft atraumatic tip. 
Figure 2 Diagram of  Proteus Catheter 
 
4.3.2 Proteus Temperature Probe 
The Proteus System measures a patient’s core body temperature using a heparin-coated 
endovascular dual output probe (X-Probe) advanced through the guidewire lumen of the 
Proteus Catheter after the catheter is placed. 
4.3.3 Proteus Cassette 
The single-use Proteus Cassette consists of a heat exchange element, a pump, a pump 
coupling to interface with the motor drive in the console and fluid lines to interface with 
the heat transfer fluid circulated by the console.  The cassette is designed to be removed 
from the portable control console allowing the catheter to remain in the patient to 

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facilitate moving the patient to another location where temperature management can 
continue using the same or another control console. 
4.3.4 Proteus Console 
The Proteus Console (Figure 3) consists of solid-state thermoelectric modules, a motor 
drive, dual fluid level detection systems and dual microprocessors.  A dilute 
polypropylene glycol/water mixture (process fluid) circulates within the console to 
provide heat exchange with the saline heat transfer fluid loop in the cassette.  This 
technology along with microprocessor proportional control of both the saline and the 
patient temperature enable the following features: 
• Designated patient temperature between 32-37°C is maintained within ± 0.3°C 
continuous calculation and display, in all ambient lighting conditions, of patient 
actual temperature, target temperature, and rate of cooling/warming 
• Redundant safety system to shut down and warn user of patient overheat or 
overcool, saline leakage, sensor failure, and electrical or mechanical malfunction 
• Control console automatically performs a hardware and software diagnostic 
check of all functional and safety systems upon startup 
• Maximum cooling and heating rates vary from patient to patient depending on 
the patient’s cardiac output, size and weight, room temperature and humidity, 
and the successful implementation of the anti-shivering medication regimen, type 
and amount anesthesia, combined use with blankets or active heating/cooling 
apparatus, body cavity exposure to the environment during surgery and other 
factors. 
Figure 3:  Proteus Console 
                                  
 
 

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Figure 4:  Proteus Catheter and Interconnection between Catheter, Temperature 
Probe (X-Probe), Cassette and Console. 
 
4.3.5 Device Labeling 
Written Instructions for Use, Operation Manual, Quick Reference Guide, and Service 
Manual for the Proteus IVTM System will be packaged with product shipped to the 
investigational sites.  The Proteus IVTM System is to be used only as part of the clinical 
investigation.  (See Proteus IVTM System Labeling) 
5 
PRIOR INVESTIGATIONS 
 
Pre-Clinical Studies 
Hypothermia has been shown to reduce metabolic demand and provide ischemic 
protection.  Recent studies across numerous different animal models have demonstrated a 
strong direct relationship between myocardial temperature and infarct size.11,12,14,18  Mild 
to moderate degrees of hypothermia (32-35°C) have resulted in significant reductions in 
infarct size when applied either before or after the onset of coronary occlusion in animal 
studies.   
In other studies, in 1996, Duncker et al, and in 1998 Miki et al, both demonstrated a dose 
response relationship between myocardial temperature and infarct size using a laboratory 
model of AMI.11,12  Subsequently, Dae et al in collaboration with Radiant Inc. 
demonstrated that therapeutic hypothermia can be induced safely and rapidly in animal 

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models using intravascular cooling.13 They then showed that hypothermic therapy initiated 
late during ischemia and continuing for several hours after reperfusion significantly 
improved reflow and reduced macroscopic zones of no-reflow and necrosis in this 
model.15  The study showed:  
• A striking reduction of myocardial infarct size.  The cooled group had an infarct 
of 9 ± 6% of the area at risk vs. 45 ± 8% of the area at risk for controls 
• Preservation of myocardial perfusion and viability in the cooled group as 
demonstrated by radionuclide imaging 
• No evidence of apoptosis in salvaged myocardium in the cooling arm.  Well-
preserved cardiac output during the cooling process. 
Of particular relevance, Gotberg et al reported in 2008 that hypothermia achieved before 
reperfusion decreased infarct size, while hypothermia initiated at the time of reperfusion 
prevented microvascular obstruction, but did not decrease myocardial infarct size. 16 
 
Human Clinical Studies   
5.2.1 COOL MI Trial  
The COOL MI Trial19 was conducted from September 2001 through April 2003. A total 
of 421 patients were enrolled (199 Control, 193 Intervention, 29 Roll-In) at 27 
investigational sites in the US, Germany and Australia.  The primary analysis population 
included 357 patients (180 Control, 177 Intervention) who received the assigned 
treatment.  The COOL MI Trial evaluated the safety and effectiveness of cooling as an 
adjunctive therapy to percutaneous coronary intervention (PCI) in patients with acute 
myocardial infarction.  Table 2 below displays enrollment characteristics. 
Table 2: COOL MI Trial Enrollment Characteristics 
 
Control  
(N=180) 
Intervention 
(N=177) 
p-value 
Anterior Myocardial 
Infarction 
77 (44%) 
74 (42%) 
0.77 
Inferior Myocardial 
Infarction 
99 (56%) 
103 (58%) 
0.77 
Failed thrombolytic therapy 
prior to enrollment 
23 (12.8%) 
18 (10.3%) 
0.67 
Time in minutes – median (interquartile range) 
From symptom onset to 
hospital presentation 
123 (69 – 201) 
114 (60 – 190) 
0.08 
From hospital presentation to 
PCI 
88 (61 – 114) 
104 (80 – 134) 
<0.0001 

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5.2.1.1 
Procedural and Angiographic Results COOL MI Trial 
The Trial demonstrated that endovascular cooling using the Radiant Medical’s (now 
ZOLL’s) Reprieve System TM in the setting of myocardial infarction was safe, well 
tolerated, and readily integrated into the existing treatment pathway.  While the primary 
effectiveness endpoint of the study was not achieved, the data provided a strong signal 
indicating that when patients were sufficiently cooled prior to reperfusion, myocardial 
damage was reduced.19 
The Control and Intervention groups were well matched in terms of culprit vessels, 
percutaneous coronary intervention (PCI) procedures and treatment success.  As expected, 
cooling did not affect the angiographic success of PCI procedures.  Of the 357 patients 
who underwent primary PCI, the majority were treated with stent implantation and a 
platelet glycoprotein receptor inhibitor.  Approximately 20% of study subjects were 
determined to have Thrombolysis in Myocardial Infarction (TIMI 3) flow prior to PCI.  
TIMI Grade Flow is a scoring system from 0-3 referring to levels of coronary blood flow 
assessed during percutaneous coronary angioplasty: 
• TIMI 0 flow (no perfusion) refers to the absence of any antegrade flow beyond a 
coronary occlusion. 
• TIMI 1 flow (penetration without perfusion) is faint antegrade coronary flow 
beyond the occlusion, with incomplete filling of the distal coronary bed. 
• TIMI 2 flow (partial reperfusion) is delayed or sluggish antegrade flow with 
complete filling of the distal territory. 
• TIMI 3 flow (complete perfusion) is normal flow which fills the distal coronary 
bed completely 
After PCI, TIMI 3 flow was achieved in approximately 92% of patients. Only about 30% 
of patients had TIMI myocardial perfusion grade 3; however the percentage was similar 
in both treatment groups and is consistent with literature reports of myocardial perfusion. 
Procedural and angiographic data are presented in Table 3 below. 
Table 3: COOL MI Trial - Procedural and Angiographic Data 
 
Control  
(N=180) 
Intervention 
(N=177) 
p-value 
Infarct related artery, Stent implantation, Glycoprotein & Stenosis Diameter 
Left anterior descending coronary 
artery 
70 (39%) 
69 (39%) 
0.91 
Circumflex artery 
13 (7%) 
14 (8%) 
0.87 
Right coronary artery 
77 (43%) 
74 (42%) 
0.93 

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*Thrombolysis in Myocardial Infarction 
5.2.1.2 
COOL MI Trial Results 
Of the 177 Intervention patients, 11 (6.2%) patients had the Reprieve Catheter placed in 
the emergency room (ER), one (0.6%) patient had the catheter placed in the cath lab 
holding area, and 165 (93.2%) patients had the catheter placed in the cath lab.  Overall, 
patients in the Intervention group received a median of 17 minutes (interquartile range 
(IQR): 10-27) of cooling prior to PCI.  During that time, patient temperature was 
decreased from a median of 36.2°C (IQR: 35.8-36.5) at the initiation of cooling to 35.1°C 
(IQR: 34.5-35.6) at the time of PCI (Figure 1).  The median of the minimum temperature 
reached by each patient was 33.1°C (IQR: 33.0-33.4), which was achieved in 75 minutes 
(IQR: 50-108).  Target patient temperature was set at a 33°C for 3 hours post-PCI.  Patients 
were then re-warmed at 1°C/hr until Investigator-determined normothermia was reached 
[median=36.5 (IQR: 36.2-36.8]).  Figure 5 below shows patient temperature over time 
with cooling and time to PCI.  The goal to reach target temperature of 33°C at PCI was 
not achieved in the trial, due to the inadequate cooling power of the Reprieve System.  As 
noted above, target temperature of 33°C was reached after 75 minutes of cooling, long 
after PCI had occurred. 
Stent implanted 
153 (92%) 
157 (94%) 
0.59 
Glycoprotein IIb/IIIa receptor inhibitor 140 (78%) 
142 (80%) 
0.74 
Initial diameter stenosis  
(mean ± std dev) 
92 ± 14% 
92 ± 12% 
0.93 
Initial TIMI flow 
Grade 0/1 
126 (71%) 
122 (69%) 
0.77 
Grade 2 
14 (8%) 
21 (12%) 
0.28 
Grade 3 
38 (21%) 
34 (19%) 
0.74 
Final diameter stenosis 
7 ± 9% 
8 ± 10% 
1.00 
Final TIMI* flow 
Grade 0/1 
2 (1%) 
5 (3%) 
0.33 
Grade 2 
7 (4%) 
12 (7%) 
0.31 
Grade 3 
170 (95%) 
160 (90%) 
0.11 
Final myocardial perfusion grade 
 
 
 
Grade 0/1 
63 (43%) 
76 (53%) 
0.11 
Grade 2 
35 (24%) 
26 (18%) 
0.27 
Grade 3 
49 (33%) 
41 (29%) 
0.54 

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Figure 5: Median Temperature and Elapsed Times for Intervention Patients 
 
5.2.1.3 
COOL MI Trial Tolerability of Cooling 
Shivering was managed according to the shivering suppression guidelines recommended 
for this study by Dr. Daniel Sessler, Chairman of the Department of Anesthesiology at the 
University of Louisville.  The recommended baseline combination of Pethidine, buspirone 
and skin warming using a forced-air blanket could be supplemented incrementally in the 
event of shivering or patient discomfort, by additional Pethidine, or by slightly increasing 
the target temperature.  If these steps were unsuccessful, patients could be actively 
rewarmed to normothermia. 
This protocol proved to be quite effective at maintaining patient comfort.  Intervention 
patients received an average of 56 mg of oral buspirone and an average of 267 mg of 
intravenous Pethidine over the course of the cooling procedure.  Of 177 patients in the 
treatment group, only one patient (0.6%) required premature warming due to intolerability 
of cooling.  Nine patients (5.1%) required a slight increase in target temperature (0.2°C – 
0.5°C) to maintain patient comfort.  Ninety-eight patients (55.7%) required supplementary 
dosing of Pethidine, but 60 of these 98 patients (61.2%) had not received the 
recommended loading dose of the anti-shivering drugs. 
COOL MI Trial Safety Results: The primary safety endpoint of the COOL MI study was 
the incidence, through 30 days, of Major Adverse Cardiac Events (MACE), defined as the 
composite of death, recurrent myocardial infarction of the target vessel and the need for 
urgent revascularization of the target vessel.  As shown in Table 4 below, there was no 
statistical difference in the incidence of MACE in the Intervention group as compared to 
the Control group.  All MACE were adjudicated by an independent Clinical Events 
Committee and none were attributed to cooling or use of the Reprieve System. Table 4 
1        2        3        4        5        6        7        8        9        10
Elapsed Time (hours)
37
36
35
34
33
Onset 
to 
Door
115 min
Door 
to 
PCI
104 min
Start Temp
= 36.2°C
Median Minimum Temp = 33.1°C
Time to Minimum Temp = 75 min
Temperature ºC
Temp at PCI = 35.1 °C
Cooling Prior to PCI = 17 min
1        2        3        4        5        6        7        8        9        10
Elapsed Time (hours)
37
36
35
34
33
Onset 
to 
Door
115 min
Door 
to 
PCI
104 min
Start Temp
= 36.2°C
Median Minimum Temp = 33.1°C
Time to Minimum Temp = 75 min
Temperature ºC
Temp at PCI = 35.1 °C
Cooling Prior to PCI = 17 min

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below demonstrates the results of the study with regard to the incidence of Major Adverse 
Cardiac Events. 
Table 4: COOL MI Trial Incidence of MACE 
 
These MACE rates observed in COOL MI compare favorably with those reported for 
similar patients in recent AMI trials, such as ADMIRAL, CADILLAC, DANAMI and 
RAPID MI-ICE (Table 5). 
 
Table 5 Incidence of MACE for Comparable Patients in Recent AMI Trials  
Trial 
Death 
Reinfarction 
Revascularization 
COOL MI (Treatment Group) 
(n=177) 
3.4% 
0.6% 
2.3% 
ADMIRAL (n=149)17 
3.4% 
1.3% 
4.7% 
CADILLAC (n=524)18 
2.7% 
0.8% 
1.6% 
DANAMI-2 (n=790)19 
6.6% 
1.6% 
NA 
RAPID MI-ICE (n=20)1 
0% 
0% 
0% 
5.2.1.4 
COOL MI Trial Adverse Events Related to Cooling 
Potential adverse events related to cooling (e.g., arrhythmia or hemodynamic 
complications) and to placement and/or use of the Reprieve Catheter (e.g., vascular or 
thrombogenic complications) were also evaluated as a secondary endpoint.  The incidence 
of these types of events is presented.  It is important to note that these complications are 
also risks of myocardial infarction and coronary intervention themselves. Table 6 below 
reports the incidence of non-MACE complications. 
Events through 30 days 
Control  
(N=180) 
Intervention 
(N=177) 
p-value 
MACE 
7 (3.9%) 
11 (6.2%) 
0.45 
 
Death 
4 (2.2%) 
6 (3.4%) 
0.71 
 
Recurrent MI 
3 (1.7%) 
1 (0.6%) 
0.63 
 
Urgent Revascularization 
0 (0%) 
4 (2.3%) 
0.12 

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Table 6: Incidence of Other Complications 
Events through 30 days 
Control  
(N=180) 
Intervention 
(N=177) 
p-value 
Bradyarrhythmia 
41 (22.8%) 
46 (26.0%) 
0.56 
Ventricular Tachycardia/Fibrillation 
36 (20.0%) 
31 (17.5%) 
0.64 
Cardiogenic Shock 
11 (6.1%) 
22 (12.4%) 
0.06 
Pulmonary Edema 
3 (1.7%) 
6 (3.4%) 
0.49 
Vascular Complications  
      Retroperitoneal bleed 
      Hematoma >6cm 
      Pseudoaneurysm 
      AV fistula 
15 (8.3%) 
2 (1.1%) 
12 (6.7%) 
1 (0.6%) 
1 (0.6%) 
15 (8.5%) 
1 (0.6%) 
13 (7.3%) 
3 (1.7%) 
0 (0%) 
0.90 
0.95 
0.99 
0.63 
0.95 
Bleeding Requiring Transfusion  
14 (7.8%) 
20 (11.3%) 
0.34 
Deep Venous Thrombosis 
0 
3 (1.7%) 
0.24 
Pulmonary Embolism 
3 (1.7%) 
0 
0.24 
Stroke 
1 (0.6%) 
0 
0.95 
Arrhythmias are a known risk of moderate to severe hypothermia.  In the COOL MI trial, 
with its mild hypothermia target temperature, arrhythmias were not more common and 
appeared to be primarily related to ischemia and/or the coronary intervention.  
Cardiogenic shock requiring treatment with an intra-aortic balloon pump trended toward 
a higher incidence in the hypothermic group.  However, the majority of shock cases 
appeared to be more related to complicated MIs and/or complex interventions than to 
cooling.  Other potential contributory factors (e.g., age, weight, Pethidine dose) were 
compared between shock and stable patients; however, no causal relationships were 
apparent.  The majority of the vascular complications reported in the Intervention group 
were related to the arterial access site for the PCI procedure rather than the venous access 
site for the cooling catheter.  Three cases of deep venous thrombosis (DVT) were reported 
in the Intervention group. 
5.2.1.5 
COOL MI Trial Effectiveness Results 
The primary effectiveness endpoint in the COOL MI study was infarct size, measured 
using SPECT imaging at 30 days.  Overall, there was no observed difference in infarct 
size (%LV) between study groups (Table 7).  The secondary effectiveness endpoints of 
LV ejection fraction, CK-MB release, and ST-segment resolution, likewise did not 
demonstrate a difference between the Intervention and Control groups. 

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Table 7: COOL MI Results 
 
Control  
Intervention 
p-value 
% LV Infarct Size  (N) 
     mean ± std dev 
     median 
157 
13.8 ± 15.1 
10 
168 
14.1 ± 14.3 
10 
0.83 
LV Ejection Fraction  (N) 
     mean ± std dev 
     median 
104 
55.2 ± 11.4 
54 
115 
53.0 ± 12.0 
53 
0.17 
Peak CK-MB  (N) 
     mean ± std dev 
     median 
167 
42.8 ± 48.1 
33.9 
168 
49.1 ± 50.7 
33.6 
0.25 
ST-segment resolution - 90 min. post-PCI 
(N) 
      < 30% 
      30 - 69% 
      ≥ 70% 
90 
11.1% 
27.8% 
53.3% 
82 
20.7% 
35.4% 
39.0% 
 
0.13 
0.36 
0.09 
ST-segment resolution - 180 min. post-PCI 
(N) 
      < 30% 
      30 - 69% 
      ≥ 70% 
79 
10.1% 
20.3% 
60.8% 
80 
16.3% 
27.5% 
51.3% 
 
0.36 
0.38 
0.30 
 
In addition, no statistically significant differences were demonstrated when the 
Intervention and Control patients were compared based on the following stratifications:  
infarct location, time from onset of symptoms to PCI, prior MI, or TIMI flow prior to PCI.  
However, subsequent analysis revealed a strong relationship between final infarct size and 
patient temperature at the time of reperfusion. 
The mean temperature at the time of reperfusion, or more specifically, at the time of first 
balloon inflation, was 35.1°C.  As shown in Figure 6, in the population of patients with 
anterior myocardial infarction, those patients who had a temperature <35°C at the time of 
reperfusion had a statistically significant reduction in final infarct size as compared to 
both the control group (9.3% vs. 18.2%, p=0.05) and those with a temperature ≥35°C 
(9.3% vs. 21.9%, p=0.01). 

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5: Mean Infarct Sizes (%LV) of Patients with Anterior Infarctions 
  
 
 
 
 
 
 
 
 
 
This effect has a strong basis in physiology and was consistent across other clinical 
measures, i.e., there was a trend toward decreased CK-MB release and increased LV 
Ejection Fraction in the cooled patients.  This effect is not attributable to differences in 
baseline clinical or angiographic variables.  In fact, those patients with a temperature 
<35°C were more likely to have occlusion of the proximal versus mid left anterior 
descending coronary artery and a longer time to reperfusion.  These factors would be 
expected to increase infarct size in this group, but the observed reduction in infarct size 
appears to be the result of cooling. 
5.2.2 COOL MI II Trial  
Because of the encouraging results in patients with anterior AMI’s in whom hypothermia 
had been achieved at the time of PCI, COOL MI II was initiated.  Additionally, COOL 
MI II Trial was intended to verify the feasibility of initiating cooling earlier in the 
treatment pathway (e.g., in the emergency department).  Only a fraction of the anticipated 
sample size were enrolled before the trial was ended early because the sponsor became 
financially insolvent after only 41 patients were enrolled. The study data were submitted 
by the sites to a Data Management CRO.  As a result, the final report is not currently 
available because the data was not released to ZOLL by the Data Management CRO upon 
ZOLL acquisition of Radiant Medical.   
In COOL MI II, all cooling was initiated in the Cath Lab even though the focus was on 
earlier cooling.  Since earlier initiation of cooling was not accomplished, reaching the goal 
of a core temperature of 35° C before PCI was dependent on the more powerful GTO 
System.  This was accomplished in 26 of the 27 patients without the intentional delay of 
PCI.  Pivotal data for 23 patients were available and the mean time to reach 35°C was 6.1 
17.9 
9.3 
21.9 
18.2 
0 
10 
20 
30 
All Treatment < 35°C 
≥ 35°C Control 
%LV 
p=0.92 
p=0.05 
p=0.30 
(n=61) 
(n=16) 
(n=38) 
(n=59) 
Subject groups: 
i)   All Intervention patients 
regardless of temperature at PCI 
ii)  Intervention patients cooled 
to      < 35°C at PCI 
iii) Intervention patients > 35°C 
at PCI 
iv) Control patients 
Subject groups: 
i)   All Intervention patients 
regardless of temperature at PCI 
ii)  Intervention patients cooled 
to      < 35°C at PCI 
iii) Intervention patients > 35°C 
at PCI 
iv) Control patients 
Figure 6: Mean Infarct Sizes (%LV) of Patients with Anterior Infarction 

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minutes (± 3.0), 34°C was 14.5 minutes (± 7.9) and 33°C was 31.3 minutes (± 29.9).  Data 
showed 15 of the patients were cooled to 32°C; the mean time was 36.1 minutes (± 14.0).  
Efforts to initiate cooling as early as possible resulted in a median of 39 minutes of cooling 
time prior to PCI, a significant improvement over the median of 18 minutes of cooling 
time achieved in the previous study.  In addition, the median door-to-balloon time was 
106 minutes for these COOL MI II patients, compared to a median of 104 minutes for 
Test patients in the previous study, indicating that PCI was not delayed by the introduction 
of cooling.  By focusing on cooling earlier in the treatment pathway, additional cooling 
time can be achieved without significant adverse impact on time to reperfusion. 
5.2.2.1 
COOL MI II Trial Adverse Events 
As with COOL MI, the primary safety endpoint of the COOL MI II study was the 
incidence, through 30 days, of MACE. Shown below are the adverse events in the COOL 
MI II trial in the intent to treat (ITT) population.  Table 8 combines the Feasibility and 
Pilot hypothermia groups for a total of 41 patients (12 Feasibility and 29 Pivotal). 

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Table 8:  Incidence of MACE and Other Complications 
Events through 30 Days 
Normothermia 
Hypothermia 
Enrollment 
10 
41 
UADE 
0 
0 
Cardiac 
  
  
     Death 
0 
1 (2.4%) 
     Repeat MI 
0 
1 (2.4%) 
     Repeat PCI 
1 (10%) 
3 (7.3%) 
     CABG 
0 
2 (4.9%) 
     Hypotension / Shock 
1 (10%) 
6 (14.6%) 
     CHF 
0 
2 (4.9%) 
     Pericardial Effusion 
0 
1 (2.4%) 
     Pericarditis 
0 
1 (2.4%) 
     HTN 
0 
1 (2.4%) 
Arrhythmias  
  
  
     Ventricular Fibrillation 
0 
4 (9.8%) 
     Vent. Tachycardia 
1 (10%) 
7 (17.1%) 
     Frequent PACs 
1 (10%) 
0 
     SVT 
0 
1 (2.4%) 
     Atrial Fibrillation 
0 
11 (26.8%) 
Vascular Events 
  
  
     Bleeding requiring transfusion 
0 
3 (7.3%) 
     Thrombocytopenia 
0 
2 (4.9%) 
     Anemia 
0 
2 (4.9%) 
     Hematoma > 6cm 
0 
2 (4.9%) 
     DVT   
0 
1 (2.4%) 
     Local Tissue Trauma 
0 
1 (2.4%) 
     Epistaxis 
1 (10%) 
0 
     Hemoptysis 
0 
1 (2.4%) 
     Stroke 
0 
0 
Respiratory Events 
  
  
     Pulmonary Edema 
0 
8 (19.5%) 
     Pulmonary Embolism 
0 
0 
     Hypoxia 
0 
1 (2.4%) 
     Respiratory Failure 
0 
1 (2.4%) 
     Plural Effusion 
0 
3 (7.3%) 
     Increased Pulmonary HTN 
1 (10%) 
0 
     Pneumonia 
1 (10%) 
0 

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Renal 
  
  
     Renal requiring Treatment 
1 (10%) 
2 (4.9%) 
     Hemodialysis 
0 
0 
     UTI 
0 
2 (4.9%) 
     Hematuria 
1 (10%) 
0 
Other 
  
  
     Nausea / Vomiting 
1 (10%) 
15 (36.6%) 
     Systemic Infection 
0 
3 (7.3%) 
     Fever 
0 
3 (7.3%) 
     Muscular Pain 
1 (10%) 
3 (7.3%) 
     Rhabdomyolysis 
1 (10%) 
0 
     Mental Status Changes 
0 
2 (4.9%) 
     Hypokalemia 
0 
1 (2.4%) 
     Vaginal Infection 
0 
1 (2.4%) 
5.2.3 COOL RCN Trial 
The COOL RCN (Radio-Contrast nephropathy) trial was undertaken to evaluate whether 
endovascular cooling provides more effective protection for patients at high risk of 
experiencing RCN.  The trial was designed as an international, multicenter, 1:1 
randomized controlled trial of up to 400 subjects at up to 35 investigational sites.  Subjects 
with a calculated Creatinine clearance of 20 – 50 mL/min and scheduled for a diagnostic 
or interventional catheterization procedure were enrolled. The trial utilized Radiant 
Medical’s Reprieve System. The study was commenced in March 2006 and was 
terminated after enrolling only 136 subjects due to the financial insolvency of Radiant 
Medical. 
Table 9: COOL RCN Trial: Adverse Events Incidence of Complications In-
Hospital  
  
Normothermia  Hypothermia 
P Value 
Enrollment 
70 
58 
  
Nausea/Vomiting 
6 / 70 (8.6%) 
26 / 58 
(44.8%) 
<0.01 
Bradycardia 
2 / 70 (2.9%) 
7 / 58 (12.1%) 0.04 
Bleeding Requiring 
Transfusion 
7 / 70 (10.0%) 
1 / 58 (1.7%) 
0.05 
Atrial Fibrillation 
2 / 70 (2.9%) 
3 / 58 (5.2%) 
0.5 
CABG 
4 / 70 (5.7%) 
1 / 58 (1.7%) 
0.25 
Pulmonary Edema 
4 / 70 (5.7%) 
1 / 58 (1.7%) 
0.25 
Renal Complication 
2 / 70 (2.9%) 
3 / 58 (5.2%) 
0.5 

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Normothermia  Hypothermia 
P Value 
     Acute Renal Failure 
2 / 70 (2.9%) 
2 / 58 (3.4%) 
0.85 
     Elevated Serum Creatinine 
0 / 70 (0%) 
1 / 58 (1.7%) 
-- 
     Hemodialysis 
2 / 70 (2.9%) 
0 / 58 (0%) 
-- 
     Urinary Tract Infection 
3 / 70 (0.4%) 
1 / 58 (1.7%) 
0.41 
Hypotension/Shock 
1 / 70 (1.4%) 
3 / 58 (5.2%) 
0.22 
Hematoma >6cm 
0 / 70 (0%) 
3 / 58 (5.2%) 
-- 
SVT 
0 / 70 (0%) 
2 / 58 (3.4%) 
-- 
MI 
0 / 70 (0%) 
1 / 58 (1.7%) 
-- 
Ventricular Tachycardia 
1 / 70 (1.4%) 
1 / 58 (1.7%) 
0.89 
Death 
0 / 70 (0%) 
1 / 58 (1.7%) 
-- 
Repeat PCI 
1 / 70 (1.4%) 
1 / 58 (1.7%) 
0.89 
Stroke 
0 / 70 (0%) 
1 / 58 (1.7%) 
-- 
 
Table 10: COOL RCN Trial: Incidence of Complications to 30 Days  
  
Normothermia 
Hypothermia 
P Value 
Enrollment 
70 
58 
  
Renal 
7 
2 
0.15 
     Acute Renal Failure 
5 
1 
0.15 
     Renal Stent 
2 
0 
-- 
     Kidney Infection 
0 
1 
-- 
Cardiac 
8 
14 
0.1 
     MI 
1 
1 
0.89 
     CABG 
2 
3 
0.5 
     PCI 
1 
3 
0.22 
 
 

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Normothermia 
Hypothermia 
P Value 
     PCI or CABG 
3 
6 
0.18 
     Death - Cardiac 
1 
2 
0.45 
     Shock 
0 
3 
-- 
     CHF 
2 
1 
0.67 
     Angina 
1 
0 
-- 
     Hypertension 
0 
1 
-- 
Arrhythmia 
3 
3 
0.81 
     Atrial Fibrillation 
2 
1 
0.67 
     Bradycardia 
0 
2 
-- 
     SVT 
1 
0 
-- 
     Ventricular Fibrillation 
0 
0 
-- 
Non-Cardiac 
3 
3 
0.81 
     Stroke 
1 
0 
-- 
     Bleed/Transfusion 
2 
3 
0.5 
     Dialysis  
0 
0 
-- 
Vascular Complications Requiring  Surgery  
0 
0 
-- 
Rehospitalization 
13 
13 
0.59 
Other 
9 
12 
0.23 
     Anasarca 
1 
  
-- 
     Fatigue 
1 
  
-- 
     Ischemic Bowel 
1 
1 
0.89 
     Hypoglycemia 
1 
  
-- 
     Lesion Excision 
1 
  
-- 
     Anemia 
1 
  
-- 
     Hiatal Hernia 
1 
1 
0.89 
     Pulmonary Edema 
1 
  
-- 
     Knee Injury 
1 
  
-- 
     Rash 
  
1 
-- 
     Debridement of Sternal Wound 
  
1 
-- 
     Leg Weakness 
  
1 
-- 
     Nausea/Vomiting 
  
2 
-- 
     Dehydration 
  
1 
-- 
     Acute Respiratory Failure 
  
1 
-- 
     Metabolic Acidosis 
  
1 
-- 
     Back Pain 
  
1 
-- 
     Systemic Infection 
  
1 
-- 

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5.2.3.1 
Unanticipated Adverse Events 
(i) 
COOL MI Trial – Unanticipated Adverse Events 
There was one Unanticipated Adverse Device Effect (UADE) in the COOL MI Trial; A 
patient experienced nasopharyngeal trauma and bleeding potentially caused by the 
nasoesophageal temperature probe used as part of the Reprieve System. This resulted in a 
modification to the Informed Consent Form to explain the risk of nasal trauma and/or 
bleeding due to the nasoesophageal probe.  
(ii) 
COOL MI II Trial – Unanticipated Adverse Events 
There were no UADE’s in the COOL MI II Trial. 
(iii) 
COOL RCN Trial – Unanticipated Adverse Events 
There was one UADE in the COOL-RCN Trial.  A 73 year old male with chronic renal 
insufficiency and a history of aortobifemoral bypass scheduled for cardiac catheterization.  
The patient was randomized to the Hypothermia arm. The Reprieve catheter was placed 
via the left femoral vein.  The angiogram and stenting procedures were performed via 
right radial arterial access.  After approximately 1 hour of cooling, the patient complained 
that his feet were itching and it was noted that the patient’s left foot and leg were cyanotic 
up to mid-thigh, with no left DP pulse, and  the right foot was slightly discolored.  He was 
subsequently rewarmed at the maximum rate for approximately 40 minutes.  It was 
observed that the cyanosis lightened as the patient rewarmed and was apparently resolved 
with no further sequelae after discontinuation of treatment with the Reprieve catheter, 
indicating that cooling with the device contributed to the reduced peripheral circulation.  
The already compromised peripheral vascular circulation is suspected to have been 
exacerbated by hypothermia induced vasoconstriction. It is known that hypothermia 
induces superficial vasoconstriction, but this degree of cyanosis had not been observed 
with previous use of the device.  Additionally, after the patient had received Pethidine and 
versed as part of the anti-shivering protocol, his respiration became depressed, requiring 
assisted ventilation, Romazicon and Narcan. It is possible that this transient hypoxic event 
may have also contributed to the cyanosis. 
 
Lower extremity cyanosis in the presence of peripheral vascular insufficiency had 
not been identified in the protocol or informed consent document as a potential risk of 
mild hypothermia or use of the Reprieve catheter. The resolution of the cyanosis upon 
rewarming and removal of the catheter indicated that these may have contributed to the 
event. The risk section of the protocol and informed consent were subsequently revised.  
5.2.4 ICE- IT Trial 
The Intravascular Cooling Adjunctive to Percutaneous Coronary Intervention for Acute 
Myocardial Infarction Trial (ICE-IT) 23 randomized 228 patients presenting with an acute 

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MI within 6 hours of symptom onset to endovascular cooling concomitant with PCI versus 
routine PCI. The primary endpoint of infarct size at 30 days as measured by SPECT 
imaging was similar between the 2 groups (10% for the hypothermia group versus 13% 
for the control group, p = 0.14). Like the COOL MI trial, ICE-IT was also an overall 
negative trial. But while TH did not demonstrate any significant decrease in infarct size 
overall, a trend towards benefit was again observed on post-hoc analysis of the subgroup 
with anterior infarction who were sufficiently cooled to a temperature of < 35°C at the 
time of revascularization (infarct size of 12.9% of the left ventricle in the TH population 
compared to 22.7% in the control group, p = 0.09).23 
5.2.5 RAPID-MI ICE Trial 
Recently, Lund University presented a preliminary report of their RAPID-MI ICE Trial.1 
This trial enrolled 20 patients presenting with acute myocardial infarction, and 10 patients 
each were randomized to TH by intravascular cooling or a control group.  Cooling was 
accomplished with a combination of 2L of cold saline infusion and the Phillips InnerCool 
catheter-based cooling system.  The endpoint was infarct size normalized to myocardium 
at risk assessed by cardiac magnetic resonance using T2 weighted imaging and late 
gadolinium enhancement.  Although the sample size is relatively small, the trial produced 
a number of potentially important results: 
• Core body temperature less than for 35°C was achievable before reperfusion without 
significant delay in the door to balloon time. 
• Infarct size normalized to myocardium at risk was reduced by a remarkable 38% in 
patients receiving hypothermia. 
• There were also significant decreases in peak and cumulative Troponin I or T in the 
hypothermia group. 
5.2.6 CHILL-MI Trial 
Lund University recently reported the results of the CHILL-MI trial37, which was a multi-
center study of 120 patients with STEMI (< 6 hours) planned to undergo PCI who were 
randomized to hypothermia induced by rapid infusion of 600 – 2000 ml of cold saline and 
endovascular cooling, or standard of care.  Hypothermia was initiated before PCI and 
continued for 1 hour after reperfusion.  The primary endpoint was infarct size as a 
percentage of the myocardium at risk (IS/MaR), assessed by cardiac MRI at 4±2 days.  
The goal to reach target temperature of 33°C at reperfusion was also not achieved in the 
CHILL-MI trial, due to the inadequate cooling power of the cooling device.  Patients 
randomized to cooling achieved a core body temperature at reperfusion of 34.7°C with a 
9 minute longer door-to-balloon time.  Hypothermia induced by cold saline infusion and 
endovascular cooling was feasible and safe, however, there was no significant difference 
in IS/MaR between the groups.  Exploratory analysis of early anterior infarctions (0-4 hrs) 
showed a significant reduction in IS/AAR of 33% (p<0.05).  Further, the incidence of 

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heart failure was lower with hypothermia at 45 days (3% vs 14%, p<0.05).  This trial, as 
the others cited above, shows potential efficacy of cooling in patients with anterior 
STEMI, supporting further research for confirmation. 
5.2.7 Induction of Mild Systemic Hypothermia With Endovascular Cooling 
During Primary Percutaneous Coronary Intervention for Acute 
Myocardial Infarction 
 
This multi-center study included 42 patients with acute myocardial infarction (AMI) 
(onset less than 6hrs) and evaluated the safety and feasibility of endovascular cooling 
during primary PCI for AMI. 39 Subjects were randomized to PCI with or without 
endovascular cooling (target core temperature 33°C). Cooling was maintained for 3 h after 
reperfusion. Skin warming, oral buspirone, and intravenous meperidine were used to 
reduce the shivering threshold. The primary end point was major adverse cardiac events 
at 30 days. Infarct size at 30 days was measured using SPECT imaging. All patients 
successfully cooled did achieved a core temperature below 34°C (mean target temp 33.2 
± 0.9°C). MACE events occurred in 0% vs. 10% (p = NS) of treated versus control 
patients. The median infarct size was not significantly smaller in patients who received 
cooling compared with the control group (2% vs. 8% of the left ventricle, p = 0.80). 
5.2.8 VELOCITY Trial 
The VELOCITY trial38 randomized 54 STEMI patients at 7 centers in the United States 
and Canada to emergent PCI with (n = 28) or without (n = 26) hypothermia induced by 
the Velomedix Automated Peritoneal Lavage System (Velomedix; Menlo Park, CA) 
between January 2013 and January 2014. Baseline characteristics were similar between 
the 2 groups, and 46.3% of all infarcts were anterior. 
Hypothermia (core temperature at or below 34.9°C) was achieved in 96.3% of patients 
and PCI was performed in all but 1 patient in each treatment group. Median door-to-
balloon time was shorter in the control vs hypothermia group (47 vs 62 minutes; P = 
.007). Among the 46 PCI patients who underwent MRI 3 to 5 days post procedure, the 
median myocardial infarct size was similar in the control vs hypothermia group (16.1% 
vs 17.2% of LV mass; P = .54). 
VELOCITY Investigators observed that prolonged door-to-balloon time in the 
hypothermia group may have attenuated the effect of hypothermia on infarct size though 
it is unlikely to have been totally responsible for absence of effect as DTB times were 
short in both groups and within the range wherein further reductions in mortality may not 
be realized. 

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At 30-day follow-up, no patients in the control group had a primary composite safety 
endpoint event, compared with 6 (21.4%) of the patients who underwent hypothermia 
(P = .01). Further details in Section 5.2.8.1. 
In conclusion, the VELOCITY study found that controlled systemic hypothermia through 
automated peritoneal lavage may be safely and rapidly established in patients with 
evolving STEMI undergoing primary PCI at the expense of a modest increase in door-to-
balloon time. In the VELOCITY randomized trial, peritoneal hypothermia was associated 
with an increased rate of adverse events (including stent thrombosis) without reducing 
infarct size. Adequately powered randomized trials (likely limited to patients with anterior 
MI) are needed to assess the effect of rapidly induced hypothermia on myocardial salvage 
and clinical outcomes after primary PCI. 
5.2.8.1 VELOCITY Trial Adverse Events at 30 Days 
At 30-day follow-up, no patients in the control group had a primary composite safety 
endpoint event (death, reinfarction, ischemia-driven TLR, major bleeding, sepsis, 
pneumonia, peritonitis, severe arrhythmias, or renal failure), compared with 6 (21.4%) 
of the patients who underwent hypothermia (P = .01). Four patients (14.3%) experienced 
MACE (cardiac death, reinfarction, or ischemia-driven TVR), and 3 (11.0%)—all in the 
hypothermia arm—developed definite stent thrombosis. 

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Table 11: VELOCITY Trial Clinical Event Rates Within 30 Days 
 
5.2.9 EU AMI Case Series 
ZOLL is currently enrolling patients in the COOL-AMI EU Case Series Trials to assess 
the ability to integrate hypothermia into the current pathway for patients receiving PCI for 
ST elevation MI.  To date, 308 patients have been enrolled at 36 sites in the EU.  Both 
anterior and non-anterior STEMI patients have been enrolled, and cooling is performed 
using the ZOLL Thermogard XP (TGXP) System or Proteus IVTM system.  A series of 
six standards has been developed and monitored to enable consistency in the execution of 
the protocol.  The standards include delivery of the antishivering regimen correctly, 
delivery of 1 L of iced saline before PCI, and at least 18 minutes of cooling delivered prior 
to wire crossing the lesion.  Feedback in the form of a report card (Figure 7) is provided 
to the site after each case as indicated in the following diagram: 
Figure 7:  Report Card Standards 
 

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These six standards are consistently achieved at all sites.  The 18 minute duration of 
cooling matches the average duration of cooling in the previous EU COOL AMI trial.  
The ability to deliver 18 minutes of cooling prior to PCI is consistently achieved in the 
recent EU Case Series, where the door to balloon (DTB) times, at all sites, were less than 
60 minutes (ranging from 38 minutes to 58 minutes).  This is far less than the maximum 
door to balloon time of 90 minutes recommended by the current guidelines for PCI, 2011 
ACCF/AHA/SCAI PCI Guideline24,50).  The experience of one of the sites has been 
published26, and notes that the average DTB time for the first 11 patients enrolled in the 
trial was 38 minutes, compared to a mean DTB time of 37 minutes for all patients 
presenting with STEMI without cooling.  In view of the validation that implementation of 
hypothermia in the treatment pathway for PCI of STEMI patients is feasible, ZOLLhas 
also conducted the COOL-AMI EU PILOT Trial, following the same standards of 
implementation, with cooling done by the more powerful Proteus device.  The goal is to 
maximize the dose of cooling prior to PCI. 
5.2.10 COOL-AMI EU PILOT Trial 
ZOLL has completed enrollment in the COOL-AMI EU PILOT Trial that evaluated the 
retention of subjects after integrating therapeutic hypothermia using the ZOLL Proteus 
IVTM System into existing STEMI treatment protocols for subjects who presented with 
acute anterior myocardial infarction.  50 subjects were randomized at 16 sites in the EU. 
22 patients (88%; 95% confidence interval [CI]: 69-97%) in the hypothermia group and 
23 patients (92%; 95% CI: 74-99) in the control group completed cardiac magnetic 
resonance imaging at four to six days and 30-day follow-up. A series of three standards 
were monitored to enable consistency in the execution of the protocol.  The standards 
included delivery of the antishivering regimen correctly, delivery of up to 1 L of iced 
saline, and 18 minutes of cooling delivered prior to wire crossing the lesion. Patients with 

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anterior STEMI were rapidly and safely cooled. Intravascular temperature at coronary 
guidewire crossing after 20.5 minutes of endovascular cooling decreased to 33.6°C 
(range 31.9-35.5°C), which is ≥1.1°C lower than in previous cooling studies. There 
was a 17-minute (95% CI: 4.6-29.8 min) cooling-related delay to reperfusion. In the “per 
protocol” analysis, median infarct size/left ventricular mass was 16.7% in the hypothermia 
group versus 23.8% in the control group (absolute reduction 7.1%, relative reduction 30%; 
p=0.31) and median left ventricular ejection fraction (LVEF) was 42% in the hypothermia 
group and 40% in the control group (absolute reduction 2.4%, relative reduction 6%; 
p=0.36). There were no statistically significant differences between the groups, in adverse 
events or serious adverse events.49 
 
Summary and Clinical Trial Rationale 
Previous clinical trials in patients experiencing acute myocardial infarction (AMI) have 
demonstrated that therapeutic hypothermia is safe, well tolerated and showed reductions 
in infarct size19. Additionally, recent preclinical results (Stanford-ZOLL data) have shown 
that temperature at reperfusion of 32 °C is superior to 35 °C for reducing infarct size, 
confirming a dose response. Future clinical trials will require more powerful cooling 
devices, and more consistency in implementing 18 minutes of cooling before reperfusion 
across all study sites in order anterior infarctions. It is therefore the objective of the 
COOL-AMI EU PIVOTAL Trial to evaluate the actual effectiveness of therapeutic 
hypothermia as a protection strategy. 
Further clinical trials are needed to evaluate more powerful cooling devices, along with a 
refined therapeutic hypothermia protocol (target temperature of 32°C + 18 minutes of 
cooling prior to PCI). It will also be important to understand whether adequate cooling to 
32°C + 18 minutes of cooling prior to PCI can be implemented into existing STEMI 
treatment protocols with no significant delay in door-to-balloon times. This trial aims to 
address the need for a powered clinical evaluation assessing the safety and effectiveness 
of the Proteus IVTM for this refined therapeutic hypothermia protocol as an adjunct 
therapy for AMI patients undergoing PCI. Among these refinements are: 1) A larger dose 
of cooling was achieved with the Proteus System (temp at PCI was 33.6°C as opposed to 
35°C for COOL MI), 2) Delivery of at least 18 minutes of cooling prior to PCI was 
possible (mean 20 minutes in the EU Pilot Study), 3) the anti-shivering protocol was 
refined and worked successfully, and 4) the use of report cards for every case to track : a) 
anti-shivering protocol impementation, b) infusion of 1 liter of cold saline prior to PCI, c) 
18 minutes of cooling prior to PCI, d) door to balloon time less than 90 minutes, e) total 
ischemic time less than 6 hours, and f) proper administration of dual antiplatelet therapy 
(DAPT) are all refinements ready to be implemented. 

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6 
CLINICAL TRIAL PLAN 
 
Trial Objective 
The objective of this randomized clinical trial is to evaluate the safety and effectiveness 
of therapeutic hypothermia, using the ZOLL Proteus IVTM System, as an adjunctive 
therapy for patients presenting with acute anterior myocardial infarction and undergoing 
PCI in comparison with patients with acute anterior myocardial infarction and undergoing 
PCI only. 
 
Trial Endpoints 
6.2.1 Primary Effectiveness Endpoint 
Relative reduction of 20% in mean anterior myocardial infarct size (IS), as determined by 
Cardiac Magnetic Resonance (cMR) imaging at 4-6 days post-infarct in the Test Arm 
(cooling + PCI) compared to the Control Arm (PCI only). Infarction Size (IS) is defined 
as % Left Ventricular Mass as measured by Cardiac Magnetic Resonance (cMR) imaging. 
Infarct Size (IS) will be assessed by Cardiac Magnetic Resonance (cMR) at 4 – 6 days 
following the index procedure. The trial is considered to have met the primary efficacy 
endpoint if the Test Arm demonstrates a 20% relative reduction in infarct size compared 
to the Control Arm. 
The ITT analysis set will be used for primary statistical analyses and summaries. The ITT 
population includes those subjects who have signed an informed consent and have been 
randomized to the Test Arm or the Control Arm of the trial. ITT subjects will be evaluated 
according to the group to which they were randomized. 
The PP analysis set will also be evaluated. The PP population includes those subjects who 
met inclusion and exclusion criteria, were randomized to either the Test or Control arm, 
received the treatment to which they were randomized, and complied substantially with 
the treatment timeline and steps of this protocol without major protocol violations. 
6.2.2 Primary Safety Endpoint 
Per-patient rate of composite Major Adverse Cardiac Events (MACE) subjects, defined 
as Cardiac Death (CD), All Myocardial Infarction (All MI) and Clinically-Indicated 
Target Lesion Revascularization (CI-TLR) at 30 day follow-up; non-inferiority to the 
control. 
6.2.3 Additional Assessments: Demographics and Other Parameters 
Subject demographics and various baseline characteristics will also be collected. 
Additional clinical data collected and evaluated will include the number of patients who 
can successfully be enrolled and randomized, the timing of subject presentation to 
hospital, the timing of therapeutic and adjunctive interventions, the timing of reaching the 
target temperature zone, temperature at PCI, subsequent maintenance of hypothermia and 

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temperature data from the IVTM System. Observations will be evaluated relating to the 
use of the ZOLL Proteus IVTM System and how it performs in relation to the induction 
of therapeutic cooling and follow-up cMR imaging. New York Health Association24 
(NYHA) Functional Class and Kansas City Cardiomyopathy Questionnaire25 (KCCQ) 
will be evaluated at12 month follow-up.. 
 
Trial Design 
This clinical trial is a multicenter, prospective, interventional, randomized-controlled trial. 
Randomization will be in a 1:1 ratio, Test Arm (PCI + Cooling) or Control Arm (PCI 
alone) in up to a total of 500 patients (250 subjects in each arm), at up to 70 clinical sites. 
 
To enhance each site’s ability to successfully integrate steps of the protocol and for 
training purposes prior to randomization, each site may enroll up to 4 Roll-In subjects in 
a non-randomized fashion. Roll-In subjects will be treated and followed as subjects in the 
Test Arm of the protocol (PCI + Cooling). Up to a total of 280 Roll-In subjects (up to 4 
per site) may be enrolled. Due to limited cMR data in patients with inferior MI who 
received an adequate dose of cooling prior to revascularization, Inferior MI subjects will 
be allowed to be included as Roll-Ins to further evaluate inferior MI infarct size by cMR 
imaging. Evaluation will be done of cMR imaging at 4-6 days. ZOLL will provide 
financial support for staff if cMRs are performed on weekends. 
 
 
Patient Population 
Subjects will include those who present to the Emergency Department (ED) and / or Cath 
lab, who meet the trial eligibility requirements and who can provide informed consent for 
cooling treatment. Subjects considered for enrollment in this trial will include adult 
patients presenting with an acute anterior myocardial infarction. To qualify, patients must 
have symptoms consistent with AMI (i.e., chest pain, arm pain, etc.) unresponsive to 
nitroglycerin, qualifying ST-segment elevation of ≥ 0.2 mV in two or more anterior 
contiguous precordial leads(V1-V4), with symptom onset greater than 30 minutes, but less 
than 4.5 hours prior to presentation at hospital, and be eligible for PCI. This ensures that 
the overall ischemic time from symptom onset to time of wire crossing is less than 6 hours. 
Subjects randomized to the Test Arm, as well as all Roll-In subjects, will receive 
intravascular cooling with the Proteus IVTM device.  While undergoing temperature 
management, the Anti-shivering Protocol must be followed (see Attachment II).  
 
Selection Criteria 
Patients shall be screened to the following inclusion and exclusion criteria. Patients are 
qualified for participation only if all Inclusion Criteria have been met and all Exclusion 
Criteria have been confirmed not present. 

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Inclusion Criteria 
All Inclusion Criteria must be answered YES for subject to satisfy Inclusion Criteria: 
 
1. The patient is ≥ 18 years of age. 
2. The patient has symptoms consistent with AMI (i.e. chest pain, arm pain, etc.) and 
unresponsive to nitroglycerin, with symptoms beginning greater than 30 minutes but 
less than 4.5 hours prior to presentation at hospital. 
3. Qualifying Infarct Location: 
a. Roll-In subjects:  Evidence of Acute Anterior or Inferior MI with ST- 
segment elevation of ≥ 0.2 mV in two or more anterior or inferior 
contiguous precordial leads (V1-V4). 
b. Randomized subjects: Evidence of Acute Anterior MI only with ST- 
segment elevation of ≥ 0.2 mV in two or more anterior contiguous 
precordial leads (v1-V4). 
4. The patient is eligible for PCI. 
5. The patient is willing to provide written informed consent to participate in this clinical 
trial. 
 
Exclusion Criteria 
All Exclusion Criteria must be answered NO for subject to satisfy Exclusion Criteria: 
 
1. The patient has had a previous Myocardial Infarction. 
2. The patient is experiencing cardiogenic shock. systolic blood pressure [SBP] <100 
mmHg, HR> 100 bpm  and arterial oxygen saturation (pulse oximetry) <92% without 
additional oxygen.   
3. The patient is presenting with resuscitated Cardiac Arrest, Atrial Fibrillation, or Killip 
risk stratification class II through IV. 
4. The patient has an aortic dissection or requires an immediate surgical or procedural 
intervention other than PCI. 
5. The patient has known history of Congestive Heart Failure (CHF), Hepatic Failure, 
end-stage kidney disease or severe Renal Failure (clearance < 30ml/min/1.73m²).  
6. The patient is febrile (temperature > 37.5 °C) or has experienced an Infection with 
Fever in the last 5 days. 
7. The patient has a known previous CABG. 
8. The patient has a known recent Stroke within 90 days of admission.  
9. Cardio-Pulmonary Decompensation that has occurred en route to the hospital or, in 
the opinion of the physician, that is imminent or likely to occur following presentation 
to the clinical site. 
10. Contraindications to hypothermia, such as patients with known Hematologic 
Dyscrasias which affect thrombosis (e.g., cryoglobulinemia, sickle cell disease, serum 

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cold agglutinins) or Vasospastic Disorders (such as Raynaud’s or thromboangitis 
obliterans). 
11. Any contraindication to cardiac MRI, or any implants in the upper body which may 
cause artifacts on cardiac MRI imaging. 
12. The patient has a known hypersensitivity or contraindication to aspirin, heparin, or 
sensitivity to contrast media, which cannot be adequately pre-medicated. 
13. The patient has a known history of Bleeding Diathesis, Coagulopathy, 
Cryoglobulinemia, Sickle Cell Anemia, or will refuse blood transfusions. 
14. The patient has a height of <1.5 meters (4 feet 11 inches). 
15. The patient has a known hypersensitivity or contraindication to buspirone 
hydrochloride or Pethidine (Meperidine) and/or has been treated with a monoamine 
oxidase inhibitor in the past 14 days. 
16. Patient has a known history of severe hepatic or renal impairment, untreated 
hypothyroidism, Addison’s disease, benign prostatic hypertrophy, or urethral stricture 
that in the opinion of the physician would be incompatible with Pethidine 
administration. 
17. The patient has an Inferior Vena Cava filter in place (IVC). 
18. The patient has a pre-MI life expectancy of <1 year due to underlying medical 
conditions or pre-existing co-morbidities. 
19. The patient has a known, unresolved history of drug use or alcohol dependency, or 
lacks the ability to comprehend or follow instructions. 
20. The patient is currently enrolled in another investigational drug or device trial. 
21. The patient is apprehensive about or unwilling to undergo the required MRI imaging 
at follow-up, has a documented or suspected diagnosis of claustrophobia, or has 
Gadolinium allergy, or is in permanent Atrial Fibrillation. 
22. The patient has received thrombolytic therapy en route to the hospital 
23. The patient shows clinical evidence of spontaneous reperfusion as observed 
symptomatically and/or from baseline ECG findings (partial or complete ST 
resolution in ECG prior to informed consent and randomization). 
24. The patient is a vulnerable subject, for instance, a person in detention (i.e., prisoner or 
ward of the state). 
25. The patient is a female who is known to be pregnant. 
 
Clinical Trial Procedures 
6.8.1 Patient Screening 
Patients presenting at participating centers with clinical signs and symptoms of AMI will 
be expeditiously triaged and offered the opportunity to participate in this clinical trial 
without regard to age, gender or ethnicity.  To ensure that patients are approached for 
potential trial participation without bias, patient screening information will be maintained 
on a patient screening log at each site.  This log will track patients that were enrolled in 

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the trial as well as patients who were excluded from participation and the reason(s) for 
their exclusion. The use of a patient screening log assures that all eligible subjects are 
given an opportunity to participate or decline participation in the trial. 
The subject’s eligibility for treatment with the Proteus IVTM System will be evaluated 
based on the medical and anatomical criteria outlined above in the inclusion/exclusion 
criteria section.  The Investigator will explain the elements of this clinical trial, including 
the risks, potential benefits and required interventional and follow-up procedures, to each 
subject prior to obtaining informed consent. 
If a subject is found to be ineligible during baseline screening and routine diagnostic tests, 
the subject shall be considered a screen failure and will be documented on the patient 
screening log.  Roll-In subjects are considered enrolled in the trial when all inclusion and 
exclusion criteria have been satisfied, and informed consent has been signed. Randomized 
subjects are considered enrolled in the trial when all inclusion and exclusion criteria have 
been satisfied, informed consent has been signed, and the patient is randomized to either 
Test or Control Arm of the trial. 
6.8.2 Informed Consent 
The reviewing Medical Ethics Committee (MEC) must review and approve an Informed 
Consent Form (ICF) specific to this study. The Sponsor will provide each study center 
with an example ICF. The study center, to meet specific requirements, may modify this 
example ICF; however, the ICF to be used for subject consent under this protocol must 
contain all of the elements required by the study Sponsor and the governing regulatory 
requirements for informed consent (21 CFR Part 50). Therefore, each investigational site 
will provide the Sponsor with a copy of the MEC approved ICF - as well as any 
amendments - for the duration of the study.  
Informed consent will be required from each subject.  The MEC approved Informed 
Consent document must be signed by the patient or by the legal authorized representative 
(LAR) prior to any related procedures (or according to the MEC’s approved guidelines), 
including the collection of data on case report forms (CRFs). Only subjects that have the 
appropriate informed consent form will be included in the trial. 
The informed consent process (including time and date of discussion), should be 
documented in the subject’s medical record and signed/dated by the individual 
(investigator or designee) who recorded it.  The original signed consent form must be filed 
in the subject’s medical record and a copy of the signed informed consent documentation 
given to the subject.  
All subjects must sign, date and note the time on the Institutional Medical Ethics 
Committee (MEC) approved informed consent prior to any clinical trial/investigation-

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specific procedures. Obtaining the consent with the documented date and time, and the 
provision of a copy to the subject will be documented in the subject’s medical record.  
Due to the emergent nature of treating acute myocardial infarction, patients who have been 
enrolled in the study may receive a subsequent consent which provides more detailed 
information about their participation in the trial (based on MEC requirements), which may 
be reviewed and signed after the acute phase of their treatment has been completed.  If the 
patient decides they no longer want to be included in the study, they will be withdrawn 
and their data will be included in the analysis up until the time of withdrawal. 
If in the course of the pre-study evaluations prior to consent, the patient is found not to be 
eligible for inclusion in the study, the patient should be notified and the reason for 
ineligibility documented on the appropriate Screening Log. 
 
All information pertinent to this clinical investigation (including at a minimum the 
description and purpose of the study, potential benefits, potential risks and 
inconveniences, active procedures, confidentiality, compensation, circumstances for 
termination and site contact persons) will be provided to the subjects in writing and in 
their native, non-technical, language by Investigator or designee, who has been trained on 
the protocol.   
If new information becomes available that can significantly affect a subject's future health 
and medical care, this information shall be provided to the affected subject(s) in written 
form. If relevant, all affected subjects shall be asked to confirm their continuing informed 
consent in writing. 
6.8.3 Roll-In Enrollment  
Prior to randomizing patients, each participating center (except German centers) may 
enroll up to 4 patients Roll-In subjects in a non-randomized fashion. Roll-In subjects are 
treated and followed as patients in the Test Arm (PCI + Cooling) for training purposes. 
The justification for the number Roll-In patients in this study is based on ZOLL’s previous 
clinical trial experience in relationship to a site’s ability to successfully incorporate the 
cooling protocol including consent, anti-shivering regimen and an adequate dose of 
cooling without significantly delaying door-to-balloon time.  Successful implementation 
takes teamwork and often several cases to assure the cooling protocol is adhered to with 
consistent accuracy. 
In light of the fact that previous clinical trials (e.g., COOL-MI19, ICE-IT23 and CHILL-
MI37) have failed to provide an adequate dose of cooling prior to reperfusion, ZOLL has 
implemented a tool called a “Report Card”.  This Report Card notes the site’s success in 
achieving critical aspects of the protocol, called “Standards”, and is provided to the site 
after every patient is enrolled into the trial.  The objective of the Report Card is to report 
back to the site their success in implementing a set of standards according to the protocol, 

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and to encourage continuous improvement following each enrollment.  The Standards, as 
noted on the Report Card, include but are not limited to accuracy of antishivering regimen 
administration and 18 minutes of cooling delivered prior to the wire crossing the lesion. 
The Standard of 18 minutes of cooling has been demonstrated in previous ZOLL trials to 
be the amount of time required to deliver an optimal dose of cooling so the patient’s core 
body temperature is as close to target temperature as possible prior to reperfusion without 
significantly delaying door-to-balloon time. 
Consistent achievement of each standard allows sites to move from Roll-In to 
randomization and enables consistency in execution of the protocol. Feedback will be 
provided to the site after each enrollment to assure the standards have been met and an 
adequate dose of cooling has been achieved.  Use of the Report Card and Standards is 
intended to assist sites in ascending their learning curve as rapidly as possible.  All centers 
will transition from Roll-In to Randomization as soon as possible once they have 
demonstrated their ability to enroll patients while consistently meeting the standards, 
thereby minimizing the number of Roll-In patients but ensuring accurate, precise 
adherence to the investigational protocol. Based on the site’s performance with the Roll-
In patients, as determined by the Sponsor, the site will be notified of authorization to 
randomize patients in the trial. 
Additionally, Roll-In patients will undergo cMR as part of the cMR training process at 
each site.  This will allow the site to train and qualify acquisition of cMR images per cMR 
protocol and ensure high quality and consistent imaging throughout the study across sites.  
Roll-In patients will not be included in the primary endpoint analysis; however, they will 
be included in the safety endpoint analysis.  All performed activities on Roll-In subjects 
will be recorded as if performed in the Test Arm of the trial and hence documented in the 
Case Report Forms (CRF) for training and evaluation. 
Roll-In subjects will be considered to be enrolled when all inclusion and exclusion criteria 
have been met and the informed consent form has been signed. 
6.8.4 Approval to Randomize in the Trial 
It will be at the discretion of the sponsor to advance a site to Randomization.  Based on 
the site’s performance with the Roll-In patients, as determined by the Sponsor, the site 
will be notified of authorization to randomize patients in the trial. 
6.8.5 Randomization 
In the randomization phase, patients who meet eligibility criteria for participation will be 
randomly assigned to either the Test Arm (PCI + Cooling) or Control Arm (PCI alone) in 
a 1:1 ratio. 
Randomization will be applied using an internet based Interactive Web Response Systems 
(IWRS). In the trial, randomization will be done using random permuted blocks (based on 

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procedure outlined in Pocock SJ. Clinical Trials: A Practical Approach. Wiley, 
Chichester, 1983), stratified by site, with 1:1 allocation ratio using a randomization list. 
At randomization, inclusion and exclusion criteria will be verified, and confirmation of 
informed consent signature will be done. 
Subjects will be considered to be enrolled in the Test Arm and Control Arms of the trial 
when all inclusion and exclusion criteria have been met, the informed consent form has 
been signed, and randomization assignment has been completed. 
6.8.6 Acute Care and Emergency Room Triage  
Prior to the initiation of this trial at each participating institution, training will be 
conducted by the Sponsor targeted toward the integrated care of each trial subject and 
emphasizing the shared responsibility between the Departments of Emergency Medicine 
and Interventional Cardiology, where applicable at each center, with the goal of rapid 
screening, enrollment and treatment of appropriate patients. 
Each center will clearly delineate departmental responsibilities for the following: 
• Assessment of patient clinical features, signs and symptoms 
• Administration of Informed Consent 
• Review of Inclusion/Exclusion Criteria 
• Assurance that diagnostic procedures mandated by the protocol are completed 
prior to randomization into this trial and are appropriately documented 
• Patient Randomization 
• Administration of pre-treatment medication(s) 
• Administration of Anti-shivering medications to subjects randomized to the Test 
Arm of the trial 
• Consensus on location in hospital where cooling using the Proteus IVTM System 
will be initiated 
• Set-up of Proteus IVTM System, including insertion of the Proteus Catheter into 
the femoral vein induction of cooling, initiation of re-warming, Proteus IVTM 
System shutdown and catheter extraction for Test Subjects. 
6.8.7 Standardized Care Prior to the Cooling Procedure 
It is anticipated that subjects may receive one or more of the following therapies as part 
of current clinical practice in the treatment of acute myocardial infarction: 
• Intravenous fluids and electrolytes 
• Oxygen  
• Antiplatelets and/or antithrombotics  
• Vasoactive agents and diuretics 
 

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Clinicians will be encouraged to manage the subject in a standardized manner with respect 
to oxygenation, anti-coagulation and/or anti-platelet medications.  
6.8.8 Documentation Procedures 
Trial procedures and treatment data will be documented on standardized Case Report 
Forms (CRFs) which may be on paper or via an electronic data capture system (EDC). 
The completion of the CRFs may be delegated to a member of the study team (e.g., the 
study coordinator) as long as that person is listed on the Delegation of Authority Log.  
However, the Principal Investigator retains responsibility for the accuracy and integrity of 
the data entered on the CRF.  The CRF will be monitored for accuracy and completeness 
per the source documents (medical records, charts, interventional systems, worksheets as 
applicable, etc.) at each clinical center.  Temperature data from the Proteus IVTM System 
will be downloaded and sent to Sponsor.  A flow diagram for the Test Arm is represented 
in Figure 10.  
It is anticipated that technology and/or techniques such as edit checks and double entry of 
data may be utilized to minimize the rate of error.  Additionally, ZOLL or its assignees 
may ask for data clarification or re-check of data for accuracy.  Monitoring visits and CRF 
completion logs will be used to track data entry in accordance with trial logistics and 
expectations.  
Any source documentation (procedure reports, imaging studies, lab reports, death 
certificates, etc.) that is sent to the Sponsor should have all patient identifiers removed and 
replaced with the subject’s trial ID, and processes ensuring patient privacy and clinical 
data confidentiality will be followed in accordance with local regulations and applicable 
laws. 
 

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6.8.9 Study Flow and Procedures 
 
Figure 8 Screening and Enrollment Flow 
Admission to Hospital
Patient Screening
Eligible?
Patient Screening Log
(If Patient doesn’t qualify, document 
Reason for Screen Failure)
Complete Informed Consent Procedure
Roll-in Up to 4 subjects 
per site
No
Yes
Turn Proteus 
Console ON
1:1 Randomization
TEST ARM
Cooling + PCI
CONTROL ARM
PCI Only
Approved by Sponsor to 
Randomize?
Yes
No
 
 
 
 

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Figure 9 Control Arm Flow 
 
1:1 Randomization
CONTROL ARM
PCI Only
Perform PCI 
Procedure
Obtain Vital Signs 
and Core Body Temp 
at Baseline
Perform 12-lead ECG 
at Baseline
Record Troponin I or 
T at Baseline and 
until peak identified
Document All 
Medications and All 
Adverse Events
Post PCI
 

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Figure 10 Test Arm Flow 
 

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Figure 11 All Patient Procedures 
 
 

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6.8.10  
Pre-Cooling Assessment Procedures 
All required procedures and data collection from the time of subject screening (presentation at 
hospital) through the pre-cooling assessment period are given below in Table 11. 
 
Table 11:  Baseline / Screening and Enrollment Procedures/Evaluations and Data 
Collection for the Test & Control Arms of the Trial 
Procedures/ 
Evaluations  
Data 
Trial 
Eligibility 
At admission to the hospital 
Informed 
Consent  
Obtain Consent from patient before any trial-related procedure is initiated. 
Trial 
Enrollment  
- 
Follow randomization process to assign patient to Roll-In, Test or 
Control Arms of the trial 
- 
Complete Enrollment Form, document randomization, and FAX  or 
email to ZOLL at 
 
+1 800.243.0360 or ami-eu@zoll.com to enter in the eCRF 
Temperature 
Document subject’s temperature using a tympanic thermometer 
Vital Signs 
Blood Pressure, Heart Rate, Respiratory Rate, BSAS measurement 
Physical Exam  
Complete Physical Examination 
Blood Studies 
RBC’s, WBC’s, Hct, Hgb, Platelets 
Lab Studies 
BUN, Creatinine, sodium, potassium, calcium, phosphate, magnesium, 
chloride, lactic acid, glucose, amylase, lipase 
Cardiac 
Markers  
Baseline and peak Troponin I or Troponin T including upper limit of normal 
ECG 
12-lead baseline 
Medications 
Document as indicated on Case Report Form since STEMI onset 
Adverse 
Events 
Collect all adverse events as soon as patients are enrolled in the trial 
 

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6.8.11 Initiation, Maintenance, and Reversal of Cooling with Proteus IVTM System 
Procedures / Evaluations and Data Collection for Subjects Enrolled in the 
Test Arm 
6.8.12 Test Arm: Temperature Management Protocol and Data Collection Time 
Points 
Treatment with therapeutic hypothermia will begin with a forced infusion of up to 1 L of cold 
saline (4°C) (according to the guideline) using pressure bags, and at the time of administration of 
the anti-shivering medication according to the anti-shivering guidelines, then will continue with 
the Proteus IVTM System as soon as possible.  Cooling will be initiated with the Proteus IVTM 
System set at a temperature of 32.0 °C, and the subject’s temperature will be measured with the 
Proteus IVTM System immediately before PCI has occurred (measured as time the wire crosses 
the target lesion). Cooling will be maintained for 3 hours and will be followed with active 
rewarming to attain normothermia 36.0 °C (96.8°F).  
Cooling induction, maintenance of hypothermia, and rewarming are described in the following 
Table 12. The data collection schedule for Test Arm subjects is summarized in Section 6.8.13. 
Table 12:  Initiation, Maintenance, and Reversal of Cooling with Proteus IVTM System 
Procedures / Evaluations and Data Collection for Subjects Enrolled in the Test Arm 
Phase 
Task 
Immediately Upon 
Arrival to the 
Hospital 
1. Turn the Proteus Console on (in preparation for cooling with the 
device) 
2. Document time of occurrence of STEMI and ECG 
3. Document time of arrival of Emergency Medical Service EMS 
(Paramedics) 

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Phase 
Task 
Baseline / 
Enrollment 
4. Immediately after informed consent is obtained and patient is 
randomized to the Test Arm of the trial, initiate anti-shivering 
medication protocol using Guidelines outlined in Attachment 
II. 
5. Begin cooling induction by forced infusion with 25mL/kg of 4°C 
cold saline using pressure bags up to 1 L of cold saline (4°C) 
(according to the guideline) at the physician’s discretion. Use Bair 
HuggerTM (CE marked device) for patient comfort. 
6. Document the time the Proteus console is turned on. The 
device will begin cooling the patient immediately; however, 
optimal cooling is achieved in 5-10 minutes after it is turned on. 
7. Perform Physical Examination and obtain Vital Signs. 
8. Obtain Blood and Lab studies. 
9. Obtain Troponin I or Troponin T . 
10. Obtain 12-lead baseline ECG. 
11. Document all medication use since STEMI onset. 
12. Measure body temperature using an independent tympanic 
thermometer.  The independent measurement is to be used in 
addition to the core body temperature collected by the Proteus 
Temperature Probe (X-Probe). 
13. Document all Adverse Events. 

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Phase 
Task 
Initiation of 
Cooling  
14. Document the volume of cold saline, the time the cold saline 
infusion is started and the time the cold saline infusion is finished. 
15. Following the ZOLL Proteus IVTM System Instructions for Use 
(IFU), insert the Proteus Catheter into the Inferior Vena Cava via 
either femoral vein.  The Proteus Catheter is then connected to the 
Cassette that has been inserted into the Proteus Console. 
16. Following insertion of the Proteus Catheter, insert the Proteus 
Temperature Probe (X-Probe). 
Access site selection may vary by both operator preference and 
anatomical considerations; however, the function of the system is not 
dependent on which femoral vein is chosen. 
17. Once the Proteus System Catheter & Proteus Temperature Probe 
(X-Probe) have been inserted, enter set point temperature to 
32.0°C on the Proteus Console and perform cooling at maximum 
power as soon as the console is ready to cool.  
18. Document the time of Proteus Catheter & X-Probe 
(temperature probe) insertion. 
19. Document the time cooling is initiated with the Proteus IVTM 
System. 
20. Document vital signs (BP, HR, RR),  and temperature 
measurements (Tympanic and Proteus Console measurements). 
21. Document all medication use. 
22. Document all adverse events since the time of enrollment. 
23. Use Bair HuggerTM warming blankets for counter-warming. 
If choosing to use low dose anticoagulation during the cooling phase, 
follow hospital’s guidelines for venous thromboembolism 
prophylaxis. 

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Phase 
Task 
Immediately Prior 
to Reperfusion 
24. If clinically relevant shivering (Bedside Shivering Assessment 
Scale (BSAS) of 2 or greater) occurs at 32° (see Anti-Shivering 
Guidelines, Attachment II, and BSAS Attachment III), increase 
the dose of Pethidine (Meperdine) as indicated in shivering 
protocol and increase set point temperature on the Proteus IVTM 
System to 32.5°C. If clinically relevant shivering continues (BSAS 
≥2), once again increase dose of Pethidine as indicated in Anti-
Shivering Protocol and increase set point temperature on the 
Proteus IVTM System to 33°C.  Continue this process until a 
temperature is reached where there is no shivering. Follow 
sedation procedures using Anti-Shivering Guidelines, 
Attachment II, and the BSAS Attachment III. 
25. Perform * angiogram after the induction of hypothermia has been 
initiated and just prior to PCI. 
26. Obtain vital signs (BP, HR, RR), BSAS and temperature 
measurements (Tympanic and Proteus Console 
measurements) just prior to PCI. 
27. Document all medication use since the initiation of cooling. 
28. Document all adverse events since the initiation of cooling. 
CAUTION: Anticipate changes in electrolytes and laboratories 
values secondary to hypothermia. 
29. Document core body temperature at the time of PCI. 
30. If subject has not reached 32.0 ± 1.0°C (or temperature where 
shivering does not occur, as indicated above) at the time of PCI, 
continue cooling induction until target temperature has been 
reached. 
31. Document the time wire crossed the target lesion. 

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Phase 
Task 
Maintenance of 
Hypothermia 
Target 
Temperature 32 
±1°C 
32. Maintain the patient at the set target temperature of 32.0 (or 
temperature where shivering does not occur, as indicated above) 
for 3 hours ± 15 minutes from the initiation of cooling with the 
Proteus System.  
33. Obtain vital signs (BP, HR, RR), BSAS and temperature 
measurements (Tympanic and Proteus Console 
measurements) every 30 minutes during the 3 hours of cooling. 
34. Document all medication use since the angiogram/ PCI procedure. 
35. Document all adverse events since the angiogram/ PCI procedure. 
36. If clinically relevant shivering [Bedside Shivering Assessment 
Scale  (BSAS) of 2 or greater] occurs at 32.0°C (See Anti-
Shivering Guidelines, Attachment II, and BSAS, Attachment 
III), increase dose of Pethidine (Meperidine) as indicated in 
shivering protocol and increase temperature on the Proteus IVTM 
System console to 32.5°C. 
37. If clinically relevant shivering continues (BSAS ≥ 2), once again 
increase dose of Pethidine as indicated in shivering protocol and 
increase temperature on the Proteus IVTM System to 33°C.  
Continue this process until a temperature is reached where there is 
no shivering.  Follow sedation procedures using Anti-Shivering 
Guidelines outlined in Attachment II and BSAS assessment in 
Attachment III. 

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Phase 
Task 
Rewarming 
38. After 3 hours of cooling with the Proteus IVTM System, begin 
active rewarming to normothermia.  Palliative care such as 
blankets, Bair Hugger patient warming systems, and warm liquids 
may be used. 
39. Using the Proteus System Console, press STOP and Increase 
target temperature to 36.0°C using the arrow touch buttons and 
then press Continue.  
40. Set rewarming rate to 1.0°C/hr using the arrow touch buttons and 
press Continue to start rewarming. 
41. Maintain the Pethidine infusion during rewarming using the Anti-
Shivering Protocol outlined in Attachment II. 
42. Obtain blood studies, lab studies and record peak Troponin I or 
Troponin T including upper limit of normal for site. 
43. Document all medication use during the rewarming phase. 
44. Document all adverse events during the rewarming phase.  
CAUTION: Anticipate changes in electrolytes and laboratories 
secondary to re-warming 

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Phase 
Task 
Catheter Removal  
45. Document core body temperature at time of Proteus Catheter 
removal. 
46. Remove Proteus Catheter and X-Probe per IFU and document 
time of removal. 
47. Dispose of the Proteus Catheter, X-Probe and Proteus Cassette per 
institution’s guidelines (single-use). 
48. Assess catheter access site for signs of bleeding, access vessel 
trauma, or hematoma formation. 
 
49. Download temperature data from the Proteus Console after 
the cooling phase has been completed. Send downloaded data 
to amidatadownload@zoll.com immediately upon 
downloading.  Device data must be saved according to Section 
16.1, Investigator Records.  
50. Document all medication use during the hypothermic phase. 
51. Document all adverse events during the hypothermic phase. 
DO NOT DISCARD SPLITTER CABLE (MULTI–USE  
TEMPERATURE CABLE) 
Normothermia 
52. Document all adverse events until patient is discharged from the 
hospital. 
Post-Procedure 
53. If required, provide additional Informed Consent document to 
patients who were consented with the short consent form (if 
required by MEC or country-specific regulations). 
NOTE:  All post-PCI times will be measured from the start of PCI, defined as time the wire 
crosses the target lesion. In the event that PCI is not performed, the time of the first 
cineangiogram of the infarct related artery will be referenced. If PCI is staged for the non-
culprit lesion, then the PCI will be performed after the 4-6 day cMR 
*Angiograms are to be uploaded for all heart failure patients.  
 

 
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6.8.13 Trial Schedule for Test Arm Subjects 
Procedure/ Interval 
Baseline / 
Enrollment 
Initiation 
of Cooling  
Immediately 
prior to 
reperfusion 
(PCI) 
Maintenance 
of Target 
Temp  
32 ±1°C 
Rewarming to 36°C 
Catheter 
Removal 
Discharge 
Follow-Up 
@ 4-6 Days  
Follow-Up 
@ 30 Days 
(±7 days) 
Follow-Up 
@ 12 
months 
(±14 days) 
Unscheduled 
Visit 
Trial Eligibility & Informed 
Consent 
upon 
arrival to 
hospital 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
X 
 
 
 
 
Anti-Shivering Protocol 
X 
 
 
X∞ 
 
 
 
 
 
 
 
Cold Saline Infusion 
 
X 
 
 
 
 
 
 
 
 
 
Catheter Insertion Time 
 
X 
 
 
 
 
 
 
 
 
 
Catheter Removal Time 
 
 
 
 
 
X 
 
 
 
 
 
Temperature Documented 
X 
X 
X 
every 30 min 
during 3 hr 
cooling 
every 60 min 
during 
rewarming 
 
 
 
 
 
 
Temperature Data Download   
 
 
 
 
 
X 
 
 
 
 
 
Vital Signs 
X 
X 
X 
every 30 min 
every 60 minutes 
 
 
 
 
 
 
Blood Studies  
RBC’s, WBC’s, Hct, Hgb, 
Platelets  
X 
 
 
 
X 
upon reaching 
normothermia 
 
 
 
 
 
 
NT-pro BNP 
 
 
 
 
 
 
 
 
 
X 
 
Lab Studies  
BUN, Creatinine, Na, K, Ca, 
Mg, Cl, P, lactic acid, 
glucose, amylase, lipase 
X 
 
 
 
upon reaching 
normothermia 
 
 
 
 
 
 
Any Medication Use 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Troponin I or T(including 
ULN) during hospitalization 
X 
Perform Troponin unitl peak value identified.  
 
 
 
 
 
 
12 lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
SAE only 
X** 
 
Catheter Access Site 
Assessment  
 
 
 
 
 
X 
X 
X 
 
 
 
Cardiac Magnetic Resonance 
(cMR) imaging 
 
 
 
 
 
 
 
X 
 
 
 
NYHA Assessment 
 
 
 
 
 
 
 
 
 
X 
 
KCCQ  
 
 
 
 
 
 
 
 
 
X 
 
∞For persistent clinically relevant shivering (BSAS ≥ 2), increase dose of Pethidine as indicated in shivering protocol and increase temperature on Proteus IVTM System console by 0.5°C.  Continue this process until a temperature is reached where there is 
no shivering.  Follow sedation procedure using Anti-Shivering Guidelines outlined in Attachment II and BSAS assessment in Attachment III Include BSAS measurement and temperatures from independent method. 
**If unscheduled visit occurred within 30 days follow-up, report all AEs. However, if unscheduled visit occurred after 30 days follow-up within 12 months, report only SAEs.

 
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6.8.14 Trial Schedule for Control Arm Subjects 
Procedure/ Interval 
Baseline / Enrollment 
Immediately prior to 
reperfusion 
(PCI)Post-PCI 
Discharge* 
Follow-Up @ 4-6 
Days  
Follow-Up @ 30 
Days 
(±7 days) 
Follow-Up @ 12 months 
(±14 days) 
Unscheduled 
Visit 
Trial Eligibility & Informed Consent 
upon arrival to 
hospital 
 
 
 
 
 
 
Physical Exam 
X 
 
X 
 
 
 
 
Catheter Insertion Time 
X 
 
 
 
 
 
 
Catheter Removal Time 
 
 
 
 
 
 
 
Temperature Documented 
X 
 
 
 
 
 
 
Vital Signs 
X 
 
 
 
 
 
 
Blood Studies  
RBC’s, WBC’s, Hct, Hgb, Platelets 
X 
 
 
 
 
 
 
 
NT-pro BNP 
 
 
 
 
 
X 
 
Lab Studies  
BUN, Creatinine, Na, K, Ca, Mg, Cl, P, 
lactic acid, glucose, amylase, lipase 
X 
 
 
 
 
 
 
 
Any Medication Use 
X 
X 
X 
X 
X 
X 
X 
Troponin I or T(including ULN) 
 X 
Perform 
Troponine until 
peak value 
identified  
 
 
 
 
 
 
12 lead ECG 
X 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
SAE only 
 
Cardiac Magnetic Resonance (cMR) 
 
 
 
X 
 
 
 
NYHA Assessment 
 
 
 
 
 
X 
 
KCCQ  
 
 
 
 
 
X 
 
**If unscheduled visit occurred within 30 days follow-up, report all AEs. However, if unscheduled visit occurred after 30 days follow-up within 12 months, report only SAEs.

 
 
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6.8.15 Control Arm Protocol and Data Collection Time Points 
The data collection schedule for Control Arm subjects is summarized in Section 6.8.14. For 
patients randomized to the Control Arm, i.e., PCI alone, the following procedures will be 
performed: 
i. 
Document time of occurrence of the STEMI & ECG results 
ii. 
Document time of arrival of Emergency Medical Service EMS (Paramedics) & 
time of arrival at hospital 
iii. 
Collect all adverse events as soon as patients are enrolled in the trial 
iv. 
Perform Blood Studies, Labs, and record Baseline and PeakTroponin I or T  
v. 
Perform PCI. If PCI is staged for the non-culprit lesion, then the PCI will be 
performed after the 4-6 day cMR 
vi. 
Monitor and record the patient’s vital signs, temperature, blood pressure, heart 
rate and respiratory rate,  at baseline 
vii. 
Obtain 12-lead baseline ECG  
viii. Monitor and record all pharmacological agents 
ix. 
Measure and record baseline Troponin I or T including upper limit of normal, 
and when a peak is identified. 
x. 
Monitor and record all adverse events for the duration of 30 days follow-up and 
serious adverse events for the duration of 12 month follow-up. 
xi. 
Complete physical exam prior to discharge.  
6.8.16 Follow-up at 4-6 days and at 30 days following the PCI Procedure 
Subjects enrolled in the Test and Control Arms, and Roll-In patients, will undergo Cardiac 
Magnetic Resonance (cMR) to assess infarct size at 4-6 days In addition, the following 
procedures are to be performed at 4 - 6 days and at 30 days after the index procedure (PCI) for 
all patients: 
i. 
Monitor and record all adverse events for the duration of 30 days follow-up. 
ii. 
Review and record all medication changes since index. 
 

 
 
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6.8.17 Follow-up at 12 months following PCI 
Following completion of the 30 day follow-up and, all subjects will be followed through 12 
months for the incidence of Serious Adverse Events, Death and Heart Failure (as assessed by 
NYHA and Kansas City Cardiomyopathy Questionnaire (KCCQ) 
i. 
 Monitor and record all serious adverse events for the duration of 12 month 
follow-up. 
ii. 
Collect NT-pro BNP value to assess clinical prognosis of Heart Failure. 
iii. 
Review and record all medication changes 
iv. 
Perform blinded NYHA Assessmentand administer Kansas City 
Cardiomyopathy Questionnaire (KCCQ). 
6.8.18 Use of other Cooling Methods 
For the purposes of this trial, no other cooling methods may be used. 
6.8.19 Transferring Subject during Cooling 
Although interruption during the induction phase of hypothermia is not recommended, if subject 
transfer is required during any phase of the cooling, follow relevant instructions in the device 
Instructions for Use.   
 
For additional detail, refer to the Proteus IVTM System Instructions for Use. The console screen 
also provides prompts for entry of user-defined parameters and system start-up.  
6.8.20 Patient Withdrawal and Discontinuation 
The term “patient withdrawal” refers to the patient deciding to terminate their participation in the 
trial.  The term “discontinuation” refers to the physician deciding that the patient will not 
continue trial participation as defined below.   
A subject has the right to withdraw from the trial at any time and for any reason without 
prejudice to his or her future medical care by the physician or the institution. Trial withdrawal by 
a subject specifically means withdrawal of consent from further participation in the trial. 
Subjects who withdraw consent after enrollment will be evaluated to the time of withdrawal, and 
withdrawal of consent precludes any further trial related treatment or data collection. If possible, 
a complete, final physical examination should be performed on all subjects who withdraw from 
the trial. At a minimum, every effort should be made to document subject outcome at the time of 
trial withdrawal.   
A subject may withdraw from the clinical investigation for the following reason:  

 
 
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o 
Subjects may choose to withdraw from the clinical investigation under the terms 
of the Declaration of Helsinki and their consent documentation without having to 
give a reason;  
A subject may be discontinued from the clinical investigation for the following reasons: 
o 
Any unanticipated adverse reaction which is, in the opinion of the Investigator, 
related to the treatment and will endanger the well-being of the patient if treatment 
is continued;  
o 
Development of any illness(es), infection or condition(s) that might interfere with 
the Clinical Investigational Plan;  
o 
Non-compliance with the clinical investigation procedures deemed by the 
Investigator to be sufficient to cause discontinuation;  
o 
Any problem deemed by the Investigator to be sufficient to cause discontinuation.  
- Investigator will treat all subjects discontinued from the investigation due to an 
unanticipated adverse reaction, directly related to the investigation, until the reaction 
resolves.  
- Investigator will not replace subjects who have withdrawn from the clinical 
investigation if they have received the investigational device. If possible, Investigator 
will perform any procedures or assessments planned for the subject at the time of 
withdrawal.  
All subjects are expected to continue in the trial through the final follow-up assessment or until 
ZOLL notifies the Investigator in writing that further follow-up is no longer required, except in 
the event of death or upon the subject's request for early withdrawal from the clinical trial.  
6.8.21 Patient Lost to Follow-up  
The investigator will attempt to contact a subject at least three times prior to designating them as 
lost-to-follow-up subjects. The investigator will document the date and type of attempted 
communication. The investigator will complete and sign the Study Exit Form when a subject is 
lost to follow-up.  
6.8.22 Early Termination of a Clinical Investigation 
Both the Sponsor and Investigator reserve the right to terminate the clinical investigation at any 
time. If necessary, and after review and consultation with the Principal Investigator, the Sponsor 
will make a final determination on whether to terminate the study. 
A clinical investigation or Investigator may be terminated at a clinical center for any of the 
following reasons, or for reasons not listed that affect patient safety or integrity of the trial: 

 
 
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• Unsatisfactory rate of patient enrollment or compliance to eligibility criteria. 
• Repeated noncompliance with the investigational plan. 
• Inaccurate, incomplete, and/or untimely submission of data. 
• Inadequate accountability of the investigational device. 
 
The sponsor may terminate this trial if there are new, previously unknown adverse events related 
to device or cooling procedure, deaths, SAEs/AEs exceeding those reported as related to 
device/cooling procedures in previous trials, and/or if recommended by Data Monitoriubg 
Committee (DMC)to stop the trial. The sponsor will make the final determination on whether to 
terminate the study. 
The sponsor may terminate the trial for any other unforeseen circumstances. In case of premature 
termination/suspension, ZOLL will stop the enrollment, inform all investigators at all sites and 
all regulatory agencies governing the study. ZOLL will perform complete device accountability 
of all investigational devices and retrieve them from the clinical sites. All study subjects will be 
followed through the specified follow-up periods. ZOLL will issue a final report of the clinical 
study. 
6.8.23 Amendments and Protocol Deviations 
Investigator will not deviate from the CIP without prior written confirmation by Sponsor, or their 
designee, except as required in a medical emergency. In medical emergencies, Sponsor does not 
require prior confirmation for protocol deviations, but Investigator will notify Sponsor within 5 
days of the incident and will notify the EC according to local requirements. Investigator, or 
designee, will record deviations with an explanation for the deviation. Investigator will report to 
Sponsor who will analyze them and assess their significance.  Significant deviations from the CIP 
will be reported to the Competent Authority. 
 
Examples of protocol deviations may include those relating to: 
• Eligibility 
• Enrollment and randomization 
• Informed consent 
• Protocol adherence (e.g., tests and assessments done as required in Trial Schedule, etc.) 
 
Routine monitoring will assess Investigator compliance to the protocol.  
 
Investigator must not modify the CIP without the prior and written permission from Sponsor. All 
modifications to the clinical protocol must be submitted to the Competent Authority (where 
required) to allow the Competent Authority review and approval.  
 

 
 
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The Sponsor is responsible for management, processing and approval of any amendment to the 
Investigational Plan. Should the site consider an amendment necessary, the Sponsor will work with 
the site to make the appropriate changes. The Sponsor will manage documentation of such changes 
through the existing document control system. A history of changes and a redline version of the 
documentation will be maintained per the applicable quality system procedures. The proposed 
amendment will be submitted to the reviewing MEC and government agency as applicable. Any 
necessary approvals will be received in writing before the requested change is implemented. 
 
This study will be conducted in compliance with ISO 14155, ICH E6 Consolidated Good Clinical 
Practice Guidance, 21 CFR 812, 21 CFR Part 50, and any requirements imposed by countries with 
participating clinical sites. The study will not commence until the necessary government and MEC 
approvals have been obtained. 
6.8.24 Trial Exit 
The Trial Exit Form (CRF) should be completed at the time a subject is exited from the trial.  A 
subject will be considered to have exited from the trial for any of the following reasons. 
• Subject completes follow-ups required by the investigational plan. 
• Subject dies. 
• Subject requests to be withdrawn. 
• Physician requests that patient be withdrawn to protect the welfare of the patient. 
• Patient is lost to follow-up. 
• Other (specify) 
6.8.25 Subject Confidentiality 
Subject confidentiality will be maintained throughout the clinical trial to the extent permitted by 
law.  That is, every attempt will be made to remove patient identifiers from clinical trial documents.  
For this purpose, a unique subject identification code (site number, subject number and subject 
initials) will be assigned and used to allow identification of all data reported for each subject.  This 
will also ensure that the information can be traced back to the source data.  
Trial data may be made available to third parties, e.g., in the case of an audit performed by 
regulatory authorities, provided the data are treated confidentially and that the subject’s privacy is 
guaranteed.  The identity of a subject will never be disclosed in the event that trial data are 
published. 
Security and Unique usernames and passwords will be utilized by data entry, data verification and 
other personnel who have database access to insure confidentiality and protection of data. 

 
 
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Trial sites must comply with Health Insurance Portability and Accountability Act (HIPPA) and/or 
the subject confidentiality provisions and privacy laws of each participating country, local 
regulations, and institutional requirements, whichever is stricter. 
6.8.26 Device Accountability 
ZOLL is responsible for the availability and traceability of all investigational products.  
Documentation is required at each step of the process via a device accountability log.  
Investigational product will be reconciled on a regular basis. 
The investigator also is required to maintain adequate records of the receipt and disposition of all 
investigational devices.  A device accountability log will be provided for this purpose. 
All unused product must be returned to ZOLL prior to the close of the trial. 
6.8.27 Return of Materials upon Trial Termination 
Sponsor will ship investigational devices only to qualified Investigators participating in this 
clinical investigation. Sponsor will not ship investigational devices to any site until evidence of 
EC approval has been provided to Sponsor, or designee.  
Investigator will control access to investigational devices, and will only use investigational devices 
in the clinical investigation and according to the CIP.  
Sponsor will keep investigational device records to document the physical location of each device. 
Record(s) will include information documenting devices shipped, devices at investigation sites, 
devices disposed of, and devices returned.  
Investigator, or designee, will keep records documenting the receipt, use, return and disposal of 
the investigational devices, which will include:  
• Date of receipt,  
• Identification of each investigational device (serial number or unique code),  
• Expiry date, if applicable,  
• Date or dates of use,  
• Subject identification,  
• Date on which the investigational device was returned, or explanted from subject, if 
applicable, and  
• Date of return of unused, expired or malfunctioning investigational devices, if applicable.  
 
After the trial procedures have been completed, all unused devices must be accounted for and 
returned to ZOLL.  Instructions for device return to ZOLL will be reviewed at the site initiation 
visit. 
6.8.28 Trial Closure 
Trial closure can occur under the following circumstances: 

 
 
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a. termination of site participation in the trial (i.e., closure that occurs prior to meeting 
defined endpoints) of the trial 
b. upon completion of the trial (i.e., when all patients enrolled have completed the follow-
up visits or previously exited the trial, and the CRFs and queries have been completed)  
Under any circumstance for closure of the trial at the site, ZOLL and/or its designees will notify 
the site of this occurrence in writing.  Trial closeout visits will be performed once a determination 
has been made that the trial is closed.  All unused trial devices and any unused trial materials and 
equipment will be collected and returned to ZOLL and/or its designees.  The monitors will ensure 
that the investigator’s regulatory files are current and complete and that any outstanding issues 
from previous visits have been resolved.  Other issues that will be reviewed at this visit include:  
discussing record retention requirements (refer to Section 14.1—Investigator Records), device 
accountability, possibility of site audits, publication policy, and notifying the Medical Ethics 
Committee and Competent Authorities of trial closure, etc., as applicable. 
 
Cardiac Magnetic Resonance (cMR) imaging Core Laboratory 
Cardiac Magnetic Resonance (cMR) imaging must be collected per the Manual of Operations 
provided by the sponsor. Images must be submitted to the core laboratory designated by the 
sponsor for analysis. 
7 
ADVERSE EVENTS & DEVICE DEFICIENCIES 
 
Definitions 
7.1.1 Adverse Event (AE) 
 
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in subjects, users or other persons, whether or not related 
to the investigational medical device. 
 
NOTE 1 This definition includes events related to the investigational medical device or the 
comparator. 
NOTE 2 This definition includes events related to the procedures involved. 
NOTE 3 For users or other persons, this definition is restricted to events related to investigational 
medical devices. 
 
7.1.2 Serious Adverse Event (SAE) 
 
Adverse event that:  

 
 
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a) led to a death, injury or permanent impairment to a body structure or a body 
function.  
b) led to a serious deterioration in health of the subject, that either resulted in:  
- a life-threatening illness or injury, or  
- a permanent impairment of a body structure or a body function, or  
- in-patient hospitalization or prolongation of existing hospitalization, or  
- in medical or surgical intervention to prevent life threatening illness  
c) led to foetal distress, foetal death or a congenital abnormality or birth defect.  
NOTE 1: Planned hospitalization for pre-existing condition, or a procedure required by the 
Clinical Investigation Plan, without a serious deterioration in health, is not considered a 
serious adverse event. 
7.1.3 Device Deficiency (DD) 
 
Inadequacy of an investigational medical device related to its identity, quality, durability, 
reliability, safety or performance. This may include malfunctions, use error, or inadequacy in the 
information supplied by the manufacturer. 
 
7.1.4 Adverse Device Effect (ADE) 
 
Adverse event related to the use of an investigational medical device. 
 
NOTE 1- This includes any adverse event resulting from insufficiencies or inadequacies in the 
instructions for use, the deployment, the implantation, the installation, the operation, or any 
malfunction of the investigational medical device. 
NOTE 2- This includes any event that is a result of a use error or intentional abnormal use of the 
investigational medical device. 
 
7.1.5 Serious Adverse Device Effect (SADE) 
 
Adverse device effect that has resulted in any of the consequences characteristic of a serious 
adverse event. 
7.1.6 Unanticipated Serious Adverse Device Effect (USADE) 
Serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report. 
NOTE: Anticipated SADE (ASADE): an effect which by its nature, incidence, severity or outcome 
has been previously identified in the risk analysis report 

 
 
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Adverse Event Reporting 
7.2.1 Adverse Event Reporting from Site to Sponsor and MEC 
The collection of AEs will begin after the informed consent is signed.  All AEs that occur through 
completion of the final follow-up visit, whether observed by the investigator or by the subject, and 
whether or not thought to be device related, will be reported in detail on the appropriate CRF and 
followed to resolution or the end of trial participation. 
The description of the AE will include the date and time of onset, seriousness, relationship to the 
device or procedure, the results of any diagnostic procedures or laboratory tests, any treatment 
recommended, and the outcome of the event.  In the circumstance that an AE has not resolved by 
the time of the subject’s completion of the trial, an explanation will be entered on the appropriate 
CRF. 
ZOLL will implement and maintain a system to ensure that the reporting of the reportable events 
by the investigator to ZOLL occur immediately, but no later than 3 calendar days after 
investigational site study personnel awareness of the event. 
7.2.2 Serious Adverse Event Reporting to Sponsor and MEC 
Serious adverse events (SAEs) and device deficiencies should be reported as soon as possible. 
Serious adverse events and device deficiencies must be reported no later than 3 calendar days 
from the site becoming aware of the event or as per the investigative site’s local requirements 
if the requirement is more stringent than those outlined. 
The date the site staff became aware of the SAE must be recorded in the source document. 
The Investigator will further report the event to the EC according to the institution’s EC 
reporting requirements. 
Serious adverse events that do not occur in the study subject but occur in the user or other 
persons need to be reported on the fax notification form titled SAE Notification Form. 
Serious adverse events that occur in the user or other persons other than the study subject 
should not be entered into the clinical database. 
Serious adverse events should be reported on the SAE Notification Form in the occurrence 
that the clinical database is not available.  This does not replace the electronic clinical 
database.  All information must still be entered in the clinical database once the system is 
back to normal function. 
7.2.3 UADE/USADE Reporting to Sponsor and MEC 
ZOLL requires the Investigator to report any USADE to the sponsor within 3 calendar days 
of the investigator’s knowledge of the event and to the EC per EC requirements. 

 
 
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7.2.4 Sponsor Reporting to National Competent Authorities (NCA) when European 
Sites Participate in the Trial 
7.2.4.1 What to Report 
The following events are considered reportable events: 
- 
any SAE, 
- 
any Device Deficiency that might have led to a SAE if: 
 suitable action had not been taken or 
 intervention had not been made or 
 if circumstances had been less fortunate 
- 
new findings/updates in relation to already reported events. 
7.2.4.2 Report to Whom 
Reportable events must be reported at the same time to all NCAs where the clinical investigation 
has commenced using the summary tabulation featured in the of MEDDEV 2.7/3. 
7.2.4.3 Reporting Timelines 
ZOLL must report to the NCAs where the clinical investigation has commenced: 
- for all reportable events as described in section 7.2.4.1 which indicate an imminent risk of death, 
serious injury, or serious illness and that requires prompt remedial action for other 
patients/subjects, users or other persons or a new finding to it: immediately, but not later than 2 
calendar days after awareness by ZOLL of a new reportable event or of new information in relation 
with an already reported event. 
- any other reportable events as described in section 7.2.4.1 or a new finding/update to it: 
immediately, but not later than 7 calendar days following the date of awareness by the ZOLL of 
the new reportable event or of new information in relation with an already reported event. 
 
Device Relationship 
Determination of whether there is a reasonable possibility that an investigational product or device 
caused or contributed to an AE is to be determined by the Investigator and recorded on the 
appropriate CRF form. Determination should be based on assessment of temporal relationships, 
biologic plausibility, association (or lack of association) with underlying disease and presence (or 
absence) of a more likely cause. 
7.3.1.1 Causality Assessment 
The relationship between the use of the medical device (including the medical - surgical procedure) 
and the occurrence of each adverse event shall be assessed and categorized. 
 
The above considerations apply also to the serious adverse events occurring in the comparison 
group. 
 
The following definitions are used to assess the relationship of the serious adverse event to the 
investigational medical device or procedures. 
 
1) Not related: relationship to the device or procedures can be excluded when: 

 
 
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• the event is not a known side effect of the product category the device belongs to or of 
similar devices and procedures; 
• the event has no temporal relationship with the use of the investigational device or the 
procedures; 
• the serious event does not follow a known response pattern to the medical device (if the 
response pattern is previously known) and is biologically implausible; 
• the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible – and reintroduction of its use (or increase 
of the level of activation/exposure), do not impact on the serious event; 
• the event involves a body-site or an organ not expected to be affected by the device or 
procedure; 
• the serious event can be attributed to another cause (e.g. an underlying or concurrent 
illness/ clinical condition, an effect of another device, drug, treatment or other risk factors); 
• the event does not depend on a false result given by the investigational device used for 
diagnosis, when applicable; 
• harms to the subject are not clearly due to use error; 
• In order to establish the non-relatedness, not all the criteria listed above might be met at 
the same time, depending on the type of device/procedures and the serious event. 
 
2) Unlikely: the relationship with the use of the device seems not relevant and/or the event can be 
reasonably explained by another cause, but additional information may be obtained. 
 
3) Possible the relationship with the use of the investigational device is weak but cannot be ruled 
out completely. Alternative causes are also possible (e.g. an underlying or concurrent illness/ 
clinical condition or/and an effect of another device, drug or treatment). Cases were relatedness 
cannot be assessed or no information has been obtained should also be classified as possible. 
 
4) Probable the relationship with the use of the investigational device seems relevant and/or the 
event cannot reasonably explained by another cause, but additional information may be obtained. 
 
5) Causal relationship: the serious event is associated with the investigational device or with 
procedures beyond reasonable doubt when: 
• the event is a known side effect of the product category the device belongs to or of similar 
devices and procedures; 
• the event has a temporal relationship with investigational device use/application or 
procedures; 
• the event involves a body-site or organ that 
• the investigational device or procedures are applied to; 
• the investigational device or procedures have an effect on; 
• the serious event follows a known response pattern to the medical device (if the response 
pattern is previously known); 

 
 
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• the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible); 
• other possible causes (e.g. an underlying or concurrent illness/ clinical condition or/and an 
effect of another device, drug or treatment) have been adequately ruled out; 
• harm to the subject is due to error in use; 
• the event depends on a false result given by the investigational device used for diagnosis 
17, when applicable; 
• In order to establish the relatedness, not all the criteria listed above might be met at the 
same time, depending on the type of device/procedures and the serious event. 
 
ZOLL and the investigators will distinguish between the serious adverse events related to the 
investigational device and those related to the procedures (any procedure specific to the clinical 
investigation). An adverse event can be related both to procedures and the investigational device. 
Complications of procedures are considered not related if the said procedures would have been 
applied to the patients also in the absence of investigational device use or application. 
 
In some particular cases the event may be not adequately assessed because information is 
insufficient or contradictory or the data cannot be verified or supplemented. The ZOLL and the 
Investigators will make the maximum effort to define and categorize the event and avoid these 
situations.  
 
Particular attention shall be given to the causality evaluation of unanticipated serious adverse 
(device) events. The occurrence of unanticipated events related to the use of the device (USADE) 
could suggest that the clinical investigation places subjects at increased risk of harm than was to 
be expected beforehand. 
 
8 
MONITORING BY DATA MONITORING COMMITTEE 
The Data Monitoring Committee (DMC) is used to ensure safety by reviewing cumulative 
data from the clinical trial at pre-defined intervals for the purpose of safe-guarding the interest 
of trial participants. The DMC will serve in an advisory role in this trial. The composition, 
guiding policies, and operating procedures governing the DMC are described in a separate 
DMC charter. Based on safety data, the DMC may recommend a modification to the protocol 
or that the sponsor stops the clinical trial/investigation. All final decisions regarding clinical 
trial/investigation modifications, however, rest with the Sponsor. 
9 
ADJUDICATION OF EVENTS 
The Clinical Events Committee (CEC) is comprised of qualified physicians who are not 
investigators in the trial.  The Clinical Events Committee is responsible for adjudicating specified 
clinical endpoints based on the specific criteria used for the categorization of clinical events in the 
trial. 

 
 
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Periprocedural MI will be adjudicated according to the Clinically Relevant Myocardial Infarction 
After Coronary Revascularization (CRMI) definition.40 Death, Stent Thrombosis, Spontaneous 
MI, and Revascularization will be adjudicated per ARC definitions.27 
Hospitalization due to Heart Failure will be adjudicated per ACC/AHA definition. 48 
 
The composition, guiding policies, and operating procedures governing the CEC are described in 
a separate CEC Manual of Operations. 
 
When applicable, sites will provide patients’ source documentation per request from the Sponsor 
and will aploade angiograms into AMBRA website through software service Dicom Grid, Inc., 
which will de-identify angiograms. 
 
10 RECOMMENDATION FOR DAPT AND STENTS 
Control and intervention group patients should receive dual antiplatelet therapy (DAPT) and 
anticoagulation medication as recommended by the ESC Guideline for the management of acute 
myocardial infarction in patients presenting with ST-segment elevation. 
• This includes aspirin 162 or 325 mg po chewed as soon as feasible. 
• This should be followed by loading dose of ticagrelor (preferably crushed or 
chewed) 180 mg before PCI. If ticagrelor not available, loading dose of prasugrel 
(60 mg) can be used. 
• Clopidogrel can be used only if the patient cannot take ticagrelor or 
prasugrel. 
• This also includes unfractionateded heparin (UFH) given as an intravenous bolus 
as soon as feasible with subsequent boluses targeted to an activated clotting time of 
200 to 250 seconds. If Bivalirudin is used, the infusion should continue for 1-2 
hours after PCI is finished . 
• Use of an intravenous GP IIb/IIIa inhibitor should be used according to the decision 
of interventional cardiologist. 
• In patients with STEMI in whom clopidogrel was initiated before coronary 
angiography, it is recommended to switch to either ticagrelor or prasugrel before, 
or during, or early after PCI, if ticagrelor or prasugrel are not contraindicated. 
• Switching from clopidogrel to ticagrelor or prasugrel should include a 
loading dose of ticagrelor 180 mg (preferably crushed or chewed if before 

 
 
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or during PCI) or prasugrel 60 mg if the patient is not at high risk of 
bleeding, irrespective of the prior dose of clopidogrel. 
• Recommended maintenance therapy consists of aspirin 81 mg once daily; ticagrelor 
90 mg twice daily for at least 12 months. If ticagrelor not available, prasugrel 5 or 
10 mg according to label recommendation can be used. 
• If needed, transition to clopidogrel can take place after 30 days post index PCI. 
• The recommended first dose of clopidogrel is 600 mg po 12 h after the last 
dose of ticagrelor or prasugrel. If maintenance therapy consists of aspirin 
and clopidogrel, the recommended doses are aspirin per local practice and 
clopidogrel 75 mg once daily. 
• Use second or third generation DES. Do not use BMS or BVS or BRS such 
as Absorb in study patients.  
 
ZOLL will pay for Ticagrelor for first 30 days in countries where it is not reimbursed 
 
11 RISK ANALYSIS 
 Risk Assessment Process 
 
ZOLL has a documented EN ISO 14971:2012 compliant Risk Management process, which 
includes the identification of risks, risk assessment, identification, implementation and verification 
of adequate controls (mitigations) to ensure that identified risks have been reduced as low as 
possible and to ensure the benefits of the intended use as compared to any residual risk is 
acceptable. 
The intent of the Risk Management process is to identify potential hazardous situations related to 
the design, manufacture, and use of the Proteus IVTM System, evaluate each risk and implement 
controls to reduce the risks as low as possible. 
Risks related to the IVTM System and Sub-Systems (Console, Catheter, Cassette and Temperature 
Probe) have been evaluated in a number of ways: 
• Hazard Analysis – The purpose of the Hazards Analysis is to identify, evaluate and 
control potential hazards to the patient, user and the environment. 

 
 
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• Software Hazards Analysis - The Software Hazards Analysis is used to investigate 
potential device Software related hazards and control the potential hazards.  
• Design FMECA - The purpose of the Design FMECA is to evaluate failure modes 
of the device components, or subsystems, to identify potential design failure risk, 
then evaluate and control potential hazards. 
• Process FMECA - The purpose of the Process FMECA is to evaluate failure modes 
of the device manufacturing process steps to identify process failure risks, then 
evaluate and control potential hazards. 
The results of the Proteus IVTM System Risk Management process was reviewed, and concluded 
that the risk controls are effective to reduce the risks as low as possible. The ZOLL Proteus IVTM 
System presents an acceptable risk benefit ratio when used in accordance with its labeling for its 
proposed intended use: The Proteus IVTM System is intended for use in adult subjects with acute 
anterior myocardial infarction to induce and maintain hypothermia prior to percutaneous coronary 
intervention as an adjunctive therapy to reduce anterior infarct size.  
Note: See the Investigator Brochure for additional information on the Proteus IVTM System, as 
applicable. 
 Expected Clinical Observations 
In subjects who have been treated for myocardial infarction, there are many sequelae of such an 
event that may be thought to be “normal” effects and not due to the treatment provided.  These 
events may be outside the range of what is considered to be “normal” (e.g., a high lab value such 
as a shift in potassium), but do not put the patient at risk for harm.  These events are therefore 
expected physiological responses to treatment with therapeutic hypothermia in all patients.  
Prospectively, these observations may include but are not limited to the following: 
• Shift in Potassium levels 
• High or low levels of glucose 
 
The expected clinical sequelae of patients treated with hypothermia include, but are not limited to, 
the following28: 
• Shivering 
• Prolonged ECG intervals 
• Bradycardia defined as a heart rate of 40 beats per minute and not requiring treatment 
(e.g., pacemaker, medications, etc.) 
• J wave (also called Osborne wave) can occur at any temperature < 32.3°C 

 
 
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• Blood electrolyte shifts: Calcium, Phosphorus, Magnesium, Chloride 
• High or low levels of glucose: Decreased insulin sensitivity and insulin secretion 
• Asymptomatic shifts in serum amylase and lipase levels 
• Peripheral pulses may be difficult to detect 
Cold Diuresis: Increased resistance to ADH or Vasopressin resulting in decreased water or solute 
reabsorption. 
 Potential Clinical Risks 
Adverse events that are inherent to a PCI procedure and expected to occur in most subjects for a 
projected duration according to the opinion of the investigator may be considered unavoidable.  
Such events include, but are not limited to, those listed in Table 14.  These adverse events should 
not be reported during this trial. 
Table 14 Expected and unavoidable adverse events related to the PCI procedure 
Description of the Event 
Time Frame from the Index Procedure (PCI) 
Back pain related to laying on Cath-lab table 
Within 48 hours 
Peripheral vasoconstriction  
Within 24 hours 
Thermal discomfort  
Within 24 hours 
Incisional pain (pain at access site) 
Within 72 hours 
Sleep problems or insomnia 
Within 72 hours 
Mild to moderate bruising or ecchymosis 
Within 168 hours 
 
A list of potential (expected) risks that may be associated with use of the Proteus IVTM System is 
provided below.  Since this clinical study utilizes an investigational device, all risks may not be 
known.   However, they are believed to be similar to those associated with the existing intra-
vascular temperature management devices in clinical use or commercially available. 
The following potential adverse events may occur during the course of the clinical trial. 
11.3.1 Potential Adverse Events associated with the Proteus Catheter and Cooling 
System: 
Potential risks related to the Proteus Catheter are reasonably believed to be consistent with the 
common, known risks of central venous catheters and/or venous introducer sheaths.  Potential risks 
related to cooling, re-warming, and/or the Proteus IVTM System include but are not limited to the 
following: 

 
 
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• Catheter related injury [embolism (air, thrombus, catheter fragment), clinically significant 
hematoma, vascular perforation or dissection, arteriovenous fistula, nerve injury, excessive 
bleeding, pseudoaneurysm) 
• Deep vein thrombosis (DVT) requiring treatment 
• Infection [local or systemic (pneumonia, sepsis, meningitis, visceral organ)] 
11.3.2 Potential Adverse Events associated with the cooling procedure include but 
are not limited to the following:   
• Acute renal failure  
• Acute renal insufficiency 
• Adverse drug reaction 
• Angina 
• Blood lysis 
• Congestive Heart Failure  
• Clinically relevant shivering (BSAS ≥ 2) that cannot be controlled by the antishivering 
medication regimen 
• Dysrhythmia [ventricular tachycardia, ventricular fibrillation or atrial fibrillation requiring 
intervention, bradycardia (HR ≤ 40 bpm, block)] 
• Hyperglycemia / Hypoglycemia 
• Hyperkalemia / Hypokalemia 
• Hyperphosphatemia / Hypophosphatemia 
• Hypotension  
• Infection (local, systemic) 
• Liver Failure 
• Myocardial infarction 
• Multi-system organ failure 
• Overcooling (temperature <31.0°C for ≥ 20 continuous minutes) 
• Overwarming (temperature >38°C for ≥ 20 continuous minutes including dehydration, 
burns and neurological damage) 
• Pancreatitis 
• Pulmonary edema  
• Peripheral vascular insufficiency  
• Thrombocytopenia 
• Rebound hyperthermia 
• Respiratory failure during cooling or rewarming 
• Seizures 

 
 
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• Stroke [Cerebral vascular Accident (CVA)] 
• Transient Ischemic Attack (TIA) 
• Unstable angina 
11.3.3 Risks Associated with Anti-shivering Medications 
In order to preserve patient comfort and suppress the shivering response during cooling, a 
combination of recommended buspirone, where available (or equivalent alternative) and required 
Pethidine (Meperidine) should be used (see Attachment II).  As identified in their labeling, the 
risks associated with the use of these pharmacologic agents in this trial population include the 
following:  
Buspirone (or equivalent alternative) 
• Interaction with MAO Inhibitors  
• Dizziness  
• Nausea  
• Headache  
• Nervousness  
• Lightheadedness  
• Excitement 
 
Pethidine (Meperidine) 
• CNS Depression  
• Hypotension  
• Respiratory Depression  
• Circulatory Depression  
• Respiratory Arrest  
• Shock  
• Cardiac Arrest 
 
Other reported reactions:  
• Lightheadedness  
• Dizziness  
• Nausea  
• Vomiting  
• Sweating 

 
 
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 Additional investigations due to the trial 
Participation in the clinical trial will involve extra blood sampling for laboratory markers 
(electrolytes, complete blood count, baseline and peak troponin including upper limit of normal), 
additional ECGs, and the need for cardiac MRI imaging.  All of these are standard clinical 
procedures, and the risks to participants are low.  Sites will be carefully monitored for adherence 
to the protocol.  Patients will be screened for appropriateness for MRI prior to enrollment. 
11.4.1 Delay in PCI through the use of hypothermia therapy 
The probability for potential delay in PCI is considered Occasional.  In prior trials of hypothermia 
for STEMI, the increase in door to balloon time ranged from 9 minutes to 18 minutes.  It is 
noteworthy that this delay was not associated with an increase in infarct size hypothermia patients 
compared to controls.  In fact, patients with anterior STEMI with < 35°C at the time of reperfusion 
showed smaller infart size.  Sites will be trained to incorporate hypothermia into the cath lab 
workflow while minimizing delay.  Feedback will be provided for each case to help maintain 
efficiency. 
11.4.2 Implementation of PCI in patients undergoing hypothermia (patient-related 
risks). 
Potential risks related to the use of hypothermia therapy in patients are outlined in sections  11.2.1 
and 11.2.2 above. These risks include: potential adverse events associated with the Proteus 
Catheter and Cooling System, potential adverse events associated with cooling, and potential risks 
associated with the anti-shivering medications. 
11.4.3 Implementation of PCI with concurrent use of endovascular hypothermia. 
The addition of hypothermia as adjunctive treatment of STEMI will potentially lead to more 
difficult conditions for the Investigator and other users.  The ability to integrate hypothermia into 
the cath lab workflow has been demonstrated successfully in prior clinical trials.  Again, thorough 
training, frequent monitoring, and rapid feedback will help mitigate the challenges of incorporating 
hypothermia into treatment for STEMI. 
11.4.4 The concurrent medication. 
Patients who have received medications such as monoamine oxidase inhibitor within a 14 day 
period will be excluded from the trial to prevent potential interaction with the anti-shivering 
medications.  In patients that receive morphine prior to arrival to the hospital, the pethidine dose 
will be lowered to decrease the likelihood of respiratory depression. 

 
 
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11.4.5 The supply of 4°C cooled saline solution 
The amount of cooled saline solution is limited to 1,000 ml, an amount shown to be well tolerated 
in the CHILL-MI trial, where the average amount of cooled saline was 1475 ml.  Again, careful 
training and monitoring will help to avoid unnecessary exposure to larger volumes of saline. 
11.4.6 Other procedures within the clinical trial 
The risk of adverse interaction or influence of other procedures within the clinical trial are deemed 
to be low.  In prior hypothermia trials in STEMI, there was no interference with the stenting 
procedure, with resuscitation efforts for arrhythmias or cardiogenic shock.  Hypothermia does 
inhibit the absorption and metabolism of clopidogrel, a anti-platelet inhibitor, given to reduce the 
risk of stent thrombosis.  This risk will be mitigated by calling for adherence to ESC guidelines 
which recommend either prasugrel or ticagrelor, both of which are less affected by hypothermia. 
 Potential Clinical Benefits 
Although no assurances or guarantees can be made, there is a reasonable expectation that the use 
of this investigational device is safe within the context of the trial and may be beneficial.  Cooling 
using the device, for instance, may result in improved temperature control relative to the standard 
techniques already in use at the sites. 
The primary benefits of therapeutic hypothermia have been shown to be:  
• Improved patient survival 
• Improved heart tissue salvage after the ischemic event 
Additional potential benefits of therapeutic hypothermia with the Proteus System may include: 
• Faster cooling 
• More accurate control of the cooling procedure than with surface cooling 
• Further improved survival  
There is no guarantee that participation in this trial or use of hypothermia will benefit the trial 
subject.  However, collection of such trial data may provide added benefit for future myocardial 
infarction subjects. 
 Methods to Minimize Risk 
All efforts will be made to minimize risks by selecting investigators who are experienced and 
skilled in using minimally invasive catheter-based cardiovascular interventions and who have been 
adequately trained.  Also, risk minimization activities were performed during development and 
design verification tests of the device.  Activities intended to minimize risks include the following. 

 
 
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• Investigator and trial personnel training will be conducted to share information regarding 
the design of the Proteus IVTM System, its application, pre-clinical results, and clinical 
trials on comparable intra-vascular cooling devices. 
• Adherence to eligibility criteria and screening procedures will ensure that appropriate 
patients are enrolled.   
• Adherence to the Proteus IVTM System Instructions for Use packaged with the device.  
• 
Corrective and preventative actions will be implemented by ZOLL, as necessary, if 
deviations from recommendations in the protocol or IFU are observed.  
• 
Clinical support by ZOLL representative will be provided during the enrollment in the 
study and thereafter if needed.  ZOLL representatives will only have advisory role.  
• The subjects will be carefully monitored throughout the trial period.   
• The investigator will evaluate the subject adverse events during the course of the trial. 
• Data submitted from the investigative centers will be monitored during the course of the 
trial.   
• Monitoring visits will be conducted to evaluate protocol compliance and data quality. 
• Safety and effectiveness data obtained during the course of the trial will be shared with 
investigators in periodic reports to increase understanding of the device and potential 
adverse events. 
• An independent Data Safety Monitoring Board (DSMB) will monitor safety throughout the 
clinical trial. Stopping rules will be discussed with the DSMB and applied for subject safety 
through enrollment. 
 
Detailed trial procedures are provided in Section 6.8 - Clinical Trial Procedures. 
 Risk – Benefit Assessment 
To date, there have been five clinical trials that have reported on the safety and effectiveness of 
therapeutic hypothermia in AMI and one in Radio-Contrast nephropathy (COOL-RCN Trial), with 
a total of more than eleven hundred patients being enrolled in total with at least half of those treated 
with therapeutic hypothermia.  The rate of adverse events are well reported in these populations 
(see section 5, Prior Investigations), and the risks are clearly categorized for these trials.  In 
summary, the number of trials, patients enrolled, and low numbers of safety events reported 
indicate that therapeutic hypothermia in this patient population is at an acceptable risk level to 
engage in this trial. 
There is significant morbidity and mortality associated with the numerous clinical conditions 
outlined in this report, and therapeutic hypothermia has shown promise to greatly improve clinical 
outcomes in these patients.  In particular, patients with anterior STEMI have a higher incidence of 
congestive heart failure, cardiogenic shock, and cardiac mortality.  A significant reduction in 

 
 
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infarct size in these patients, with therapeutic hypothermia, has the promise to reduce these adverse 
clinical outcomes.  Risks associated with the use of the Proteus IVTM system have been reduced 
via the Risk Management Process, and are deemed acceptable, considering the potential benefits.  
We conclude that the use of the Proteus IVTM system for medical practice is justified and 
warranted. 
 
Risk assessment of the Proteus IVTM System has been performed in accordance with the ISO 
14971:2012.306  The Proteus IVTM System is safe and presents an acceptable risk benefit ratio to 
provide cooling or warming of patients when: 
• Used by and under the supervision of a qualified medical practitioner 
• In patients for whom the risks of a central line are acceptable 
• In intensive care environments equipped to handle clinical conditions warranting 
use of the device under this protocol 
• Used according to the Instructions For Use (IFU) 
12 RECORDS AND REPORTS 
Throughout the course of this clinical trial, ZOLL, the investigators, and reviewing MEC are 
responsible for the records and reports detailed in the following sections.  
 Investigator Records 
Investigators must retain all trial records required by ZOLL and by the applicable regulations in a 
secure and safe facility.  The investigator must consult a ZOLL representative before disposal of 
any trial records and must notify ZOLL of any change in the location, disposition, or custody of 
the trial files. 
Trial records are those that individually and collectively permit evaluation of the conduct of the 
trial and the quality of the data produced.  ZOLL’s SOP requires that all clinical trial data be kept 
for a minimum of 15 years and all data used in submissions be kept for the life of the corporation.  
It is the site’s obligation to inform ZOLL if their own policy does not comply with the sponsor’s 
requirement so necessary arrangements can be negotiated.  It is ZOLL’s responsibility to inform 
the investigator/institution as to when these documents no longer need to be retained. 
The investigator is responsible for the preparation (review and signature) and retention of the 
records cited below. 
• All correspondence with another investigator, MEC, ZOLL, a monitor, or FDA, including 
required reports and trial documents which pertain to the investigation. 

 
 
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• Records of receipt, use, and final disposition of a device.    
• Records of each subject's case history and exposure to the device.  Case histories include 
the Case Report Forms (CRFs) and supporting source data (signed and dated informed 
consent forms, medical records, e.g., progress notes of the physician, patient’s hospital 
chart, nursing notes).   
• The clinical investigational plan, with documents showing the dates of and reasons for each 
deviation from the protocol.  
• Any other records that are required to be maintained by local regulations or by specific 
regulatory requirements for a category of investigations or a particular investigation. 
• Any other record that the reviewing MEC requires to be maintained for the subject 
investigation. 
 Investigator Responsibilities 
The participating investigator is responsible for adhering to this Clinical Investigational Plan 
(CIP), FDA CFR,  ISO 14155 and Declaration of Helsinki  (Regulatory requirements of his/her 
country local law). 
Specifically, the Principal Investigator at each site shall: 
a) indicate his/her acceptance of the CIP in writing, 
b) conduct the clinical investigation in compliance with the CIP, 
c) create and maintain source documents throughout the clinical investigation and make 
them available as requested during monitoring visits or audits, 
d) ensure that the investigational device is used solely by authorized users as specified in 
6.2, and in accordance with the CIP and instructions for use, 
e) propose to the sponsor any appropriate modification(s) of the CIP or investigational 
device or of the use of the investigational device, 
f) refrain from implementing any modifications to the CIP without agreement from the 
sponsor, EC and regulatory authorities, if required, 
g) document and explain any deviation from the approved CIP that occurred during the 
course of the clinical investigation, 
h) ensure that an adequate investigation site team and facilities exist and are maintained 
and documented during the clinical investigation, 
i) ensure that maintenance and calibration of the equipment relevant for the assessment of 
the clinical investigation is appropriately performed and documented, where applicable, 
j) ensure the accuracy, completeness, legibility and timeliness of the data reported to the 
sponsor in the CRFs and in all required reports, 
k) maintain the device accountability records, 
l) allow and support the sponsor to perform monitoring and auditing activities, 

 
 
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m) be accessible to the monitor and respond to questions during monitoring visits, 
n) allow and support regulatory authorities and the EC when performing auditing activities, 
o) ensure that all clinical-investigation-related records are retained as required by the 
applicable regulatory requirement(s), and 
p) sign the clinical investigation report, where applicable. 
 
The investigator is responsible for the preparation and submission of the reports cited in Table 15.  
Reports must be prepared in complete, accurate and timely manner.  These reports may be subject 
to regulatory inspection (and ZOLL) and copying, and the retention requirements described above 
for Investigator Records.  In addition to the reports listed in Table 15, the reviewing MEC may 
request reports pertaining to any aspect of the clinical trial. 
Written approval from the Medical Ethics Committee (MEC) with authority for the participating 
site will be obtained prior to the start of the study. The investigator or if applicable, the Sponsor, 
is responsible for submitting all required documents to the MEC. At a minimum the following 
documents will be submitted: 
• Clinical Investigational Plan (CIP) 
• Patient Informed Consent documents in the local language 
• Any other written information to be provided to the subjects in the local language 
• Investigator Brochure (IB) (as required) 
• Other documents will be submitted as per local requirements 
After obtaining MEC approval, the investigator will submit the approval letter indicating the 
approved version of the CIP, Patient Informed Consent, IB and any other reviewed documentation 
to ZOLL. 
 
 

 
 
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Table 15 Investigator Reporting Responsibilities to Sponsor and MEC 
REPORT 
SUBMIT TO 
DESCRIPTION/CONSTRAINTS 
Withdrawal of 
MEC Approval 
Sponsor 
The investigator must report a withdrawal of the reviewing 
authority within 5 working days.  
Case Report Form  
(CRF)  
Sponsor & 
Monitor 
CRFs should be completed as soon as possible after any trial 
related procedure takes place. 
Deviation from 
Investigation Plan 
(Emergency) 
Sponsor & 
MEC 
Notification must be made within 5 working days if the 
deviation was made to protect the life or physical well-being of 
a subject. 
Deviation from 
Investigation Plan 
(Other – Non 
Emergency) 
Sponsor & 
MEC 
If the deviation may affect the scientific soundness of the plan 
or the rights, safety and welfare of the subjects (and is not an 
emergency), then the deviation must be approved by ZOLL, 
the MEC, and the reviewing authority prior to its 
implementation.  If the deviation does not affect these issues 
(trial soundness, rights, safety, etc.) then only ZOLL must 
approve it, (except in cases which are beyond the control of the 
investigator—see section on Protocol Deviations). 
Failure to Obtain 
Informed Consent 
Sponsor & 
MEC 
The Investigator must notify ZOLL and the reviewing authority 
within 5 working days after device use. The investigator must 
submit notification after device use or after the investigator 
first learns of the absence of informed consent. The report must 
include a brief description of the circumstances surrounding the 
failure to obtain informed consent and include written 
concurrence by a licensed physician not involved in the 
investigation. Failure to obtain informed consent must be 
reported to the MEC as required by local regulations. 
Final Report 
Sponsor & 
MEC 
This report must be submitted within 3 months after 
termination or completion of the investigation. 
 
 Sponsor Records  
All Sponsor documents and records shall be maintained as indicated by ZOLL’s Quality System. 
ZOLL will maintain the following trial -related records in accordance with ZOLL record retention 
policies and procedures following the completion of this investigational plan. Clinical data for 
regulatory submissions and publications will be retained for the life of the corporation. 
• All correspondence pertaining to the investigation with the sponsor, a monitor, an 
investigator, an MEC, regulatory agencies, including required reports.    
• Records of shipment and disposition of the investigational device.  

 
 
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• Signed investigator agreements including the financial disclosure information required to 
be collected and current signed and dated curriculum vitae.  
• Records of adverse events and device deficiencies.  
• List of participating institutions 
• Investigational product accountability reports including record of receipt, use, or 
disposition of the device(s) that relate to type, quantity, serial numbers of devices, and date 
of receipt, names of persons who received, used, or disposed of each device and why and 
how many devices have been returned to ZOLL or otherwise disposed 
• All signed and dated case report forms submitted by investigator, samples of patient 
informed consents, and other information provided to the subjects 
• Copies of all MEC approval letters and relevant MEC correspondence 
• Names and evidence of the institutions in which the clinical investigation will be conducted 
• Insurance certificates 
• Forms for reporting adverse events and device deficiencies  
• Names/contact addresses of monitors 
• Statistical analyses and underlying supporting data 
• Final report of the clinical investigation 
• The Clinical Investigational Plan, Clinical Monitoring  Plan (CMP), Investigator Brochure 
(as applicable), and study related reports 
• Study training records for center personnel and ZOLL personnel participating in the trial 
• Any other records that MEC and /or competent authority requires to be maintained by 
regulation or by specific requirement for a category of investigation or a particular 
investigation. 
 Sponsor Reports 
ZOLL Circulation, Inc. is responsible for the classification and reporting of reportable adverse 
events and device deficiencies and ongoing safety evaluation of the clinical investigation in line 
with local regulatory requirements. 
ZOLL Circulation, Inc. will assure that all Serious Adverse Events and reportable Device 
Deficiencies are reported to the Competent Authorities in accordance with European Medical 
Devices directives and all applicable national regulations. 
ZOLL Circulation, Inc. is responsible for the reports cited in Table 16.  These reports are subject 
to regulatory retention and inspection requirements.  Governing Regulatory Agencies or the 
reviewing MEC may request reports pertaining to any aspect of the clinical trial. 

 
 
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Table 16:  ZOLL Reporting Responsibilities 
REPORT 
SUBMIT TO 
DESCRIPTION 
Unanticipated 
Adverse Device 
Effects; SAEs and 
Reportable DDs 
Relevant 
authorities and 
MECs 
Reporting timeframe as per local regulatory 
requirements. 
Investigators 
Notification throughout the course of the trial 
when appropriate (based on perceived risk) 
Premature 
termination or 
suspension of the 
Clinical 
investigation 
Investigators, 
MECs, Relevant 
Authorities 
Provide prompt notification of termination or 
suspension and reason(s). 
Subject 
enrollment 
Completed 
Investigators, 
MEC and 
Relevant 
regulatory 
Authorities upon 
request 
ZOLL will notify the investigators within 30 
working days of the completion of 
enrollment. Investigators will, in turn, inform 
their MECs, when required. 
Withdrawal of 
MEC approval 
Investigators, 
MECs 
Notification within five working days. 
Final Report 
Investigators, 
MECs, (and other 
relevant 
Authorities upon 
request) 
A final report will be submitted to 
investigators, and MECs within six months 
after completion or termination of this study. 
The investigators shall have the opportunity 
to review and comment on the final report. If 
a clinical investigator does not agree with the 
final report, his/her comments shall be 
communicated to the other investigators. The 
principal clinical investigator in each center 
shall sign the report. 
13 MONITORING AND AUDITING PROCEDURES 
 Clinical Trial Sponsor and Monitors 
ZOLL is the Sponsor of the clinical trial.  It is the responsibility of the sponsor to ensure that proper 
monitoring of the investigation is conducted.  Clinical trial monitoring and auditing will be done 

 
 
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by appropriately trained personnel appointed by the trial sponsor to ensure that the investigation 
is conducted in accordance with ZOLL’s requirements and applicable laws and regulations. 
A monitor is an individual designated by a sponsor or contract research organization to oversee 
the progress of an investigation.  The monitor may be an employee of a sponsor or a consultant to 
the sponsor, or an employee of or consultant to a contract research organization.  The monitor will 
be trained on the device, investigational plan, informed consent, instructions for use, applicable 
ZOLL procedures, electronic data capture system, and regulatory requirements.  The monitor will 
periodically check and report on the progress of the clinical trial at an investigational site or other 
data gathering organization or ZOLL facility.   
 Monitoring Methods 
Monitoring of the clinical trial will be a continuous, interactive process to ensure that high-quality 
data is obtained in compliance with the clinical investigational plan and regulatory requirements.  
Monitoring functions will be conducted by ZOLL, and/ or a contract research organization and/or 
other designees. Specific monitoring requirements are detailed in the Trial Monitoring Plan 
(maintained in the ZOLL COOL-AMI clinical trial project files).  Frequent communication will 
be maintained with each investigational site to keep both the clinical center and ZOLL up-to-date 
and aware of the trial progress.  Case Report Forms will be reviewed for completeness and 
accuracy.   
ZOLL will monitor sites in accordance with the monitor’s tasks set under Section 8.2.4 of Standard 
DIN EN ISO 14155:2012-01. These include visits to the clinical trial sites before the start of, 
during and at the end of the clinical trial. On-site monitoring of all trial centers will be frequent 
enough (at a minimum annually) to assure continued integrity and acceptability of the data.  
Accuracy of data reported on case report forms will be verified by comparison to source 
documents.  Reports of monitoring visits will be provided to the clinical trial personnel at each 
site.  Corrective action will be taken to resolve any issues of noncompliance.  If ZOLL finds that 
an investigator is not complying with the executed trial agreements, the investigational plan, the 
applicable national regulations, or the requirements of the reviewing MEC, then prompt action will 
be taken to secure compliance.  In addition, shipment of the device may be stopped or the 
participation of the investigator may be terminated.  Additional information is provided in Section 
6.30 – Trial Closure. 
 Monitoring Visits 
Scheduled visits to the clinical investigational site will occur at the following times:  prior to the 
start of the clinical trial (pre- trial qualification visit), at initiation of the trial (during first index 

 
 
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procedure or shortly thereafter), interim visits throughout the clinical trial as required, annually, 
and upon completion of the clinical trial. 
 Pre-trial Qualification Visit 
A pre- trial visit will be conducted by ZOLL personnel (or designees) to review the clinical 
investigational plan and regulatory requirements with the investigator and the trial personnel to 
assure that they:  
• Understand the investigational status of the device and the requirements for its use and 
accountability. 
• Understand the clinical investigational plan. 
• Understand the requirements for an adequate and well-controlled clinical trial. 
• Understand and accept the obligation to conduct the clinical investigation in accordance 
with the national regulations. 
• Understand and accept the obligation to obtain informed consent in accordance with the 
national regulations. 
• Understand and accept the obligation to obtain MEC approval before the clinical trial is 
initiated, ensure continuing review of the trial by the MEC, and keep ZOLL informed of 
MEC approval and actions concerning the clinical trial. 
• Have access to an adequate number of eligible patients to participate in the trial (at a 
minimum: 1 patient/center/month). 
• Have adequate facilities and resources to conduct the trial.  This includes resources 
appropriate for use of electronic data capture systems. 
• Have sufficient time from other obligations to carry out the responsibilities of the clinical 
trial. 
• Sign the Investigator Agreement and trial contracts (prior to enrollment of patients). 
A report of the pre- trial qualification visit will be completed.  Resolution of any concerns or 
completion of any appropriate follow-up activities stemming from the pre- trial visit also will be 
documented. 
 Initiation Visit 
ZOLL clinical personnel (or designees) will provide assistance for both technical concerns and 
trial management issues during the initiation visit.  Enrollment of the first patient at each clinical 
site may or may not coincide with this visit.  Any observations will be documented and issues 
requiring follow-up will be identified on a monitoring report.  Training of trial personnel also will 
be documented. 

 
 
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 On-Site Interim Monitoring Visits 
On-site monitoring visits will be made on an as-required basis (and at least annually) to assess 
adherence to the clinical investigation plan, MEC review of trial progress, maintenance of records 
and reports, and selected review of source documents for accuracy, completeness, legibility, and 
omissions.  The monitors will acquire information to assess the progress of the trial (toward 
meeting trial objective) and identify any concerns that stem from observation of device 
performance and/or review of the investigator's patient records, trial management documents, and 
patient informed consent documents.  Monitoring reports will be generated along with 
communications to the investigator, which document the result of the monitoring visit and any 
recommended actions.  Resolution of concerns and completion of assigned tasks will be 
documented. 
 Audits 
An on-site audit may be completed periodically throughout the trial at each clinical site by an 
independent group.  The purpose of the audit will be to ensure compliance to the investigational 
plan and regulatory requirements, e.g., written informed consent was documented, information 
recorded on the case report forms is complete and accurate as compared to source documentation, 
protocol deviations are noted, and device accountability is accurate and complete.  A randomly 
selected number of patient records and other supporting documents will be compared to the case 
report forms.  A record of the findings and recommended actions to correct deficiencies will be 
documented on the audit report. 
 Final Monitoring Review 
Depending upon the status of the trial at each center, a close-out or final visit may be conducted.  
Any ongoing responsibilities will be discussed with the investigator and the trial center 
coordinator.  A final monitoring report, which includes, at a minimum, disposition of any unused 
devices, will be completed. 
14 DATA MANAGEMENT PROCEDURES 
 
ZOLL will oversee all data management functions.  ZOLL will be responsible for database 
development, system maintenance, user training, data queries, and report generation. 
 Case Report Forms 
ZOLL will use an electronic data capture (EDC) system to collect patient data.  The electronic case 
report forms (eCRFs) are the primary component of EDC and are based on the sample forms that 

 
 
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will be provided in a separate document.  Training on use of the system will be provided to the 
trial site personnel.  Instructions for completion of the eCRFs also will be provided. 
The eCRFs must be completed, saved, and locked via electronic signature by the Investigator using 
a unique ID and password.  This ID and password are for the use of the investigator only and may 
not be used by any other person.  Because of the potential for errors or inaccuracies in transcribing 
data into eCRFs, source documentation must be maintained in each subject’s hospital chart and/or 
electronic medical record.  The eCRFs and source documentation must be available at all times for 
inspection by the trial monitors or regulatory inspectors. 
Changes made to eCRFs will be electronically recorded in a complete audit trail that cannot be 
changed, but can be accessed by authorized personnel at any time.  All data are transmitted via the 
Internet in an encrypted fashion.  When received at the server site, the data are decrypted and 
stored.  Data can be extracted for ZOLL review and analysis at any time. 
 Source Documentation 
Regulations require that an investigator maintain information in the trial subject’s medical records 
to corroborate data collected on the eCRF.  To comply with these regulatory requirements, the 
following information will be maintained and made available as required by ZOLL and/or its 
designees and/or regulatory inspectors.  Shadow charts are not appropriate or adequate source 
documentation.  Complete medical (clinical and hospital) records include the following 
documentation.   
• Medical history/physical condition of the patient before involvement in the trial sufficient 
to verify clinical protocol eligibility criteria. 
• Description of cooling procedure (material used, drugs administered during the procedure, 
device identification information and disposition, date, time, angiographic and clinical 
findings, etc.).  
• Electronic data downloaded from the ZOLL Proteus IVTM System. 
• Signed notes in the subject’s medical record on the enrollment day that identify and 
include:  the subject’s date of enrollment, procedure date, the trial sponsor (ZOLL), clinical 
site name, the subject-assigned identification number, the subject- assigned enrollment 
number, and documentation and confirmation that the appropriate informed consent was 
obtained. 
• Dated and signed notes for each subject’s trial visit. 
• Lab results.   
• Baseline ECG, angiogram, and MRI reports, etc.   
• Dated printouts or reports of special assessments (ECG baseline report, imaging report, 
etc.). 

 
 
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• Adverse event reporting and follow-up of the adverse events.  Information in the medical 
chart should include at a minimum the following:  event description, severity, seriousness, 
onset date, date site became aware of event, duration, relation to trial device, treatment, 
and outcome of the adverse event. 
• Trial subject’s condition upon completion of or withdrawal from the trial. 
• Trial subject’s medical status, including all SAEs out to 1 year following trial enrollment. 
• All notes related to trial subject’s KCCQ and the New York Heart Association Functional 
Class questionnaires. 
 Transmission of Data 
Required data will be recorded on the appropriate eCRF at the time of or as soon as possible after 
the patient visit.  The eCRFs and any requested supporting source documents must be sent to ZOLL 
and/or retrieved from the investigator during monitoring visits.  Questions about completion of the 
eCRFs may be directed to the ZOLL COOL AMI clinical team at Clin-safety@zoll.com 
 Data Queries  
During monitoring visits, the Monitor will perform a 100% review of all variables, i.e., 
demography, inclusion/exclusion criteria, safety, effectiveness, on the eCRFs with each subject’s 
source documents. Any discrepancies will be queried by ZOLL or its designee and must be 
resolved by the investigational site staff and investigator in a timely manner.  Queries also will be 
generated by ZOLL data management personnel during routine review of the data on the electronic 
data capture system. 
15 STATISTICAL ANALYSIS PLAN 
The objective of this trial is to evaluate the safety and effectiveness of therapeutic hypothermia, 
using the ZOLL Proteus IVTM System, as an adjunctive therapy for patients presenting with acute 
anterior myocardial infarction (AMI) and undergoing percutaneous coronary intervention (PCI). 
An analysis summarizing outcomes for the Primary Effectiveness Endpoint and the Primary Safety 
Endpoint will be created after the last randomized subject has completed the 30 day follow-up 
interval. The results of the primary endpoints will be summarized in the final clinical study report. 
Two interim analyses are planned to be performed at approximately 50% and 75% of 
randomization, once subjects have completed 4-6 day cMR follow-up. At the interim stage, the 
trial will be stopped to reject the null hypothesis of no difference or continue enrolling. Another 
report will be issued summarizing all endpoints after all subjects have completed 12 month follow-
up. 

 
 
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 Data Analysis 
Analysis Data Sets 
The Intention-to-Treat (ITT) analysis set will be used for primary statistical analyses and 
summaries. The ITT population includes subjects who have signed an informed consent and have 
been randomized to the Test Arm or the Control Arm of the trial. ITT subjects will be evaluated 
according to the group to which they were randomized. 
The Per-Protocol (PP) analysis set will also be evaluated. The PP population includes those 
subjects who met inclusion and exclusion criteria, were randomized to either the Test or Control 
arm, received the treatment to which they were randomized, and complied substantially with the 
treatment timeline and steps of this protocol without major protocol violations. 
The Safety Analysis Set will be used to evaluate safety endpoints. These will be all of the subjects 
included in the study as defined by the ITT analysis set and will include Roll-In subjects. For the 
safety analysis, subjects will be followed for all adverse events for 30 days post procedure. 
Additionally, all subjects will be followed for 12 months for the incidence of  Serious Adverse 
Events (SAEs), Death and Heart Failure (as assessed by NYHA and Kansas City Cardiomyopathy 
Questionnaire (KCCQ). 
Infarction Size (IS) is defined as % Left Ventricular Mass as measured by Cardiac Magnetic 
Resonance (cMR) imaging. Infarct Size (IS) will be assessed by Cardiac Magnetic Resonance 
(cMR) at 4 – 6 days following the index procedure. Infarct Size will be assessed in subjects in the 
ITT analysis set and also in the Per-Protocol analysis set. 
 
The Safety Analysis Set will be used to evaluate safety endpoints. These will be all of the subjects 
included in the study as defined by the ITT analysis set and will include the following clinical 
components evaluated at 30 day follow-up visit (30 day ± 7 days): 
Secondary Endpoint Analysis: 
The following clinical components of MACE will be evaluated at 30 day follow-up visit (30 day 
± 7 days): 
o Death (Cardiac, Vascular, Non-Cardiovascular) 
o Myocardial Infarction (MI) 
 Attributable to target vessel (TV-MI) 
 Not attributable to target vessel (NTV-MI) 
o Target Lesion Revascularization (TLR) 

 
 
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 Clinically-indicated TLR (CI-TLR) 
 Not clinically-indicated TLR (NCI-TLR) 
o Target Vessel Revascularization (TVR non TLR,) 
 Clinically-indicated TVR non TLR 
 Not clinically-indicated TVR non TLR 
o Non-Target Vessel Revascularization (NTVR,) 
 Clinically-indicated NTVR 
 Not clinically-indicated NTVR 
o All coronary revascularization 
In addition, Stent Thrombosis will be evaluated at 30 day follow-up visit (30 day ± 7 days): 
 
o Evidence (Definite and Probable) 
 Timing (Acute, Sub-acute) 
Additional Observational and Descriptive Analysis:  
In addition to the secondary endpoint, safety of the trial is also analysed by the following 
observational and descriptive analysis.  These events are not endpoints for the study: 
o the following serious adverse events will be evaluated at 30 day follow-up visit (30 day 
± 7 days): 
 Stroke 
 Cardiogenic shock 
 Pulmonary embolism 
 Pulmonary edema 
 Atrial fibrillation 
 Ventricular fibrillation 
 Vascular complications requiring intervention 
 Bleeding requiring transfusion of 2 units or greater 
 Cooling catheter access site infection 
 Systemic infection 
 Deep Venous Thrombosis (DVT) 
 Bradycardia 
 Hypotension 
o The following serious adverse events will be evaluated at 12 month follow-up visit (12 
month ± 14 days): 
 Death (Cardiac, Vascular, Non-Cardiovascular) 
 Stent Thrombosis 
• Timing (Acute, Sub-acute) 
• Evidence (Definite and Probable) 

 
 
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 Hospitalizations due to Heart Failure 
 Statistical Methods 
Baseline demographic and clinical characteristics will be summarized for each arm using 
descriptive statistics. Continuous variables will be reported with mean, standard deviation, median, 
and range. Discrete variables will be reported as frequency and proportion. A χ2 test or Fisher 
exact test (for small frequencies) will be used to compare discrete variables; t-test or Wilcoxon test 
(for non-normal data) will be used to compare the 2 arms with continuous variables for randomized 
subjects in the trial. 
 
The primary effectiveness endpoint is to detect a 20% reduction of mean infarct size in the Test 
Arm compared to Control Arm where infarct size (%LV Mass) is measured by cMR at 4-6 days. 
The mean, median, standard deviation, and range will be presented for infarct size. A two sample 
t-test will be used to test the null-hypothesis of no difference in average infarct size test and control 
arm P-value will be reported with p<0.05 considered statistically significant. Infarct size will 
further be evaluated in subgroups and with ANOVA models. 
 
For the primary safety endpoint of MACE (as defined by CD, All MI, and CI-TLR) at 30 days, all 
events will be tabulated and reported. Per-patient rate of composite MACE will be compared 
between the two arms with 1-sided Fisher’s exact test. 
Two interim analyses are planned to be performed at approximately 50% and 75% of 
randomization, once subjects have completed 4-6 day cMR follow-up. At the interim stage, the 
trial will be stopped to reject the null hypothesis of no difference or will continue enrolling. Based 
on the Lan-DeMets method for group sequential trials using O’Brien-Fleming boundaries, the 
levels of significance for the interim analyses are alpha=0.00305 (50% information fraction), 
alpha=0.01832 (75% information fraction), and alpha=0.044 (final analysis).  
All analyses for effectiveness will be conducted in intent-to-treat and per-protocol analyses set. 
All analyses for safety will be conducted in the safety dataset. Imputation will be made for missing 
infarct size (LV%) in intent-to-treat analyses set per Intention-to-Treat principle; details are 
described in the Statistical Analysis Plan. 
 Sample Size Justification  
The primary effectiveness analyses is designed to detect a relative reduction of 20% in mean 
anterior myocardial infarct size (IS), as determined by Cardiac Magnetic Resonance (cMR) 
imaging at 4-6 days post infarct in the Test Arm (cooling + PCI) compared to the Control Arm 
(PCI only). The absolute magnitude of a relative reduction of 20% depends on the mean IS in the 

 
 
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control arm, which is assumed to be approximately 17 %LV.  Therefore, the treatment effect of 
interest is an absolute difference of 3.5 %LV.  
 
The hypothesis for the primary effectiveness endpoint is the following for patients randomized 1:1 
in Treatment Arm vs Control Arm: 
Null hypothesis:  
 
The null hypothesis is that the mean infarct size in the Test Arm is equal to the mean IS in the 
Control Arm.   
 
Alternative hypothesis:  
 
The mean infarct size in the control arm is not equal to mean infarct size of control arm. 
This 20% relative reduction is defined as absolute value 3.5 %LV and accounted for in our sample 
size calculation as minimally detectable effect. This assumption is based on previous studies with 
anterior infarct size measured with cMR reporting between 17-20% absolute %LV in anterior 
infarct (Tables 17 & 18). Therefore, a relative reduction of 20% can vary depending on the mean 
infarct size of the control arm. Assuming a representative mean infarct size of ~17% in controls, 
we assume absolute difference of 3.5 %LV is equivalent to 20% mean anterior infarct size would 
be an adequate detection limit for effect. 
Based on these assumptions-- standard deviation of 12.0 %LV, two-tailed t-test of difference 
between means, a normal distribution, 80% power (beta=0.2) with the final analysis to be 
conducted using a two-sided test at the alpha=0.044 level of significance (adjusted for the two 
interim analyses)-- the required total sample to detect a mean difference of 3.5 %LV with 80% 
power is 384 subjects (192 subjects per group).  Further, assuming 24% loss to follow-up, the trial 
plans for an enrolment up to 500 randomized subjects (250 in each arm) for 4-6 days cMR imaging 
follow-up. 
 
 

 
 
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Table 17: Clinical trials reporting anterior mean infarct size measured by cMR 4-6 days in 
PCI trials (Control Group Only) and calculated 20% relative reduction  
Study name 
Anterior n 
Mean 
infarct size 
Standard 
Deviation 
20% relative 
reduction 
APEX-AMI41 
60 
16.6 
10.7 
3.3 
LIPSIAABCIXIMAB42 
63 
25.3 
16.1 
5.1 
LIPSIA-STEMI43 
38 
18 
16.0 
3.6 
CRISP-AMI 44* 
142 
37.5 
20.1 
7.5 
INFUSE-AMI45 
172 
17.3 
10.2 
3.5 
RAPID-MI ICE1 
7 
19.7 
8.5 
3.9 
CHILL-MI37 
21 
26.5 
10.9 
5.3 
AMI EU PILOT  
21 
23.3 
12.0 
4 
*>60% are large proximal infarcts 
 
A range of standard deviation in the table expected is represented by anterior infarct data 
measured with cMR from separate and pooled analyses of previous hypothermia trials with AMI 
patients cooled below 35°C: RAPID-MI ICE (2009), CHILL-MI (2013), AMI EU Pilot 
(ongoing) as described below in Table 18. 
Table 18: Hypothermia trials using cMR measured infarct size as primary outcome 
RAPID-MI 
ICE (2009) 
CHILL-MI 
(2013) 
AMI EU 
Pilot (2017) 
Pooled  
AMI EU Pilot, RAPID-
MI-ICE, CHILL-MI 
n (Control vs 
Cooled) 
7 vs 5 
21 vs 15 
21 vs 19 
49 vs 39 
Control Mean 
LV% 
19.7 
26.5 
23.3 
24.5 

 
 
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RAPID-MI 
ICE (2009) 
CHILL-MI 
(2013) 
AMI EU 
Pilot (2017) 
Pooled  
AMI EU Pilot, RAPID-
MI-ICE, CHILL-MI 
20% reduction 
in infarct 
3.94 
5.3 
4.7 
4.9 
Std Dev 
(control) 
8.5 
10.9 
12.0 
10.5 
Std Dev (cooled) 
6.5 
9.3 
10.3 
11.0 
 
The potential impact of variations in control infarct size and variability is presented in Table 19.  
Table 19: Sample size estimates with alternative standard deviation and detection limit 
Mean Difference 
in infarct size for 
detection (%) 
 Standard Deviation Estimated Sample Size 
Total Enrollment 
(with 24% drop-out) 
3.0 
 
9 
288 
380 
3.0 
 
10 
356 
468 
3.0 
 
11 
430 
566 
3.0 
 
12 
506 
666 
3.5 
 
9 
212 
280 
3.5 
 
10 
260 
342 
3.5 
 
11 
314 
414 
3.5 
 
12 
374 
500 
4.0 
 
9 
162 
214 
4.0 
 
10 
200 
264 
4.0 
 
11 
240 
316 
4.0 
 
12 
286 
376 

 
 
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The primary safety endpoint is a composite endpoint. For the sample size calculation, expected 
incidence is based on a literature review of acute MI hypothermia trials that combined six studies: 
Dixon et al, COOL MI, ICE-IT, RAPID MI-ICE, CHILL-MI, VELOCITY46 which resulted in a 
30-day MACE rate of 6.6% in the Control patients and 7.5% in treatment patients. Previously, 
AMIHOT II trial defined 30-day MACE rate comprised of death, reinfarction, target vessel 
revascularization, and stroke used a non-inferiority hypothesis with a 6% equivalence delta and 
7% in the Control patients47. 
The hypothesis for the primary safety endpoint is the following:  
H0: πT ≥ πC + 6%  
HA: πT < πC + 6%  
πT and πC are the underlying proportion of patients having a MACE event.  
An enrollment of 500 patients would be able to demonstrate 91% power and 95% 1-sided 
significance. The safety endpoint will be considered to have been met if there is a high posterior 
probability of non-inferiority [i.e. P (πt < πc + 6% >95%)]. With a drop-out rate of 20%, the 
power is calculated to be 86%. 
 
16 PUBLICATION 
At the conclusion of the trial, a multi-center manuscript will be prepared for publication. 
Publications will be managed by the Sponsor, its designee and the Advisory board. Additional 
publications from any single site will be considered but only after the multi-center publication. 
17 INTELLECTUAL PROPERTY 
In all documents the company name of ZOLL Circulation® will be referred to in short hand as 
ZOLL.  ZOLL® is a registered trademark of ZOLL Medical Corporation.  The Proteus IVTM 
System is a trademark of ZOLL Circulation, Inc.  Proteus Catheters, Cassettes and Temperature 
Probes (X-Probe) are registered trademarks of ZOLL Circulation, Inc. 

 
 
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18 STATEMENT OF COMPLIANCE 
1. Sponsor and Investigator will conduct the clinical investigation in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki. 
2. Sponsor and Investigator will comply with ISO 14155:2011 and any regional or national 
regulations, as appropriate. 
3. Investigator will not begin the clinical investigation until Investigator obtains the required 
written approval or favorable opinion from the MEC or regulatory authority, if appropriate.  
4. Investigator will follow any additional requirements imposed by the MEC or regulatory 
authority, if appropriate. 

 
 
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ATTACHMENT II – ANTI-SHIVERING PROTOCOL  
Shivering Suppression Guidelines 
Turn on IVTM System console to initiate system and begin cooling of coldwell 
↓ 
Obtain Informed Consent 
↓ 
Administer Buspirone 60 mg PO/NG x 1 immediately 
↓ 
Place Bair Hugger on upper body; set to “high”; forced-air cover should be adjacent to skin.   
Put one blanket on top. 
↓ 
Closer to the time of device deployment, Pethidine 1 mg/kg IV (up to 100 mg)  
 
***Morphine and/or other sedatives are often administered in the setting of an acute MI 
Morphine and Pethidine (Demerol) are both opiate narcotics and if possible, morphine should 
be held as the combination may cause over-sedation.  Consider 0.5 mg/kg Pethidine 
IV, if Morphine has been administered. 
↓ 
At 15 minutes, Pethidine 0.5mg/kg IV should be administered. 
 
Then a 25 mg/hr IV infusion of Pethidine (up to 80 kg patient) or 35mg/hr (> 80 kg 
patient) should be initiated and maintained for the duration of device deployment. 
***Make sure the patient has a respiratory rate ≥ 10 breaths/minute. 
 
What to do if shivering occurs: 
First, try repositioning the Bair Hugger or changing its settings to increase the heat delivered to 
the patient’s surface. 
 
Second, consider increasing dose of Pethidine.  Prior to giving additional Pethidine, look for 
signs of respiratory depression (i.e. decreased Respiratory Rate, decreased O2 Saturation by 
Pulse Ox.)  If it is decided that the patient can tolerate additional Pethidine the following may be 
tried: 
1. An IV dose of 25 mg x 1 may be given 
2. If Infusion rate is 25mg/hr, the rate may be increased to a maximum of 35 mg/hr 

 
 
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If the shivering persists following the above measures, consider raising the target temperature 
on the Proteus Console by 0.5°C (i.e. from 32.0°C to 32.5°C).  If this does not work after 5-10 
minutes at the new target temperature, then the process can be repeated until a temperature where 
no shivering is obtained. 
 

 
 
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ATTACHMENT III – BEDSIDE SHIVERING ASSESSMENT SCALE (BSAS) 
SCORE 
SEVERITY 
DEFINITION 
0 
None 
No shivering noted on palpation of the masseter, neck or chest 
wall 
1 
Mild 
Shivering localized to the neck and/or thorax only 
2 
Moderate 
Shivering involves gross movement of the upper extremities in 
addition to neck and thorax 
3 
Severe 
Shivering involves gross movements of the trunk, upper and lower 
extremities 
SCORE 
SEVERITY 
DEFINITION 
0 
None 
No shivering noted on palpation of the masseter, neck or chest 
wall 
1 
Mild 
Shivering localized to the neck and/or thorax only 
2 
Moderate 
Shivering involves gross movement of the upper extremities in 
addition to neck and thorax 
3 
Severe 
Shivering involves gross movements of the trunk, upper and lower 
extremities 

 
 
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ATTACHMENT IV – SPECIFIC NEW-ONSET ADVERSE EVENT DEFINITIONS 
SPECIFIC NEW-
ONSET ADVERSE 
EVENT  
DEFINITION 
1. All-Cause  
Mortality 
Deaths will be classified as cardiac, vascular or 
noncardiovascular as defined by the Academic Research 
Consortium.27 
 
All deaths are considered cardiac unless an unequivocal non-
cardiac cause can be established. Specifically, any 
unexpected death even in patients with coexisting potentially 
fatal non-cardiac disease (e.g. cancer, infection) should be 
classified as cardiac.  
 
Cardiac death (CD):  
Any death due to proximate cardiac cause (e.g. MI, low-
output failure, fatal arrhythmia), unwitnessed death and 
death of unknown cause, all procedure related deaths 
including those related to concomitant treatment.  
 
Vascular death:  
Death due to non-coronary vascular causes such as 
cerebrovascular disease, pulmonary embolism, ruptured 
aortic aneurysm, dissecting aneurysm, or other vascular 
cause.  
 
Non-cardiovascular death:  
Any death not covered by the above definitions such as 
death caused by infection, malignancy, sepsis, pulmonary 
causes, accident, suicide or trauma. 
2. Recurrent MI 27,31 
Recurrent MI or re-infarction may be diagnosed when 
cardiac biomarker levels are stable on 2 samples that are >6 
hours apart or are in decline if a subsequent value 3 to 6 
hours after the procedure is increased by > 20% from the 
baseline sample. If the baseline value is not stable, then 
insufficient data exists to recommend biomarker criteria for 
diagnosis, and the Academic Research Consortium27,31 
recommends that the event be considered as pre-procedure 
MI.  Periprocedural MI is that which occurs within the first 
48 hrs after PCI or within the first 72 hrs after coronary 
artery bypass grafting (CABG). 
 
Q wave MI:  

 
 
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Development of new, pathological Q wave on the baseline 
ECG (≥ 0.04 seconds in duration and ≥ 1 mm in depth) in ≥ 
2 contiguous precordial leads or ≥ 2 adjacent limb leads)  
 
Non-Q wave MI:  
Those MIs which are not Q-wave MI. 
3. Need for 
revascularization of 
the target vessel 
(TVR)27 
TVR is defined as any repeat percutaneous intervention or 
surgical bypass of any segment of the target vessel. The 
target vessel is defined as the entire major coronary vessel 
proximal and distal to the target lesion, which includes 
upstream and downstream branches and the target lesion 
itself.  
4. Stroke 
Development of a new neurological deficit that persists > 24 
hours, or worsening of previous neurological symptoms that 
persist > 24 hours. 
5. Cardiogenic shock 
Systolic blood pressure of less than 90 mmHg for at least 30 
minutes which is secondary to myocardial dysfunction, 
leading to decreased cardiac output and evidence of tissue 
hypoxia in the presence of adequate intravascular volume.  
6. Pulmonary 
embolism 
Sudden onset of pleuritic chest pain, cough, hemoptysis, 
hypoxia, tachycardia, and a positive ventilation/perfusion 
scan or a CT scan. 
7. Ventricular 
Fibrillation (V-  
Fib) 
Rapid uncoordinated fluttering contractions of the heart 
ventricles recognized by the occurrence on the 
electrocardiogram of coarse and irregular oscillations 
without discernible QRS complexes or T waves 
8. Vascular 
complications 
requiring intervention 
Complications arising from the use of the  Proteus Catheter 
including the development of a vessel tear, hematoma, 
pseudoaneurysm, arteriovenous (AV) fistula, or 
retroperitoneal bleeding which require an additional surgical 
intervention for treatment. 
9. Bleeding requiring 
transfusion of 2 units 
or greater 
Any periprocedural bleeding which occurs as a result of the 
PCI and/ or cooling procedure which requires transfusing > 
2 units. 
10. Systemic Infection  Sepsis with confirmed positive blood cultures. 
11. Cooling Catheter 
Access Site Wound 
infection 
Infection and inflammation of the incision or puncture site 
requiring drainage and/or debridement in addition to 
antibiotic therapy, e.g., cellulitis. 
12. Pulmonary Edema Abnormal accumulation of fluid in the lungs 
13. Deep Venous 
Thrombosis 
(DVT)32 
Formation of one or more blood clots in one of the body’s 
large veins, most commonly in the lower limbs. The clot(s) 
can cause partial or complete blocking of circulation in the 
vein, which in some patients leads to pain, swelling, 

 
 
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tenderness, discoloration, or redness of the affected area, and 
skin that is warm to the touch.  As many patients enrolled in 
the trial will have pre-existing DVT, for the purposes of this 
trial DVT is defined as the de novo onset of DVT following 
enrollment which required treatment or worsening of pre-
existing DVT. 

 
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ATTACHMENT V – ADVERSE EVENT DEFINITIONS 
Adverse Event Definitions 
In addition to the definitions provided in Attachment IV– Specific New Onset Serious 
Adverse Event Definitions, the following definitions apply to expected adverse events 
that may occur and must be reported throughout this clinical trial.  Events reported should 
represent a new onset or increase in the severity of the condition from the time of 
enrollment. 
A. CARDIAC  
COMPLICATIONS 
DEFINITION 
Recurrent 
Myocardial 
ischemia 31  
Recurrent Myocardial Ischemia : is evidenced through baseline 
ECG changes identified during continuous multilead baseline 
ECG–ischemia monitoring (or Holter monitoring) which may 
be accompanied by the development of new clinical symptoms 
suggesting an ischemic cardiac episode.  
Arrhythmias 
The development of a new atrial and/or ventricular arrhythmia, 
significant increase in the severity of a preexisting arrhythmia, 
or any episode of cardiac arrest. 
Congestive Heart 
Failure34 
Defined as patients with defined or presumed cardiac disease 
and one of the following: Class I: without limitations of 
physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, or dyspnea. Class II: slight 
limitation of physical activity. They are comfortable at rest. 
Ordinary physical activity results in fatigue, palpitation, or 
dyspnea. Class III: marked limitation of physical activity. They 
are comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, or dyspnea. Class IV: inability to carry on 
any physical activity without discomfort. Symptoms are 
present even at rest or minimal exertion. 
 
B. PULMONARY 
COMPLICATIONS 
DEFINITION 
Pneumonia 
Clinical evidence as determined by physical, radiographic, and 
laboratory findings requiring treatment with antibiotics, 
inhalation therapy, intubation, or suctioning. 
Atelectasis 
Clinical evidence as determined by physical, radiographic, and 
laboratory findings requiring treatment with antibiotics, 
inhalation therapy, intubation, or suctioning. 

 
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Respiratory Failure 
Need for mechanical ventilation for > 24 hours 
postoperatively, or reintubation for any reason. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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C. RENAL 
COMPLICATIONS 
DEFINITION 
Acute Kidney 
injury (AKI)35 
AKI is defined as any of the following:  
Increase in SCr by ≥.3 mg/dl (≥26.5 µmol/l) within 48 hours; 
or Increase in SCr to ≥ 1.5 times baseline, which is known or 
presumed to have occurred within the prior 7 days; or Urine 
volume < 0.5 ml/kg/h for 6 hours.  
 
D. VASCULAR 
COMPLICATIONS 
DEFINITION 
Arteriovenous 
Fistula 
Formation of an abnormal connection between the lumens of 
an artery and a vein as documented by CT, ultrasound, 
angiography, or direct observation. 
Embolism 
The obstruction of a blood vessel by a blood clot or foreign 
substance, e.g., air, fat, bacteria. 
Vessel perforation 
Defined as perforation of the access vessel wall or vena cava 
confirmed by extravasation of contrast under fluoroscopy, 
angiography, CT scan, and/ or direct observation at surgery or 
autopsy.  
Hematoma 
An abnormal localized collection of blood (clotted or partially 
clotted) and situated within an organ or a soft tissue space, 
such as within a muscle.  Development of an incisional or 
retroperitoneal hematoma requiring surgical intervention, 
evacuation, transfusion or prolonged hospitalization. 
Hemorrhage 
Post-procedural bleeding requiring transfusion of ≥ 2 units. 
Hypotension 
Abnormally low systolic blood pressure that is < 80 mm Hg 

 
 
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D. VASCULAR 
COMPLICATIONS 
DEFINITION 
Peripheral vascular 
insufficiency (PVI) 
Inadequate peripheral blood flow resulting from the occlusion 
of vessels by atherosclerotic plaques, thrombi, or emboli; 
damaged, diseased, or intrinsically weak vascular walls; 
arteriovenous fistulas; hematologic hypercoagulability; and 
heavy smoking. Signs of vascular insufficiency include pale, 
cyanotic, or mottled skin over the affected area; swelling of an 
extremity; absent or reduced tactile sensation; tingling; 
diminished sense of temperature; muscle pain, such as 
intermittent claudication in the calf; and, in advanced disease, 
ulcers and atrophy of muscles in the involved extremity.  
As many patients enrolled in the trial will have pre-existing 
Peripheral Vascular Insufficiency (PVI), for the purposes of 
this trial PVI is defined as the de novo onset of PVI following 
enrollment which requires treatment or worsening of pre-
existing PVI. 
Pseudoaneurysm 
Enlargement of the aorta, iliac, or femoral arteries, which 
contain some or all of the medial layer, the adventitia, and 
periaortic tissue most commonly associated with previous 
aortic operative procedures, trauma, and/or infection.  
Pseudoaneurysms typically present as a well-defined collection 
of blood outside the vessel wall from contained rupture.  
Stenosis 
A reduction in the diameter of the vessel lumen when 
compared to the reference diameter, as documented by 
angiography, which requires intervention and is related to the 
procedure, e.g., access vessel.  
Thrombosis  
Clotting within a blood vessel which may cause infarction of 
tissues supplied by the vessel; it may be occlusive or attached 
to the vessel or heart wall without obstructing the lumen. 
Transient Ischemic 
Attack (TIA) 
A brief episode of neurological dysfunction caused by focal 
brain or retinal ischemia with clinical symptoms typically 
lasting 1 - 24 hours and without evidence of acute infarction. 
 
E. WOUND 
COMPLICATIONS 
DEFINITION 
Hematoma 
An abnormal localized collection of blood (clotted or 
partially clotted) and situated within an organ or a soft tissue 
space, such as within a muscle.  Development of an 

 
 
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incisional or retroperitoneal hematoma requiring surgical 
intervention, evacuation, transfusion or prolonged 
hospitalization. 
Arteriovenous Fistula 
Formation of an abnormal connection between the lumens 
of an artery and a vein as documented by CT, ultrasound, 
angiography, or direct observation. 
Nerve 
Injury/Peripheral 
Neuropathy 
Direct damage to nerves surrounding the access site, 
operative field, or catheter deployment site, and the resultant 
signs and/or symptoms of such damage which may include 
pain and numbness in the affected area associated with 
muscle weakness and decreased patellar reflex lasting > 1 
month after treatment. 
 
F. SYSTEMIC 
COMPLICATIONS 
DEFINITION 
Coagulopathy 
The development of an abnormal bleeding disorder, e.g., 
disseminated intravascular coagulopathy or thrombocytopenia, 
documented by appropriate laboratory studies and requiring 
therapy with medication or transfusion. 
Anesthetic 
Complications 
Reaction or complication caused by administration of an 
anesthetic. 
Liver failure33 
Acute liver failure is defined as the rapid development of 
hepatocellular dysfunction, specifically coagulopathy and 
mental status changes (encephalopathy) in a patient without 
known prior liver disease.  
 
F. SYSTEMIC 
COMPLICATIONS 
DEFINITION 
Pancreatitis33 
Evidenced on two of the following three conditions: 1) 
abdominal pain suggestive strongly of acute pancreatitis 
(epigastric pain often radiating to the back), 2) serum amylase 
and/or lipase activity at least 3 times greater than the upper 
limit of normal, (imaging is to be used if the elevated values 
are <3 times normal); and 3) characteristic findings of acute 
pancreatitis on transabdominal ultrasound or on Contrast 
Enhanced Computed Tomography (CECT) 32 
 
 
 
 
 

 
 
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ATTACHMENT VI – INVESTIGATOR LIST 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ATTACHMENT VII – LIST OF ABBREVIATIONS 

 
 
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AAR 
Area at Risk 
ACC 
American College of Cardiology 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AHA 
American Heart Assocation 
AKI 
Acute Kidney Injury 
AMI 
Acute Myocardial Infarction 
ASADE 
Anticipated Serious Adverse Device Effect 
AV 
Arteriovenous 
BSAS 
Bedside Shivering Assessment Scale 
CABG 
 Coronary Artery Bypass Grafting  
CD 
Cardiac Death 
CEC 
Clinical Events Committee 
CHF 
Congestive Heart Failure 
CIP 
Clinical Investigation Plan 
CI-TLR 
Clinically-Indicated Target Lesion Revascularization 
CMP 
Clinical Monitoring Plan 
cMR 
Cardiac Magnetic Resonance 
CNS 
Central Nervous System 
CRO 
Clinincal Research Organization 
CRF 
Case Report Form 
CRMI 
Clinically Relevant Myocardial Infarction 
CVA 
Cerebral Vascular Accident 
CVP 
Central Venous Pressure 
DAPT 
Dual Antiplatelet Therapy 
DD 
Device Deficiency 
DES 
Drug Eluting Stent 
DMC 
Data Monitoring Committee 
DP 
Dorsalis Pedis        
DSMB 
Data Safety Monitoring Board 
DTB 
Door-to-Balloon 
DVT 
Deep Vein Thrombosis 
EC 
Ethics Committee 
ECG 
Electrocardiography 
EDC 
Electronic Data Capture 
ED 
Emergency Department 

 
 
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ER 
Emergency Room 
ESC 
European Society of Cardiology 
EU 
European Union 
Fr 
French 
FMECA 
Failure Mode, Effects and Criticality Analysis 
FEP 
Fluorinated Ethylene Propylene 
GLP 
Good Laboratory Practice 
HDPE 
High-density Polyethylene 
HIPPA 
Heath Insurance Portability and Accountability Act 
HTN 
Hypertension 
ICF 
Informed Consent Form 
IEC 
International Electrotechnical Commission 
IFU 
Instructions for Use 
IQR 
Interquartile Range 
IRB 
Institutional Review Board 
IRI 
Ischemia Reperfusion Injury 
IS 
Infarct Size 
ISO 
International Organization for Standardization 
ITT 
Intention-to-Treat 
IVC 
Inferior Vena Cava 
IVTM 
Intravascular Temperature Management 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LAL 
Limulus Amebocyte Lysate 
LED 
Light-emitting Diode 
LV 
Left Ventricular 
LVEF 
Left Ventricular Ejection Fraction 
MACE 
Major Adverse Cardiac Events 
MAO 
Monoamine Oxidase 
MaR 
Myocardium at Risk   
MEC 
Medical Ethics Committee 
MEM 
Minimum Essential Medium 
MI 
Myocardial Infarction 
MRI 
Magnetic Resonance Imaging 
NCA 
National Competent Authority 

 
 
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NYHA 
New York Health Association 
OD 
Outer Diameter 
PCI 
Percutaneous Coronary Intervention 
PETG 
Polyethylene Terephthalate - Glycol modified 
PP 
Per-protocol 
PVI 
Peripheral Vascular Insufficiency 
PVP 
Polyvinylpyrrolidone 
RCN 
Radio-Contrast Nephropathy 
RF 
Radiofrequency 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Events 
SBP 
Systolic Blood Pressure 
SOP 
Standard Operating Procedure 
SPECT 
Single-photon Emission Computed Tomography  
STEMI 
ST-segment Elevation Myocardial Infarction 
SVT 
Supraventricular Tachycardia 
TIA 
Transient Ischemic Attack 
TIMI 
Thrombolysis In Myocardial Infarction 
TH 
Therapeutic Hypothermia 
TVR 
Target Vessel Revascularization 
UADE 
Unanticipated Adverse Device Effect 
UFH 
Unfractioned Heparin 
USADE 
Unanticipated Serious Adverse Device Effect 
USP 
United States Pharmacopeia 
UTI 
Urinary Tract Infection 
 

 
 
 
 
 
 
 
 
 
APPENDIX D 
 
COOL-AMI EU Pivotal Trial Clinical Investigational Plan 
 
France Protocol (Rev. 3) 
 
(127 pages) 
 
 
 

Page 1 of 127 
COOL-AMI EU Pivotal Trial EDC-3135 Rev 3  
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Clinical Investigation Plan 
 
 
COOL-AMI EU PIVOTAL TRIAL: A MULTICENTER, PROSPECTIVE, 
RANDOMIZED-CONTROLLED TRIAL TO ASSESS THE SAFETY AND 
EFFECTIVENESS OF COOLING AS AN ADJUNCTIVE THERAPY TO 
PERCUTANEOUS INTERVENTION IN PATIENTS WITH ACUTE 
MYOCARDIAL INFARCTION 
 
PROTOCOL NO.: EDC 3135 
 
Revision: 3 
 
EFFECTIVE DATE: JUNE 19, 2018 
 
 
 
 
CONFIDENTIAL & PROPRIETARY 
 
The information in this Protocol is confidential and proprietary and is to be used only in 
connection with matters authorized by ZOLL and no part is to be disclosed to others 
without prior written permission from ZOLL 
 
 
 
 
 
 

CLINICAL INVESTIGATION PLAN APPROVAL PAGE 
CLINICAL INVESTIGATION PLAN: 
COOL-AMI EU Pivotal Trial: A 
multicenter, prospective, randomized 
controlled Trial to assess the safety and 
effectiveness of cooling as an adjunctive 
therapy to percutaneous intervention in 
patients with acute myocardial infarction 
PROTOCOL NO.: 
SPONSOR: 
EDC-3135 
ZOLL Circulation, Inc. 
2000 Ringwood A venue 
San Jose, CA 95131 
SPONSOR 
REPRESENTATIVE: 
ZOLL Medical Deutschland GmbH 
Emil-Hoffmann - StraBe 13 
CLINICAL TRIAL SPONSOR'S 
CONTACT: 
REVISION NUMBER : 
50996 KOln, Germany 
Philippa Hill 
3 
pro) of Clinical Investigation Plan by Sponsor: 
'-P'l1"'-
VG\;(A 
) N f. 
/ C//k 201[' 
Philippa Hil 
f-1-' 
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Senior Director, Clinical Affairs 
COOL-AMI EU Pivotal Trial EDC-3135 Rev 3 
CONFIDENTIAL & PROPRJETARY 
Page 2 of127 

Page 3 of 127 
COOL-AMI EU Pivotal Trial EDC-3135 Rev 3  
CONFIDENTIAL & PROPRIETARY  
Signature Page 
 
Clinical Investigation Plan  
 
COOL-AMI EU PIVOTAL TRIAL: A MULTICENTER, PROSPECTIVE, RANDOMIZED-
CONTROLLED TRIAL TO ASSESS THE SAFETY AND EFFECTIVENESS OF COOLING AS 
AN ADJUNCTIVE THERAPY TO PERCUTANEOUS INTERVENTION IN PATIENTS WITH 
ACUTE MYOCARDIAL INFARCTION 
PROTOCOL NO.: EDC-3135 
Revision: 3 
Effective Date: JUNE 19, 2018 
 
Signatures of Investigator below constitute their approval of this clinical investigation 
plan (CIP) and provide necessary assurances that they have read the CIP, understand it, 
and will work according to all stipulations of it, and to the ethical principles stated in the 
latest version of the Declaration of Helsinki and the ISO 14155:2011 (Clinical 
Investigation of Medical Devices for Human Subjects – Good Clinical Practice). 
 
 
 
 
Investigator Name (Please Print) 
 
 
 
 
 
 
Investigator Signature 
 
Date 
 
 
 
 
 
 
Institution Name 
 
 
 
 
 
Institution Address 
 
 
 
 
 
ZOLL Circulation, Inc. 
 
 
Sponsor Name 
 
 
 
 
 
2000 Ringwood Avenue, San Jose CA 95131 
Sponsor Address 
 
 
 
 
 
ZOLL Medical Deutschland GmbH 
 
 
Sponsor Representative 
 
 
 

Page 4 of 127 
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Table of Contents 
 
1. 
SYNOPSIS .............................................................................................................. 9 
2 
INTRODUCTION ................................................................................................ 15 
3 
BACKGROUND .................................................................................................. 17 
4 
INTENDED USE, SYSTEM OVERVIEW, & DEVICE DESCRIPTION .......... 18 
 
Intended Use / Indication for Use ..................................................................... 18 
 
System Overview .............................................................................................. 18 
 
Device Description ............................................................................................ 19 
4.3.1 Proteus Catheter ................................................................................................ 19 
4.3.2 Proteus Temperature Probe ............................................................................... 20 
4.3.3 Proteus Cassette................................................................................................. 20 
4.3.4 Proteus Console ................................................................................................. 20 
4.3.5 Device Labeling ................................................................................................ 22 
5 
PRIOR INVESTIGATIONS ................................................................................. 22 
 
Pre-Clinical Studies ........................................................................................... 22 
 
Human Clinical Studies ..................................................................................... 23 
5.2.1 COOL MI Trial ................................................................................................. 23 
5.2.2 COOL MI II Trial .............................................................................................. 30 
5.2.3 COOL RCN Trial .............................................................................................. 33 
5.2.4 ICE- IT Trial...................................................................................................... 36 
5.2.5 RAPID-MI ICE Trial ........................................................................................ 37 
5.2.6 CHILL-MI Trial ................................................................................................ 37 
5.2.7 Induction of Mild Systemic Hypothermia With Endovascular Cooling During 
Primary Percutaneous Coronary Intervention for Acute Myocardial Infarction .......... 38 
5.2.8 VELOCITY Trial .............................................................................................. 38 
5.2.9 EU AMI Case Series ......................................................................................... 40 
5.2.10 COOL-AMI EU PILOT Trial ........................................................................... 41 
 
Summary and Clinical Trial Rationale .............................................................. 42 
6 
CLINICAL TRIAL PLAN .................................................................................... 43 
 
Trial Objective................................................................................................... 43 

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Trial Endpoints .................................................................................................. 43 
6.2.1 Primary Effectiveness Endpoint ........................................................................ 43 
6.2.2 Primary Safety Endpoint ................................................................................... 43 
6.2.3 Additional Assessments: Demographics and Other Parameters ....................... 43 
 
Trial Design ....................................................................................................... 44 
 
Patient Population ............................................................................................. 44 
 
Selection Criteria ............................................................................................... 44 
 
Inclusion Criteria ............................................................................................... 45 
 
Exclusion Criteria .............................................................................................. 45 
 
Clinical Trial Procedures ................................................................................... 46 
6.8.1 Patient Screening ............................................................................................... 46 
6.8.2 Informed Consent .............................................................................................. 47 
6.8.3 Roll-In Enrollment ............................................................................................ 48 
6.8.4 Approval to Randomize in the Trial .................................................................. 49 
6.8.5 Randomization .................................................................................................. 49 
6.8.6 Acute Care and Emergency Room Triage......................................................... 50 
6.8.7 Standardized Care Prior to the Cooling Procedure ........................................... 50 
6.8.8 Documentation Procedures ............................................................................... 51 
6.8.9 Study Flow and Procedures ............................................................................... 52 
6.8.10  Pre-Cooling Assessment Procedures ................................................................ 56 
6.8.11 Initiation, Maintenance, and Reversal of Cooling with Proteus IVTM System 
Procedures / Evaluations and Data Collection for Subjects Enrolled in the Test Arm 57 
6.8.12 Test Arm: Temperature Management Protocol and Data Collection Time 
Points 57 
6.8.13 Trial Schedule for Test Arm Subjects ............................................................... 65 
6.8.14 Trial Schedule for Control Arm Subjects .......................................................... 66 
6.8.15 Control Arm Protocol and Data Collection Time Points .................................. 67 
6.8.16 Follow-up at 4-6 days and at 30 days following the PCI Procedure ................. 67 
6.8.17 Follow-up at 12 months following PCI ............................................................. 68 
6.8.18 Use of other Cooling Methods .......................................................................... 68 
6.8.19 Transferring Subject during Cooling................................................................. 68 

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6.8.20 Patient Withdrawal and Discontinuation........................................................... 68 
6.8.21 Patient Lost to Follow-up .................................................................................. 69 
6.8.22 Early Termination of a Clinical Investigation ................................................... 69 
6.8.23 Amendments and Protocol Deviations .............................................................. 70 
6.8.24 Trial Exit ........................................................................................................... 71 
6.8.25 Subject Confidentiality ...................................................................................... 71 
6.8.26 Device Accountability ....................................................................................... 72 
6.8.27 Return of Materials upon Trial Termination ..................................................... 72 
6.8.28 Trial Closure ...................................................................................................... 73 
 
Cardiac Magnetic Resonance (cMR) imaging Core Laboratory ....................... 73 
7 
ADVERSE EVENTS & DEVICE DEFICIENCIES ............................................ 73 
 
Definitions ......................................................................................................... 73 
7.1.1 Adverse Event (AE) .......................................................................................... 73 
7.1.2 Serious Adverse Event (SAE) ........................................................................... 74 
7.1.3 Device Deficiency (DD).................................................................................... 74 
7.1.4 Adverse Device Effect (ADE)........................................................................... 74 
7.1.5 Serious Adverse Device Effect (SADE) ........................................................... 74 
7.1.6 Unanticipated Serious Adverse Device Effect (USADE) ................................. 75 
 
Adverse Event Reporting .................................................................................. 75 
7.2.1 Adverse Event Reporting from Site to Sponsor and MEC................................ 75 
7.2.2 Serious Adverse Event Reporting to Sponsor and MEC................................... 75 
7.2.3 UADE/USADE Reporting to Sponsor and MEC .............................................. 76 
7.2.4 Sponsor Reporting to NCAs (National Competent Authority) when European 
Sites Participate in the Trial ......................................................................................... 76 
 
Device Relationship .......................................................................................... 77 
8 
MONITORING BY DATA MONITORING COMMITTEE .............................. 79 
9 
ADJUDICATION OF EVENTS........................................................................... 79 
10 
RECOMMENDATION FOR DAPT AND STENTS........................................... 80 
11 
RISK ANALYSIS ................................................................................................. 81 
 
Risk Assessment Process .................................................................................. 81 
 
Expected Clinical Observations ........................................................................ 82 

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Potential Clinical Risks ..................................................................................... 82 
11.3.1 Potential Adverse Events associated with the Proteus Catheter and Cooling 
System: ......................................................................................................................... 83 
11.3.2 Potential Adverse Events associated with the cooling procedure include but are 
not limited to the following: ......................................................................................... 83 
11.3.3 Risks Associated with Anti-shivering Medications .......................................... 84 
 
Additional investigations due to the trial .......................................................... 85 
11.4.1 Delay in PCI through the use of hypothermia therapy ...................................... 85 
11.4.2 Implementation of PCI in patients undergoing hypothermia (patient-related 
risks). 86 
11.4.3 Implementation of PCI with concurrent use of endovascular hypothermia. ..... 86 
11.4.4 The concurrent medication. ............................................................................... 86 
11.4.5 The supply of 4°C cooled saline solution ......................................................... 86 
11.4.6 Other procedures within the clinical trial .......................................................... 86 
 
Potential Clinical Benefits ................................................................................. 87 
 
Methods to Minimize Risk ................................................................................ 87 
 
Risk – Benefit Assessment ................................................................................ 88 
12 
RECORDS AND REPORTS ................................................................................ 89 
 
Investigator Records .......................................................................................... 89 
 
Investigator Responsibilities ............................................................................. 90 
 
Sponsor Records ................................................................................................ 92 
 
Sponsor Reports ................................................................................................ 93 
13 
MONITORING AND AUDITING PROCEDURES............................................ 95 
 
Clinical Trial Sponsor and Monitors ................................................................. 95 
 
Monitoring Methods .......................................................................................... 95 
 
Monitoring Visits .............................................................................................. 96 
 
Pre-trial Qualification Visit ............................................................................... 96 
 
Initiation Visit ................................................................................................... 96 
 
On-Site Interim Monitoring Visits .................................................................... 97 
 
Audits ................................................................................................................ 97 
 
Final Monitoring Review .................................................................................. 97 
14 
DATA MANAGEMENT PROCEDURES........................................................... 97 

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Case Report Forms ............................................................................................ 98 
 
Source Documentation ...................................................................................... 98 
 
Transmission of Data ........................................................................................ 99 
 
Data Queries ...................................................................................................... 99 
15 
STATISTICAL ANALYSIS PLAN ..................................................................... 99 
 
Data Analysis .................................................................................................. 100 
 
Statistical Methods .......................................................................................... 102 
 
Sample Size Justification ................................................................................ 103 
16 
PUBLICATION .................................................................................................. 107 
17 
INTELLECTUAL PROPERTY ......................................................................... 107 
18 
STATEMENT OF COMPLIANCE .................................................................... 107 
ATTACHMENT I – REFERENCES ......................................................................... 108 
ATTACHMENT II – ANTI-SHIVERING PROTOCOL ........................................ 112 
ATTACHMENT III – BEDSIDE SHIVERING ASSESSMENT SCALE (BSAS) 114 
ATTACHMENT IV – SPECIFIC NEW-ONSET ADVERSE EVENT 
DEFINITIONS ............................................................................................................. 115 
ATTACHMENT V – ADVERSE EVENT DEFINITIONS ..................................... 118 
ATTACHMENT VI – INVESTIGATOR LIST ........................................................ 124 
ATTACHMENT VII – LIST OF ABBREVIATIONS ............................................. 125 
 
 
 

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1. SYNOPSIS 
Clinical Trial 
Title 
COOL-AMI EU PIVOTAL TRIAL: A MULTICENTER, 
PROSPECTIVE, RANDOMIZED-CONTROLLED TRIAL TO 
ASSESS THE SAFETY AND EFFECTIVENESS OF COOLING 
AS AN ADJUNCTIVE THERAPY TO PERCUTANEOUS 
INTERVENTION IN PATIENTS WITH ACUTE 
MYOCARDIAL INFARCTION 
Clinical Trial 
Sponsor 
ZOLL® Circulation, Inc. 
Clinical Trial 
Sponsor’s 
Contact 
Philippa Hill 
Senior Director, Clinical Affairs 
ZOLL Circulation, Inc. 
2000 Ringwood Ave. 
San Jose, CA 95131 
Main:    +1 (408) 541-2140 
Fax:  +1 (408) 541-1030 
PHill@zoll.com@zoll.com 
Trial Number 
EDC-3135 
Investigational 
Device 
Proteus™ Intravascular Temperature Management (IVTM) 
System 
Trial Objective The objective of this trial is to evaluate the safety and effectiveness of 
therapeutic hypothermia, using the ZOLL Proteus IVTM System, as 
an adjunctive therapy for patients presenting with acute anterior 
myocardial infarction (AMI) and undergoing percutaneous coronary 
intervention (PCI) in comparison with patients with acute anterior 
myocardial infarction and undergoing PCI only. 
Trial Design 
A multicenter, prospective, interventional, randomized-controlled trial. 
Randomization will be in a 1:1 ratio, Test Arm (PCI + Cooling) or 
Control Arm (PCI alone) in up to 500 randomized subjects (250 
subjects in each arm). 
 
Roll-In Subjects: To enhance each site’s ability to successfully 
integrate steps of the protocol and for training purposes prior to 
randomizing subjects in the trial, each site may enroll up to 4 Roll-In 
subjects in a non-randomized fashion. Roll-In subjects will be treated 

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and followed in the same manner as subjects in the Test Arm of the 
protocol (PCI + Cooling). Up to a total of 280 Roll-In subjects (up to 4  
per site) may be enrolled. Due to limited cMR data available in 
patients with inferior MI who received an adequate dose of cooling 
prior to revascularization, Inferior MI subjects will be allowed to be 
included as Roll-Ins to further evaluate inferior MI infarct size by 
cMR imaging. Evaluation of infarct size will be performed by cMR 
imaging at 4-6 days. 
Primary 
Effectiveness 
Endpoint  
Relative reduction of 20% in mean anterior myocardial infarct size as 
determined by Cardiac Magnetic Resonance (cMR) imaging at 4-6 
days post infarct in the Test Arm (cooling + PCI) relative to the 
Control Arm (PCI only). 
Primary Safety 
Endpoint 
Per-patient rate of composite Major Adverse Cardiac Events (MACE) 
in randomized subjects, defined as Cardiac Death (CD), All 
Myocardial Infarction (All MI) and Clinically-Indicated Target Lesion 
Revascularization (CI-TLR) at 30 day follow-up; non-inferiority to the 
control. 
Investigational 
Sites 
Up to 70 clinical sites in Europe 
Inclusion & 
Exclusion 
Criteria 
Patients shall be screened to the following inclusion and exclusion 
criteria. Subjects are qualified for participation only if all Inclusion 
Criteria have been met and all Exclusion Criteria have been confirmed 
not present. 
 
Inclusion Criteria 
All Inclusion Criteria must be answered YES for subject to satisfy 
Inclusion Criteria: 
 
1. The patient is ≥ 18 years of age. 
2. The patient must have symptoms consistent with AMI (i.e. chest 
pain, arm pain, etc.) and unresponsive to nitroglycerin, with 
symptoms beginning greater than 30 minutes but less than 4.5 
hours prior to consent. 
3. Qualifying Infarct location: 
a. Roll-In subjects:  Evidence of Acute Anterior or Inferior 
MI with ST-segment elevation of  ≥ 0.2 mV in two or more 
anterior or inferior contiguous precordial leads.(V1-V4) 

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b. Randomized subjects:  Evidence of Acute Anterior MI 
only with ST-segment elevation of  ≥ 0.2 mV in two or 
more anterior contiguous precordial leads. (V1-V4) 
4. The patient is eligible for PCI. 
5. The patient is willing to provide written informed consent to 
participate in this clinical trial. 
 
Exclusion Criteria 
All Exclusion Criteria must be answered NO for subject to satisfy 
Exclusion Criteria: 
1. The patient has had a previous Myocardial Infarction. 
2. The patient is experiencing cardiogenic shock, systolic blood 
pressure [SBP] <100 mmHg, HR>100 bpm and arterial oxygen 
saturation (pulse oximetry) <92% without additional oxygen.   
3. The patient is presenting with resuscitated cardiac arrest, atrial 
fibrillation, or Killip risk stratification class II through IV. 
4. The patient has an aortic dissection or requires an immediate 
surgical or procedural intervention other than PCI. 
5. The patient has known history of Congestive Heart Failure (CHF), 
hepatic failure, end-stage kidney disease or severe renal failure 
(clearance < 30ml/min/1.73m²).  
6. The patient is febrile (temperature > 37.5 °C) or has experienced 
an infection with fever in the last 5 days. 
7. The patient has a known previous CABG. 
8. The patient has a known recent stroke within 90 days of admission.  
9. Cardio-pulmonary decompensation that has occurred prior to 
consent or, in the opinion of the physician, that is imminent or 
likely to occur following presentation to the clinical site. 
10. Contraindications to hypothermia, such as patients with known 
hematologic dyscrasias which affect thrombosis (e.g., 
cryoglobulinemia, sickle cell disease, serum cold agglutinins) or 
vasospastic disorders (such as Raynaud’s or thromboangitis 
obliterans). 
11. Any contraindication to cardiac MRI, or any implant in the upper 
body which may cause artifacts on cardiac MRI imaging. 
12. The patient has a known hypersensitivity or contraindication to 
aspirin, heparin, or sensitivity to contrast media, which cannot be 
adequately pre-medicated. 

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13. The patient has a known history of bleeding diathesis, 
coagulopathy, cryoglobulinemia, sickle cell anemia, or will refuse 
blood transfusions. 
14. The patient has a height of <1.5 meters (4 feet 11 inches). 
15. The patient has a known hypersensitivity or contraindication to 
buspirone hydrochloride or Pethidine (Meperidine) and/or has 
been treated with a monoamine oxidase inhibitor in the past 14 
days. 
16. Patient has a known history of severe hepatic or renal impairment, 
untreated hypothyroidism, Addison’s disease, benign prostatic 
hypertrophy, or urethral stricture that in the opinion of the 
physician would be incompatible with Pethidine administration. 
17. The patient has an Inferior Vena Cava filter in place (IVC). 
18. The patient has a pre-MI life expectancy of <1 year due to 
underlying medical conditions or pre-existing co-morbidities. 
19. The patient has a known, unresolved history of drug use or alcohol 
dependency, or lacks the ability to comprehend or follow 
instructions. 
20. The patient is currently enrolled in another investigational drug or 
device trial. 
21. The patient is apprehensive about or unwilling to undergo the 
required MRI imaging at follow-up, has a documented or 
suspected diagnosis of claustrophobia, or has Gadolinium allergy, 
or is in permanent Atrial Fibrillation. 
22. The patient has received thrombolytic therapy prior to consent. 
23. The patient shows clinical evidence of spontaneous reperfusion as 
observed symptomatically and/ or from baseline ECG findings 
(partial or complete ST resolution in baseline ECG prior to 
informed consent and randomization). 
24. The patient is a vulnerable subject, for instance, a person in 
detention (i.e., prisoner or ward of the state). 
25. The patient is a female who is known to be pregnant. 
Clinical Trial 
Population 
Adult male and female patients presenting with an acute myocardial 
infarction. To qualify, patients must have symptoms consistent with 
AMI (i.e. chest pain, arm pain, etc.) unresponsive to nitroglycerin, 
with symptom onset greater than 30 minutes but less than 4.5 hours 
prior to arrival of the Emergency Medical Services or upon arrival to 
hospital and be eligible for PCI. 
 

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Randomized subjects must have evidence of Acute Anterior MI only 
with ST-segment elevation of ≥ 0.2 mV in two or more anterior 
contiguous precordial leads (V1-V4) will be included. 
 
Roll-In subjects with evidence of Acute Anterior or Inferior MI with 
ST-segment elevation of ≥ 0.2 mV in two or more anterior or inferior 
contiguous precordial leads(V1-V4) will be included. 
Intervention 
Intravascular permissive hypothermia as an adjunct to PCI.  Cooling 
will be initiated prior to PCI with infusion of up to 1 L of cold saline 
(4°C) (according to the guideline) and with the Proteus Console set at 
32.0 degrees Celsius.  Total cooling time will be 3 hours (± 15 
minutes) and will be followed with active rewarming with the Proteus 
IVTM System to attain normothermia [36 °C (96.8°F)]. 
Length of 
Follow Up 
12 months 
Enrollment 
Initiation of enrollment: December 2017 
Completion of Enrollment: June 2019 
Follow up completed: June 2020 
Summary of 
Statistical 
Analysis 
Primary efficacy endpoint of infarct size measured as percentage of 
total LV mass by cMR, the null hypothesis of equal infarct size 
between two arms will be tested with t-test for the study population. 
For the safety endpoint, comparison of per patient MACE rate for non-
inferiority will be made with Fisher’s exact Test. 
Planned 
Interim 
Analyses 
Two interim analyses are planned to be performed at approximately 
50% and 75% of randomization, once subjects have completed 4-6 day 
cMR follow-up. At the interim stage, the trial will be stopped to reject 
the null hypothesis of no difference or continue enrollment. 
Analysis Sets 
The Intention-to-Treat (ITT) population will be used for primary 
statistical analyses and summaries for all analyses except for Safety 
endpoints. The ITT population includes subjects who have signed an 
informed consent and have been randomized to the Test Arm or the 
Control Arm of the trial. ITT subjects will be evaluated according to 
the group to which they were randomized. 
The Per-Protocol (PP) population includes those subjects who met 
inclusion and exclusion criteria, were randomized to either the Test 
Arm or Control Arm, received the treatment to which they were 

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randomized, and complied substantially with the treatment timeline 
and steps of this protocol without major protocol violations. 
The Safety Analysis Set will be used to evaluate safety endpoints. 
These will be all subjects included in the study as defined by the ITT 
analysis set and Roll-In subjects. For the safety analysis subjects will 
be followed for all Adverse Events 30 days post procedure. 
Additionally, all subjects will be followed through 12 months post 
procedure for the incidence of Serious Adverse Events (SAEs), Death 
and Heart Failure (as assessed by NYHA and Kansas City 
Cardiomyopathy Questionnaire (KCCQ)). 
Trial 
Oversight 
Each participating site will dedicate one Principal Investigator to 
oversee the execution of the clinical trial in accordance with the 
protocol. 

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2 
 INTRODUCTION 
Clinical investigations have shown that induction of hypothermia before reperfusion of 
acute coronary occlusion reduces infarct size.  A pilot study from Lund University 
demonstrated that the induction of mild hypothermia (<35°C) in ST Elevation Myocardial 
Infarction (STEMI) patients prior to performing Percutaneous Coronary Intervention 
(PCI) can save (preserve) 38% more cardiac tissue compared with the PCI alone.1 
Hypothermia has proven to be one of the most potent and consistent adjunctive therapies 
for infarct size reduction in numerous preclinical studies, when administered prior to 
reperfusion.  This is unlike the well accepted approach for therapeutic hypothermia for 
cardiac arrest, where cooling is applied after reperfusion. The mechanisms leading to 
protection are multifactorial.  However, unlike the consistent findings in preclinical 
studies, clinical trials (COOL -MI, ICE-IT, CHILL-MI) have failed to show a decrease in 
infarct size.  The major reason is likely due to the difficulty in achieving adequate cooling 
prior to reperfusion.  As shown in Table 1 below, none of the clinical trials to date has 
reached target temperature prior to reperfusion, as has been done in all of the animal 
studies. 
Table 1: Major Cooling Trials in STEMI. 
Major Cooling Trials in STEMI 
Trial 
Sample 
Size 
Target 
Temp 
(°C) 
Actual 
Temp at 
Reperfusion 
(°C) 
Temp Miss 
(°C) 
Cooling Time 
before 
Reperfusion 
(min) 
COOL -MI 168 – 
Hyp 
157 – 
Control 
33.0 
35.0 
2.0 
18 
ICE-IT 
105 – 
Hyp 
99 – 
Control 
33.0 
35 
2.0 
16 

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CHILL-MI 61 – 
Hyp 
59 – 
Control 
33.0 
34.7 
1.7 
13 
 
The target temperature for each trial was 33.0 °C.  The actual temperature at the time of 
reperfusion was 1.7-2.0 °C higher than target.  This is a miss in temperature “dose” of 
around 50% [normal temperature is 37.0 °C, target temperature was 33.0 °C, (37.0 – 35.0) 
/ (37.0 – 33.0) = 50%].     
Post hoc analysis of these trials showed that patients with anterior MI that were cooled to 
less than 35°C at the time of PCI showed a significant reduction in infarct size, supporting 
the idea of a dose response (See Figure 1).  Recent preclinical results (Stanford-ZOLL 
data) have shown that temperature at reperfusion of 32 °C is superior to 35 °C for reducing 
infarct size, confirming a dose response.  Future clinical trials will require more powerful 
cooling devices, and more consistency in implementing 18 minutes of cooling before 
reperfusion across all study sites in order to evaluate the actual effectiveness of therapeutic 
hypothermia as a protection strategy. 
 
 
Figure 1: Temperature at reperfusion for the Major Therapeutic Hypothermia in 
AMI Clinical trials. 

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The Proteus device has a confirmed faster cooling rate.  With a duration of cooling of 18 
minutes prior to reperfusion, as occurred in the COOL -MI trial, the expected temperature 
at reperfusion is 33.3°C with the Proteus device.  This is significantly better than the 35°C 
achieved in COOL -MI and ICE-IT, and 34.7°C achieved in CHILL-MI. The relative 
effectiveness of the Proteus device for cooling, compared to the performance of the prior 
studies is shown in Figure 1 above. The addition of a bolus infusion of 4°C cold saline is 
expected to further enhance the temperature achieved at reperfusion with the Proteus 
System.  
This Investigational Plan was developed in accordance with the requirements set forth in 
the Good Clinical Practices (E6)2, ISO 14155:2011 Clinical investigation of medical 
devices for human subjects3 - Good clinical practice, the Declaration of Helsinki, and the 
local regulatory requirements an adjunctive therapy to PCI. 
3 
BACKGROUND 
Coronary heart disease complicated by acute myocardial infarction (AMI) remains a 
leading cause of death and disability worldwide.  AMI most commonly occurs when a 
coronary artery becomes occluded by thrombus following the rupture of an atherosclerotic 
plaque. Factors that may affect the size of the subsequent infarction include duration of 
ischemia, size of ischemic territory, collateral blood flow, and myocardial metabolic rate. 
Long-term sequelae of AMI include ventricular remodeling, loss of ventricular function, 
congestive heart failure, dysrhythmias, and sudden death. 

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Although major gains have been made in improving the outcome of patients suffering 
AMI, and early myocardial reperfusion with the use of thrombolytic therapy or primary 
percutaneous coronary intervention (PCI) are effective, morbidity and mortality remain 
substantial.  This may be because restoration of blood flow to the ischemic myocardium 
can itself induce injury through myocardial “ischemia reperfusion injury” (IRI), which 
can be defined as that portion of the ischemia-reperfusion continuum which is preventable 
by treatment initiated after restoration of blood flow.4 It has been proposed that 50% of 
the final infarct size may be a function of IRI. 4 
Ischemia reperfusion injury is protean in its components, likely including free radical and 
reactive oxygen species, disordered vasculature, inflammatory injury, programmed cell 
death, and pathologic remodeling among others.5   Unfortunately, the cascading nature of 
these events challenge and, in the end, may defeat the single molecular target 
pharmacologic model.  The long list of failed IRI pharmacologic agents includes 
antioxidants, calcium channel blockers, anti-inflammatory drugs, sodium hydrogen 
exchange inhibitors, among others, has led some to question the importance of reperfusion 
injury in the myocardium.6  Large infarctions still occur despite timely reperfusion, due to 
reperfusion injury.  Numerous treatments have been studied to reduce reperfusion injury, 
with little success to date. 7-9 
Therapeutic hypothermia (TH) has been studied for many years as a potential therapy for 
ischemia and reperfusion.10 -16 The past few years have seen development of a broad 
literature reporting both laboratory and clinical trials of mild post-reperfusion TH in the 
treatment of disease entities as diverse as acute cardiac arrest, stroke, and myocardial 
infarction, among others.  Unlike single pharmacologic agents, TH has the potential to 
modify and ameliorate multiple pathways of injury. 
4 
INTENDED USE, SYSTEM OVERVIEW, & DEVICE DESCRIPTION 
 
Intended Use / Indication for Use 
The ZOLL® Proteus™ Intravascular Temperature Management (IVTM) System is 
indicated for use in adult subjects with acute myocardial infarction to induce and maintain 
hypothermia prior to percutaneous coronary intervention as an adjunctive therapy to 
reduce anterior infarct size.  The Proteus IVTM System is to be used only as part of the 
clinical investigation. 
 
System Overview 
The Proteus Intravascular Temperature Management (IVTM) System consists of four 
primary components: a single-use heat exchange catheter; heat exchange cassette; a 
temperature probe and a reusable microprocessor-driven console.  The system is designed 

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to achieve and maintain patient temperatures within the range of 32 - 37°C. Its 
performance profile includes: 
1. Rapid patient cooling and warming 
2. Precise achievement and maintenance of a desired patient target temperature 
3. Quick and simple deployment: See the catheterization lab, critical care unit, 
emergency department, and other hospital settings 
Reference the Investigator Brochure for additional information on the Proteus 
IVTM System. 
The Proteus IVTM System couples a heat exchange catheter with a dual microprocessor-
driven controller to manage patient temperature. The Proteus IVTM System is designed 
to rapidly cool and warm patients, achieve and precisely maintain a target patient 
temperature and to be quickly and easily deployed. 
Cool or warm sterile saline is continuously circulated through the catheter, thereby cooling 
or warming the blood as it flows over the catheter without perfusion of fluids into the 
body. The saline is transported from the catheter to the cassette (mounted in the console) 
via extension lines. The cassette has an integral heat exchange element and a pump that 
couples with the console to cool or warm the saline being pumped through the closed 
circuit comprised of the cassette and catheter. The Proteus IVTM Console continuously 
monitors the patient temperature and controls the catheter temperature to cool, warm or 
maintain the target temperature. 
 
Device Description 
4.3.1 Proteus Catheter 
The Proteus Catheter (Figure 2) is a single-use, heparin coated, endovascular heat 
exchange catheter consisting of a triple lobed, helically wound balloon mounted on the 
distal portion of a multi-lumen shaft.  The catheter is designed for placement in the Inferior 
Vena Cava via the femoral vein using a 12Fr or a 14Fr hemostatic introducer sheath.  The 
catheter has a fluid supply lumen, a fluid return lumen, a guidewire port at the proximal 
end of the catheter connecting to a guidewire lumen that accommodates guidewires with 
diameters up to 0.038”.  The expanded balloon portion of the catheter has an expanded 
diameter of 17 mm and a length of 26 cm during system operation.  The catheter has a 
radiopaque marker mounted at the distal and proximal end of the balloon portion of the 
catheter.  The distal end of the catheter has a non-traumatic soft tip.  The fluid supply and 
fluid return lumens of the catheter are connected to the cassette via extension lines 
approximately 2 meters in length, which provide the closed heat transfer fluid circuit.  The 

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0.038”, 145-cm. stainless steel guidewire included in the package has a soft atraumatic 
tip. 
Figure 2 Diagram of  Proteus Catheter 
 
4.3.2 Proteus Temperature Probe 
The Proteus System measures a patient’s core body temperature using a heparin-coated 
endovascular dual output probe (X-Probe) advanced through the guidewire lumen of the 
Proteus Catheter after the catheter is placed. 
4.3.3 Proteus Cassette 
The single-use Proteus Cassette consists of a heat exchange element, a pump, a pump 
coupling to interface with the motor drive in the console and fluid lines to interface with 
the heat transfer fluid circulated by the console.  The cassette is designed to be removed 
from the portable control console allowing the catheter to remain in the patient to facilitate 
moving the patient to another location where temperature management can continue using 
the same or another control console. 
4.3.4 Proteus Console 
The Proteus Console (Figure 3) consists of solid-state thermoelectric modules, a motor 
drive, dual fluid level detection systems and dual microprocessors.  A dilute 
polypropylene glycol/water mixture (process fluid) circulates within the console to 
provide heat exchange with the saline heat transfer fluid loop in the cassette.  This 
technology along with microprocessor proportional control of both the saline and the 
patient temperature enable the following features: 
• Designated patient temperature between 32-37°C is maintained within ± 0.3°C 
continuous calculation and display, in all ambient lighting conditions, of patient 
actual temperature, target temperature, and rate of cooling/warming 

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• Redundant safety system to shut down and warn user of patient overheat or 
overcool, saline leakage, sensor failure, and electrical or mechanical malfunction 
• Control console automatically performs a hardware and software diagnostic check 
of all functional and safety systems upon startup 
• Maximum cooling and heating rates vary from patient to patient depending on the 
patient’s cardiac output, size and weight, room temperature and humidity, and the 
successful implementation of the anti-shivering medication regimen, type and 
amount anesthesia, combined use with blankets or active heating/cooling 
apparatus, body cavity exposure to the environment during surgery and other 
factors. 
Figure 3:  Proteus Console 
                                  
 
 

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Figure 4:  Proteus Catheter and Interconnection between Catheter, Temperature 
Probe (X-Probe), Cassette and Console. 
 
4.3.5 Device Labeling 
Written Instructions for Use, Operation Manual, Quick Reference Guide, and Service 
Manual for the Proteus IVTM System will be packaged with product shipped to the 
investigational sites.  The Proteus IVTM System is to be used only as part of the clinical 
investigation.  (See Proteus IVTM System Labeling) 
5 
PRIOR INVESTIGATIONS 
 
Pre-Clinical Studies 
Hypothermia has been shown to reduce metabolic demand and provide ischemic 
protection.  Recent studies across numerous different animal models have demonstrated a 
strong direct relationship between myocardial temperature and infarct size.11,12,14-18  Mild 
to moderate degrees of hypothermia (32-35°C) have resulted in significant reductions in 
infarct size when applied either before or after the onset of coronary occlusion in animal 
studies.   
In other studies, in 1996, Duncker et al, and in 1998 Miki et al, both demonstrated a dose 
response relationship between myocardial temperature and infarct size using a laboratory 
model of AMI.11,12 Subsequently, Dae et al in collaboration with Radiant Inc. 
demonstrated that therapeutic hypothermia can be induced safely and rapidly in animal 

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models using intravascular cooling.13 They then showed that hypothermic therapy initiated 
late during ischemia and continuing for several hours after reperfusion significantly 
improved reflow and reduced macroscopic zones of no-reflow and necrosis in this 
model.15  The study showed:  
• A striking reduction of myocardial infarct size.  The cooled group had an infarct 
of 9 ± 6% of the area at risk vs. 45 ± 8% of the area at risk for controls 
• Preservation of myocardial perfusion and viability in the cooled group as 
demonstrated by radionuclide imaging 
• No evidence of apoptosis in salvaged myocardium in the cooling arm.  Well-
preserved cardiac output during the cooling process. 
Of particular relevance, Gotberg et al reported in 2008 that hypothermia achieved before 
reperfusion decreased infarct size, while hypothermia initiated at the time of reperfusion 
prevented microvascular obstruction, but did not decrease myocardial infarct size. 16 
 
Human Clinical Studies   
5.2.1 COOL MI Trial  
The COOL MI Trial19 was conducted from September 2001 through April 2003. A total 
of 421 patients were enrolled (199 Control, 193 Intervention, 29 Roll-In) at 27 
investigational sites in the US, Germany and Australia.  The primary analysis population 
included 357 patients (180 Control, 177 Intervention) who received the assigned 
treatment.  The COOL MI Trial evaluated the safety and effectiveness of cooling as an 
adjunctive therapy to percutaneous coronary intervention (PCI) in patients with acute 
myocardial infarction.  Table 2 below displays enrollment characteristics. 
Table 2: COOL MI Trial Enrollment Characteristics 
 
Control  
(N=180) 
Intervention 
(N=177) 
p-value 
Anterior Myocardial 
Infarction 
77 (44%) 
74 (42%) 
0.77 
Inferior Myocardial 
Infarction 
99 (56%) 
103 (58%) 
0.77 
Failed thrombolytic therapy 
prior to enrollment 
23 (12.8%) 
18 (10.3%) 
0.67 
Time in minutes – median (interquartile range) 
From symptom onset to 
hospital presentation 
123 (69 – 201) 
114 (60 – 190) 
0.08 
From hospital presentation to 
PCI 
88 (61 – 114) 
104 (80 – 134) 
<0.0001 

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5.2.1.1 
Procedural and Angiographic Results COOL MI Trial 
The Trial demonstrated that endovascular cooling using the Radiant Medical’s (now 
ZOLL’s) Reprieve System TM in the setting of myocardial infarction was safe, well 
tolerated, and readily integrated into the existing treatment pathway.  While the primary 
effectiveness endpoint of the study was not achieved, the data provided a strong signal 
indicating that when patients were sufficiently cooled prior to reperfusion, myocardial 
damage was reduced.19 
The Control and Intervention groups were well matched in terms of culprit vessels, 
percutaneous coronary intervention (PCI) procedures and treatment success.  As expected, 
cooling did not affect the angiographic success of PCI procedures.  Of the 357 patients 
who underwent primary PCI, the majority were treated with stent implantation and a 
platelet glycoprotein receptor inhibitor.  Approximately 20% of study subjects were 
determined to have Thrombolysis in Myocardial Infarction (TIMI 3) flow prior to PCI.  
TIMI Grade Flow is a scoring system from 0-3 referring to levels of coronary blood flow 
assessed during percutaneous coronary angioplasty: 
• TIMI 0 flow (no perfusion) refers to the absence of any antegrade flow beyond a 
coronary occlusion. 
• TIMI 1 flow (penetration without perfusion) is faint antegrade coronary flow 
beyond the occlusion, with incomplete filling of the distal coronary bed. 
• TIMI 2 flow (partial reperfusion) is delayed or sluggish antegrade flow with 
complete filling of the distal territory. 
• TIMI 3 flow (complete perfusion) is normal flow which fills the distal coronary 
bed completely 
After PCI, TIMI 3 flow was achieved in approximately 92% of patients. Only about 30% 
of patients had TIMI myocardial perfusion grade 3; however the percentage was similar 
in both treatment groups and is consistent with literature reports of myocardial perfusion. 
Procedural and angiographic data are presented in Table 3 below. 
Table 3: COOL MI Trial - Procedural and Angiographic Data 
 
Control  
(N=180) 
Intervention 
(N=177) 
p-value 
Infarct related artery, Stent implantation, Glycoprotein & Stenosis Diameter 
Left anterior descending coronary 
artery 
70 (39%) 
69 (39%) 
0.91 
Circumflex artery 
13 (7%) 
14 (8%) 
0.87 
Right coronary artery 
77 (43%) 
74 (42%) 
0.93 

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*Thrombolysis in Myocardial Infarction 
5.2.1.2 
COOL MI Trial Results 
Of the 177 Intervention patients, 11 (6.2%) patients had the Reprieve Catheter placed in 
the emergency room (ER), one (0.6%) patient had the catheter placed in the cath lab 
holding area, and 165 (93.2%) patients had the catheter placed in the cath lab.  Overall, 
patients in the Intervention group received a median of 17 minutes (interquartile range 
(IQR): 10-27) of cooling prior to PCI.  During that time, patient temperature was 
decreased from a median of 36.2°C (IQR: 35.8-36.5) at the initiation of cooling to 35.1°C 
(IQR: 34.5-35.6) at the time of PCI (Figure 1).  The median of the minimum temperature 
reached by each patient was 33.1°C (IQR: 33.0-33.4), which was achieved in 75 minutes 
(IQR: 50-108).  Target patient temperature was set at a 33°C for 3 hours post-PCI.  Patients 
were then re-warmed at 1°C/hr until Investigator-determined normothermia was reached 
[median=36.5 (IQR: 36.2-36.8]).  Figure 5 below shows patient temperature over time 
with cooling and time to PCI.  The goal to reach target temperature of 33°C at PCI was 
not achieved in the trial, due to the inadequate cooling power of the Reprieve System.  As 
noted above, target temperature of 33°C was reached after 75 minutes of cooling, long 
after PCI had occurred. 
Stent implanted 
153 (92%) 
157 (94%) 
0.59 
Glycoprotein IIb/IIIa receptor inhibitor 140 (78%) 
142 (80%) 
0.74 
Initial diameter stenosis  
(mean ± std dev) 
92 ± 14% 
92 ± 12% 
0.93 
Initial TIMI flow 
Grade 0/1 
126 (71%) 
122 (69%) 
0.77 
Grade 2 
14 (8%) 
21 (12%) 
0.28 
Grade 3 
38 (21%) 
34 (19%) 
0.74 
Final diameter stenosis 
7 ± 9% 
8 ± 10% 
1.00 
Final TIMI* flow 
Grade 0/1 
2 (1%) 
5 (3%) 
0.33 
Grade 2 
7 (4%) 
12 (7%) 
0.31 
Grade 3 
170 (95%) 
160 (90%) 
0.11 
Final myocardial perfusion grade 
 
 
 
Grade 0/1 
63 (43%) 
76 (53%) 
0.11 
Grade 2 
35 (24%) 
26 (18%) 
0.27 
Grade 3 
49 (33%) 
41 (29%) 
0.54 

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Figure 5: Median Temperature and Elapsed Times for Intervention Patients 
 
5.2.1.3 
COOL MI Trial Tolerability of Cooling 
Shivering was managed according to the shivering suppression guidelines recommended 
for this study by Dr. Daniel Sessler, Chairman of the Department of Anesthesiology at the 
University of Louisville.  The recommended baseline combination of Pethidine, buspirone 
and skin warming using a forced-air blanket could be supplemented incrementally in the 
event of shivering or patient discomfort, by additional Pethidine, or by slightly increasing 
the target temperature.  If these steps were unsuccessful, patients could be actively 
rewarmed to normothermia. 
This protocol proved to be quite effective at maintaining patient comfort.  Intervention 
patients received an average of 56 mg of oral buspirone and an average of 267 mg of 
intravenous Pethidine over the course of the cooling procedure.  Of 177 patients in the 
treatment group, only one patient (0.6%) required premature warming due to intolerability 
of cooling.  Nine patients (5.1%) required a slight increase in target temperature (0.2°C – 
0.5°C) to maintain patient comfort.  Ninety-eight patients (55.7%) required supplementary 
dosing of Pethidine, but 60 of these 98 patients (61.2%) had not received the 
recommended loading dose of the anti-shivering drugs. 
COOL MI Trial Safety Results: The primary safety endpoint of the COOL MI study was 
the incidence, through 30 days, of Major Adverse Cardiac Events (MACE), defined as the 
composite of death, recurrent myocardial infarction of the target vessel and the need for 
urgent revascularization of the target vessel.  As shown in Table 4 below, there was no 
statistical difference in the incidence of MACE in the Intervention group as compared to 
the Control group.  All MACE were adjudicated by an independent Clinical Events 
Committee and none were attributed to cooling or use of the Reprieve System. Table 4 
1        2        3        4        5        6        7        8        9        10
Elapsed Time (hours)
37
36
35
34
33
Onset 
to 
Door
115 min
Door 
to 
PCI
104 min
Start Temp
= 36.2°C
Median Minimum Temp = 33.1°C
Time to Minimum Temp = 75 min
Temperature ºC
Temp at PCI = 35.1 °C
Cooling Prior to PCI = 17 min
1        2        3        4        5        6        7        8        9        10
Elapsed Time (hours)
37
36
35
34
33
Onset 
to 
Door
115 min
Door 
to 
PCI
104 min
Start Temp
= 36.2°C
Median Minimum Temp = 33.1°C
Time to Minimum Temp = 75 min
Temperature ºC
Temp at PCI = 35.1 °C
Cooling Prior to PCI = 17 min

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below demonstrates the results of the study with regard to the incidence of Major Adverse 
Cardiac Events. 
Table 4: COOL MI Trial Incidence of MACE 
 
These MACE rates observed in COOL MI compare favorably with those reported for 
similar patients in recent AMI trials, such as ADMIRAL, CADILLAC, DANAMI and 
RAPID MI-ICE (Table 5). 
 
Table 5 Incidence of MACE for Comparable Patients in Recent AMI Trials  
Trial 
Death 
Reinfarction 
Revascularizatio
n 
COOL MI (Treatment Group) 
(n=177) 
3.4% 
0.6% 
2.3% 
ADMIRAL (n=149)17 
3.4% 
1.3% 
4.7% 
CADILLAC (n=524)18 
2.7% 
0.8% 
1.6% 
DANAMI-2 (n=790)19 
6.6% 
1.6% 
NA 
RAPID MI-ICE (n=20)1 
0% 
0% 
0% 
5.2.1.4 
COOL MI Trial Adverse Events Related to Cooling 
Potential adverse events related to cooling (e.g., arrhythmia or hemodynamic 
complications) and to placement and/or use of the Reprieve Catheter (e.g., vascular or 
thrombogenic complications) were also evaluated as a secondary endpoint.  The incidence 
of these types of events is presented.  It is important to note that these complications are 
also risks of myocardial infarction and coronary intervention themselves. Table 6 below 
reports the incidence of non-MACE complications. 
Events through 30 days 
Control  
(N=180) 
Intervention 
(N=177) 
p-value 
MACE 
7 (3.9%) 
11 (6.2%) 
0.45 
 
Death 
4 (2.2%) 
6 (3.4%) 
0.71 
 
Recurrent MI 
3 (1.7%) 
1 (0.6%) 
0.63 
 
Urgent Revascularization 
0 (0%) 
4 (2.3%) 
0.12 

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Table 6: Incidence of Other Complications 
Events through 30 days 
Control  
(N=180) 
Intervention 
(N=177) 
p-value 
Bradyarrhythmia 
41 (22.8%) 
46 (26.0%) 
0.56 
Ventricular Tachycardia/Fibrillation 
36 (20.0%) 
31 (17.5%) 
0.64 
Cardiogenic Shock 
11 (6.1%) 
22 (12.4%) 
0.06 
Pulmonary Edema 
3 (1.7%) 
6 (3.4%) 
0.49 
Vascular Complications  
      Retroperitoneal bleed 
      Hematoma >6cm 
      Pseudoaneurysm 
      AV fistula 
15 (8.3%) 
2 (1.1%) 
12 (6.7%) 
1 (0.6%) 
1 (0.6%) 
15 (8.5%) 
1 (0.6%) 
13 (7.3%) 
3 (1.7%) 
0 (0%) 
0.90 
0.95 
0.99 
0.63 
0.95 
Bleeding Requiring Transfusion  
14 (7.8%) 
20 (11.3%) 
0.34 
Deep Venous Thrombosis 
0 
3 (1.7%) 
0.24 
Pulmonary Embolism 
3 (1.7%) 
0 
0.24 
Stroke 
1 (0.6%) 
0 
0.95 
Arrhythmias are a known risk of moderate to severe hypothermia.  In the COOL MI trial, 
with its mild hypothermia target temperature, arrhythmias were not more common and 
appeared to be primarily related to ischemia and/or the coronary intervention.  
Cardiogenic shock requiring treatment with an intra-aortic balloon pump trended toward 
a higher incidence in the hypothermic group.  However, the majority of shock cases 
appeared to be more related to complicated MIs and/or complex interventions than to 
cooling.  Other potential contributory factors (e.g., age, weight, Pethidine dose) were 
compared between shock and stable patients; however, no causal relationships were 
apparent.  The majority of the vascular complications reported in the Intervention group 
were related to the arterial access site for the PCI procedure rather than the venous access 
site for the cooling catheter.  Three cases of deep venous thrombosis (DVT) were reported 
in the Intervention group. 
5.2.1.5 
COOL MI Trial Effectiveness Results 
The primary effectiveness endpoint in the COOL MI study was infarct size, measured 
using SPECT imaging at 30 days.  Overall, there was no observed difference in infarct 
size (%LV) between study groups (Table 7).  The secondary effectiveness endpoints of 
LV ejection fraction, CK-MB release, and ST-segment resolution, likewise did not 
demonstrate a difference between the Intervention and Control groups. 

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Table 7: COOL MI Results 
 
Control  
Intervention 
p-value 
% LV Infarct Size  (N) 
     mean ± std dev 
     median 
157 
13.8 ± 15.1 
10 
168 
14.1 ± 14.3 
10 
0.83 
LV Ejection Fraction  (N) 
     mean ± std dev 
     median 
104 
55.2 ± 11.4 
54 
115 
53.0 ± 12.0 
53 
0.17 
Peak CK-MB  (N) 
     mean ± std dev 
     median 
167 
42.8 ± 48.1 
33.9 
168 
49.1 ± 50.7 
33.6 
0.25 
ST-segment resolution - 90 min. post-PCI 
(N) 
      < 30% 
      30 - 69% 
      ≥ 70% 
90 
11.1% 
27.8% 
53.3% 
82 
20.7% 
35.4% 
39.0% 
 
0.13 
0.36 
0.09 
ST-segment resolution - 180 min. post-PCI 
(N) 
      < 30% 
      30 - 69% 
      ≥ 70% 
79 
10.1% 
20.3% 
60.8% 
80 
16.3% 
27.5% 
51.3% 
 
0.36 
0.38 
0.30 
 
In addition, no statistically significant differences were demonstrated when the 
Intervention and Control patients were compared based on the following stratifications:  
infarct location, time from onset of symptoms to PCI, prior MI, or TIMI flow prior to PCI.  
However, subsequent analysis revealed a strong relationship between final infarct size and 
patient temperature at the time of reperfusion. 
The mean temperature at the time of reperfusion, or more specifically, at the time of first 
balloon inflation, was 35.1°C.  As shown in Figure 6, in the population of patients with 
anterior myocardial infarction, those patients who had a temperature <35°C at the time of 
reperfusion had a statistically significant reduction in final infarct size as compared to 
both the control group (9.3% vs. 18.2%, p=0.05) and those with a temperature ≥35°C 
(9.3% vs. 21.9%, p=0.01). 

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5: Mean Infarct Sizes (%LV) of Patients with Anterior Infarctions 
  
 
 
 
 
 
 
 
 
 
This effect has a strong basis in physiology and was consistent across other clinical 
measures, i.e., there was a trend toward decreased CK-MB release and increased LV 
Ejection Fraction in the cooled patients.  This effect is not attributable to differences in 
baseline clinical or angiographic variables.  In fact, those patients with a temperature 
<35°C were more likely to have occlusion of the proximal versus mid left anterior 
descending coronary artery and a longer time to reperfusion.  These factors would be 
expected to increase infarct size in this group, but the observed reduction in infarct size 
appears to be the result of cooling. 
5.2.2 COOL MI II Trial  
Because of the encouraging results in patients with anterior AMI’s in whom hypothermia 
had been achieved at the time of PCI, COOL MI II was initiated.  Additionally, COOL 
MI II Trial was intended to verify the feasibility of initiating cooling earlier in the 
treatment pathway (e.g., in the emergency department).  Only a fraction of the anticipated 
sample size were enrolled before the trial was ended early because the sponsor became 
financially insolvent after only 41 patients were enrolled. The study data were submitted 
by the sites to a Data Management CRO.  As a result, the final report is not currently 
available because the data was not released to ZOLL by the Data Management CRO upon 
ZOLL acquisition of Radiant Medical.   
In COOL MI II, all cooling was initiated in the Cath Lab even though the focus was on 
earlier cooling.  Since earlier initiation of cooling was not accomplished, reaching the goal 
of a core temperature of 35° C before PCI was dependent on the more powerful GTO 
System.  This was accomplished in 26 of the 27 patients without the intentional delay of 
PCI.  Pivotal data for 23 patients were available and the mean time to reach 35°C was 6.1 
17.9 
9.3 
21.9 
18.2 
0 
10 
20 
30 
All Treatment < 35°C 
≥ 35°C Control 
%LV 
p=0.92 
p=0.05 
p=0.30 
(n=61) 
(n=16) 
(n=38) 
(n=59) 
Subject groups: 
i)   All Intervention patients 
regardless of temperature at PCI 
ii)  Intervention patients cooled 
to      < 35°C at PCI 
iii) Intervention patients > 35°C 
at PCI 
iv) Control patients 
Subject groups: 
i)   All Intervention patients 
regardless of temperature at PCI 
ii)  Intervention patients cooled 
to      < 35°C at PCI 
iii) Intervention patients > 35°C 
at PCI 
iv) Control patients 
Figure 6: Mean Infarct Sizes (%LV) of Patients with Anterior Infarction 

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minutes (± 3.0), 34°C was 14.5 minutes (± 7.9) and 33°C was 31.3 minutes (± 29.9).  Data 
showed 15 of the patients were cooled to 32°C; the mean time was 36.1 minutes (± 14.0).  
Efforts to initiate cooling as early as possible resulted in a median of 39 minutes of cooling 
time prior to PCI, a significant improvement over the median of 18 minutes of cooling 
time achieved in the previous study.  In addition, the median door-to-balloon time was 
106 minutes for these COOL MI II patients, compared to a median of 104 minutes for 
Test patients in the previous study, indicating that PCI was not delayed by the introduction 
of cooling.  By focusing on cooling earlier in the treatment pathway, additional cooling 
time can be achieved without significant adverse impact on time to reperfusion. 
5.2.2.1 
COOL MI II Trial Adverse Events 
As with COOL MI, the primary safety endpoint of the COOL MI II study was the 
incidence, through 30 days, of MACE. Shown below are the adverse events in the COOL 
MI II trial in the intent to treat (ITT) population.  Table 8 combines the Feasibility and 
Pilot hypothermia groups for a total of 41 patients (12 Feasibility and 29 Pivotal). 

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Table 8:  Incidence of MACE and Other Complications 
Events through 30 Days 
Normothermia 
Hypothermia 
Enrollment 
10 
41 
UADE 
0 
0 
Cardiac 
  
  
     Death 
0 
1 (2.4%) 
     Repeat MI 
0 
1 (2.4%) 
     Repeat PCI 
1 (10%) 
3 (7.3%) 
     CABG 
0 
2 (4.9%) 
     Hypotension / Shock 
1 (10%) 
6 (14.6%) 
     CHF 
0 
2 (4.9%) 
     Pericardial Effusion 
0 
1 (2.4%) 
     Pericarditis 
0 
1 (2.4%) 
     HTN 
0 
1 (2.4%) 
Arrhythmias  
  
  
     Ventricular Fibrillation 
0 
4 (9.8%) 
     Vent. Tachycardia 
1 (10%) 
7 (17.1%) 
     Frequent PACs 
1 (10%) 
0 
     SVT 
0 
1 (2.4%) 
     Atrial Fibrillation 
0 
11 (26.8%) 
Vascular Events 
  
  
     Bleeding requiring transfusion 
0 
3 (7.3%) 
     Thrombocytopenia 
0 
2 (4.9%) 
     Anemia 
0 
2 (4.9%) 
     Hematoma > 6cm 
0 
2 (4.9%) 
     DVT   
0 
1 (2.4%) 
     Local Tissue Trauma 
0 
1 (2.4%) 
     Epistaxis 
1 (10%) 
0 
     Hemoptysis 
0 
1 (2.4%) 
     Stroke 
0 
0 
Respiratory Events 
  
  
     Pulmonary Edema 
0 
8 (19.5%) 
     Pulmonary Embolism 
0 
0 
     Hypoxia 
0 
1 (2.4%) 
     Respiratory Failure 
0 
1 (2.4%) 
     Plural Effusion 
0 
3 (7.3%) 
     Increased Pulmonary HTN 
1 (10%) 
0 
     Pneumonia 
1 (10%) 
0 

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Renal 
  
  
     Renal requiring Treatment 
1 (10%) 
2 (4.9%) 
     Hemodialysis 
0 
0 
     UTI 
0 
2 (4.9%) 
     Hematuria 
1 (10%) 
0 
Other 
  
  
     Nausea / Vomiting 
1 (10%) 
15 (36.6%) 
     Systemic Infection 
0 
3 (7.3%) 
     Fever 
0 
3 (7.3%) 
     Muscular Pain 
1 (10%) 
3 (7.3%) 
     Rhabdomyolysis 
1 (10%) 
0 
     Mental Status Changes 
0 
2 (4.9%) 
     Hypokalemia 
0 
1 (2.4%) 
     Vaginal Infection 
0 
1 (2.4%) 
5.2.3 COOL RCN Trial 
The COOL RCN (Radio-Contrast nephropathy) trial was undertaken to evaluate whether 
endovascular cooling provides more effective protection for patients at high risk of 
experiencing RCN.  The trial was designed as an international, multicenter, 1:1 
randomized controlled trial of up to 400 subjects at up to 35 investigational sites.  Subjects 
with a calculated Creatinine clearance of 20 – 50 mL/min and scheduled for a diagnostic 
or interventional catheterization procedure were enrolled. The trial utilized Radiant 
Medical’s Reprieve System. The study was commenced in March 2006 and was 
terminated after enrolling only 136 subjects due to the financial insolvency of Radiant 
Medical. 
Table 9: COOL RCN Trial: Adverse Events Incidence of Complications In-
Hospital  
  
Normothermia  Hypothermia 
P Value 
Enrollment 
70 
58 
  
Nausea/Vomiting 
6 / 70 (8.6%) 
26 / 58 
(44.8%) 
<0.01 
Bradycardia 
2 / 70 (2.9%) 
7 / 58 (12.1%) 0.04 
Bleeding Requiring 
Transfusion 
7 / 70 (10.0%) 
1 / 58 (1.7%) 
0.05 
Atrial Fibrillation 
2 / 70 (2.9%) 
3 / 58 (5.2%) 
0.5 
CABG 
4 / 70 (5.7%) 
1 / 58 (1.7%) 
0.25 
Pulmonary Edema 
4 / 70 (5.7%) 
1 / 58 (1.7%) 
0.25 
Renal Complication 
2 / 70 (2.9%) 
3 / 58 (5.2%) 
0.5 

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Normothermia  Hypothermia 
P Value 
     Acute Renal Failure 
2 / 70 (2.9%) 
2 / 58 (3.4%) 
0.85 
     Elevated Serum Creatinine 
0 / 70 (0%) 
1 / 58 (1.7%) 
-- 
     Hemodialysis 
2 / 70 (2.9%) 
0 / 58 (0%) 
-- 
     Urinary Tract Infection 
3 / 70 (0.4%) 
1 / 58 (1.7%) 
0.41 
Hypotension/Shock 
1 / 70 (1.4%) 
3 / 58 (5.2%) 
0.22 
Hematoma >6cm 
0 / 70 (0%) 
3 / 58 (5.2%) 
-- 
SVT 
0 / 70 (0%) 
2 / 58 (3.4%) 
-- 
MI 
0 / 70 (0%) 
1 / 58 (1.7%) 
-- 
Ventricular Tachycardia 
1 / 70 (1.4%) 
1 / 58 (1.7%) 
0.89 
Death 
0 / 70 (0%) 
1 / 58 (1.7%) 
-- 
Repeat PCI 
1 / 70 (1.4%) 
1 / 58 (1.7%) 
0.89 
Stroke 
0 / 70 (0%) 
1 / 58 (1.7%) 
-- 
 
Table 10: COOL RCN Trial: Incidence of Complications to 30 Days  
  
Normothermia 
Hypothermia 
P Value 
Enrollment 
70 
58 
  
Renal 
7 
2 
0.15 
     Acute Renal Failure 
5 
1 
0.15 
     Renal Stent 
2 
0 
-- 
     Kidney Infection 
0 
1 
-- 
Cardiac 
8 
14 
0.1 
     MI 
1 
1 
0.89 
     CABG 
2 
3 
0.5 
     PCI 
1 
3 
0.22 
 
 

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Normothermia 
Hypothermia 
P Value 
     PCI or CABG 
3 
6 
0.18 
     Death - Cardiac 
1 
2 
0.45 
     Shock 
0 
3 
-- 
     CHF 
2 
1 
0.67 
     Angina 
1 
0 
-- 
     Hypertension 
0 
1 
-- 
Arrhythmia 
3 
3 
0.81 
     Atrial Fibrillation 
2 
1 
0.67 
     Bradycardia 
0 
2 
-- 
     SVT 
1 
0 
-- 
     Ventricular Fibrillation 
0 
0 
-- 
Non-Cardiac 
3 
3 
0.81 
     Stroke 
1 
0 
-- 
     Bleed/Transfusion 
2 
3 
0.5 
     Dialysis  
0 
0 
-- 
Vascular Complications Requiring  Surgery  
0 
0 
-- 
Rehospitalization 
13 
13 
0.59 
Other 
9 
12 
0.23 
     Anasarca 
1 
  
-- 
     Fatigue 
1 
  
-- 
     Ischemic Bowel 
1 
1 
0.89 
     Hypoglycemia 
1 
  
-- 
     Lesion Excision 
1 
  
-- 
     Anemia 
1 
  
-- 
     Hiatal Hernia 
1 
1 
0.89 
     Pulmonary Edema 
1 
  
-- 
     Knee Injury 
1 
  
-- 
     Rash 
  
1 
-- 
     Debridement of Sternal Wound 
  
1 
-- 
     Leg Weakness 
  
1 
-- 
     Nausea/Vomiting 
  
2 
-- 
     Dehydration 
  
1 
-- 
     Acute Respiratory Failure 
  
1 
-- 
     Metabolic Acidosis 
  
1 
-- 
     Back Pain 
  
1 
-- 
     Systemic Infection 
  
1 
-- 

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5.2.3.1 
Unanticipated Adverse Events 
COOL MI Trial – Unanticipated Adverse Events 
There was one Unanticipated Adverse Device Effect (UADE) in the COOL MI Trial; A 
patient experienced nasopharyngeal trauma and bleeding potentially caused by the 
nasoesophageal temperature probe used as part of the Reprieve System. This resulted in a 
modification to the Informed Consent Form to explain the risk of nasal trauma and/or 
bleeding due to the nasoesophageal probe.  
COOL MI II Trial – Unanticipated Adverse Events 
There were no UADE’s in the COOL MI II Trial. 
COOL RCN Trial – Unanticipated Adverse Events 
There was one UADE in the COOL-RCN Trial.  A 73 year old male with chronic renal 
insufficiency and a history of aortobifemoral bypass scheduled for cardiac catheterization.  
The patient was randomized to the Hypothermia arm. The Reprieve catheter was placed 
via the left femoral vein.  The angiogram and stenting procedures were performed via 
right radial arterial access.  After approximately 1 hour of cooling, the patient complained 
that his feet were itching and it was noted that the patient’s left foot and leg were cyanotic 
up to mid-thigh, with no left DP pulse, and  the right foot was slightly discolored.  He was 
subsequently rewarmed at the maximum rate for approximately 40 minutes.  It was 
observed that the cyanosis lightened as the patient rewarmed and was apparently resolved 
with no further sequelae after discontinuation of treatment with the Reprieve catheter, 
indicating that cooling with the device contributed to the reduced peripheral circulation.  
The already compromised peripheral vascular circulation is suspected to have been 
exacerbated by hypothermia induced vasoconstriction. It is known that hypothermia 
induces superficial vasoconstriction, but this degree of cyanosis had not been observed 
with previous use of the device.  Additionally, after the patient had received Pethidine and 
versed as part of the anti-shivering protocol, his respiration became depressed, requiring 
assisted ventilation, Romazicon and Narcan. It is possible that this transient hypoxic event 
may have also contributed to the cyanosis. 
 
Lower extremity cyanosis in the presence of peripheral vascular insufficiency had 
not been identified in the protocol or informed consent document as a potential risk of 
mild hypothermia or use of the Reprieve catheter. The resolution of the cyanosis upon 
rewarming and removal of the catheter indicated that these may have contributed to the 
event. The risk section of the protocol and informed consent were subsequently revised.  
5.2.4 ICE- IT Trial 
The Intravascular Cooling Adjunctive to Percutaneous Coronary Intervention for Acute 
Myocardial Infarction Trial (ICE-IT) 23 randomized 228 patients presenting with an acute 

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MI within 6 hours of symptom onset to endovascular cooling concomitant with PCI versus 
routine PCI. The primary endpoint of infarct size at 30 days as measured by SPECT 
imaging was similar between the 2 groups (10% for the hypothermia group versus 13% 
for the control group, p = 0.14). Like the COOL MI trial, ICE-IT was also an overall 
negative trial. But while TH did not demonstrate any significant decrease in infarct size 
overall, a trend towards benefit was again observed on post-hoc analysis of the subgroup 
with anterior infarction who were sufficiently cooled to a temperature of < 35°C at the 
time of revascularization (infarct size of 12.9% of the left ventricle in the TH population 
compared to 22.7% in the control group, p = 0.09).23 
5.2.5 RAPID-MI ICE Trial 
Recently, Lund University presented a preliminary report of their RAPID-MI ICE Trial.1 
This trial enrolled 20 patients presenting with acute myocardial infarction, and 10 patients 
each were randomized to TH by intravascular cooling or a control group.  Cooling was 
accomplished with a combination of 2L of cold saline infusion and the Phillips InnerCool 
catheter-based cooling system.  The endpoint was infarct size normalized to myocardium 
at risk assessed by cardiac magnetic resonance using T2 weighted imaging and late 
gadolinium enhancement.  Although the sample size is relatively small, the trial produced 
a number of potentially important results: 
• Core body temperature less than for 35°C was achievable before reperfusion without 
significant delay in the door to balloon time. 
• Infarct size normalized to myocardium at risk was reduced by a remarkable 38% in 
patients receiving hypothermia. 
• There were also significant decreases in peak and cumulative Troponin I or T in the 
hypothermia group. 
5.2.6 CHILL-MI Trial 
Lund University recently reported the results of the CHILL-MI trial37, which was a multi-
center study of 120 patients with STEMI (< 6 hours) planned to undergo PCI who were 
randomized to hypothermia induced by rapid infusion of 600 – 2000 ml of cold saline and 
endovascular cooling, or standard of care.  Hypothermia was initiated before PCI and 
continued for 1 hour after reperfusion.  The primary endpoint was infarct size as a 
percentage of the myocardium at risk (IS/MaR), assessed by cardiac MRI at 4±2 days.  
The goal to reach target temperature of 33°C at reperfusion was also not achieved in the 
CHILL-MI trial, due to the inadequate cooling power of the cooling device.  Patients 
randomized to cooling achieved a core body temperature at reperfusion of 34.7°C with a 
9 minute longer door-to-balloon time.  Hypothermia induced by cold saline infusion and 
endovascular cooling was feasible and safe, however, there was no significant difference 
in IS/MaR between the groups.  Exploratory analysis of early anterior infarctions (0-4 hrs) 
showed a significant reduction in IS/AAR of 33% (p<0.05).  Further, the incidence of 

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heart failure was lower with hypothermia at 45 days (3% vs 14%, p<0.05).  This trial, as 
the others cited above, shows potential efficacy of cooling in patients with anterior 
STEMI, supporting further research for confirmation. 
5.2.7 Induction of Mild Systemic Hypothermia With Endovascular 
Cooling During Primary Percutaneous Coronary Intervention for 
Acute Myocardial Infarction 
 
This multi-center study included 42 patients with acute myocardial infarction (AMI) 
(onset less than 6hrs) and evaluated the safety and feasibility of endovascular cooling 
during primary PCI for AMI.39 Subjects were randomized to PCI with or without 
endovascular cooling (target core temperature 33°C). Cooling was maintained for 3 h after 
reperfusion. Skin warming, oral buspirone, and intravenous meperidine were used to 
reduce the shivering threshold. The primary end point was major adverse cardiac events 
at 30 days. Infarct size at 30 days was measured using SPECT imaging. All patients 
successfully cooled did achieved a core temperature below 34°C (mean target temp 33.2 
± 0.9°C). MACE events occurred in 0% vs. 10% (p = NS) of treated versus control 
patients. The median infarct size was not significantly smaller in patients who received 
cooling compared with the control group (2% vs. 8% of the left ventricle, p = 0.80). 
5.2.8 VELOCITY Trial 
The VELOCITY trial38 randomized 54 STEMI patients at 7 centers in the United States 
and Canada to emergent PCI with (n = 28) or without (n = 26) hypothermia induced by 
the Velomedix Automated Peritoneal Lavage System (Velomedix; Menlo Park, CA) 
between January 2013 and January 2014. Baseline characteristics were similar between 
the 2 groups, and 46.3% of all infarcts were anterior. 
Hypothermia (core temperature at or below 34.9°C) was achieved in 96.3% of patients 
and PCI was performed in all but 1 patient in each treatment group. Median door-to-
balloon time was shorter in the control vs hypothermia group (47 vs 62 minutes; P = 
.007). Among the 46 PCI patients who underwent MRI 3 to 5 days post procedure, the 
median myocardial infarct size was similar in the control vs hypothermia group (16.1% 
vs 17.2% of LV mass; P = .54). 
VELOCITY Investigators observed that prolonged door-to-balloon time in the 
hypothermia group may have attenuated the effect of hypothermia on infarct size though 
it is unlikely to have been totally responsible for absence of effect as DTB times were 
short in both groups and within the range wherein further reductions in mortality may not 
be realized. 

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At 30-day follow-up, no patients in the control group had a primary composite safety 
endpoint event, compared with 6 (21.4%) of the patients who underwent hypothermia 
(P = .01). Further details in Section 5.2.8.1. 
In conclusion, the VELOCITY study found that controlled systemic hypothermia through 
automated peritoneal lavage may be safely and rapidly established in patients with 
evolving STEMI undergoing primary PCI at the expense of a modest increase in door-to-
balloon time. In the VELOCITY randomized trial, peritoneal hypothermia was associated 
with an increased rate of adverse events (including stent thrombosis) without reducing 
infarct size. Adequately powered randomized trials (likely limited to patients with anterior 
MI) are needed to assess the effect of rapidly induced hypothermia on myocardial salvage 
and clinical outcomes after primary PCI. 
5.2.8.1 VELOCITY Trial Adverse Events at 30 Days 
At 30-day follow-up, no patients in the control group had a primary composite safety 
endpoint event (death, reinfarction, ischemia-driven TLR, major bleeding, sepsis, 
pneumonia, peritonitis, severe arrhythmias, or renal failure), compared with 6 (21.4%) 
of the patients who underwent hypothermia (P = .01). Four patients (14.3%) experienced 
MACE (cardiac death, reinfarction, or ischemia-driven TVR), and 3 (11.0%)—all in the 
hypothermia arm—developed definite stent thrombosis. 

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Table 11: VELOCITY Trial Clinical Event Rates Within 30 Days 
 
5.2.9 EU AMI Case Series 
ZOLL is currently enrolling patients in the COOL-AMI EU Case Series Trials to assess 
the ability to integrate hypothermia into the current pathway for patients receiving PCI for 
ST elevation MI.  To date, 308 patients have been enrolled at 36 sites in the EU.  Both 
anterior and non-anterior STEMI patients have been enrolled, and cooling is performed 
using the ZOLL Thermogard XP (TGXP) System or Proteus IVTM system.  A series of 
six standards has been developed and monitored to enable consistency in the execution of 
the protocol.  The standards include delivery of the antishivering regimen correctly, 
delivery of 1 L of iced saline before PCI, and at least 18 minutes of cooling delivered prior 
to wire crossing the lesion.  Feedback in the form of a report card (Figure 7) is provided 
to the site after each case as indicated in the following diagram: 
Figure 7:  Report Card Standards 
 

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These six standards are consistently achieved at all sites.  The 18 minute duration of 
cooling matches the average duration of cooling in the previous EU COOL AMI trial.  
The ability to deliver 18 minutes of cooling prior to PCI is consistently achieved in the 
recent EU Case Series, where the door to balloon (DTB) times, at all sites, were less than 
60 minutes (ranging from 38 minutes to 58 minutes).  This is far less than the maximum 
door to balloon time of 90 minutes recommended by the current guidelines for PCI, 2011 
ACCF/AHA/SCAI PCI Guideline24,50).  The experience of one of the sites has been 
published26, and notes that the average DTB time for the first 11 patients enrolled in the 
trial was 38 minutes, compared to a mean DTB time of 37 minutes for all patients 
presenting with STEMI without cooling.  In view of the validation that implementation of 
hypothermia in the treatment pathway for PCI of STEMI patients is feasible, ZOLL has 
also conducted the COOL-AMI EU PILOT Trial, following the same standards of 
implementation, with cooling done by the more powerful Proteus device.  The goal is to 
maximize the dose of cooling prior to PCI. 
5.2.10 COOL-AMI EU PILOT Trial 
ZOLL has completed enrollment in the COOL-AMI EU PILOT Trial that evaluated the 
retention of subjects after integrating therapeutic hypothermia using the ZOLL Proteus 
IVTM System into existing STEMI treatment protocols for subjects who presented with 
acute anterior myocardial infarction.  50 subjects were randomized at 16 sites in the EU. 
22 patients (88%; 95% confidence interval [CI]: 69-97%) in the hypothermia group and 
23 patients (92%; 95% CI: 74-99) in the control group completed cardiac magnetic 
resonance imaging at four to six days and 30-day follow-up. A series of three standards 
were monitored to enable consistency in the execution of the protocol.  The standards 
included delivery of the antishivering regimen correctly, delivery of up to 1 L of iced 
saline, and 18 minutes of cooling delivered prior to wire crossing the lesion. Patients with 

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anterior STEMI were rapidly and safely cooled. Intravascular temperature at coronary 
guidewire crossing after 20.5 minutes of endovascular cooling decreased to 33.6°C 
(range 31.9-35.5°C), which is ≥1.1°C lower than in previous cooling studies. There 
was a 17-minute (95% CI: 4.6-29.8 min) cooling-related delay to reperfusion. In the “per 
protocol” analysis, median infarct size/left ventricular mass was 16.7% in the hypothermia 
group versus 23.8% in the control group (absolute reduction 7.1%, relative reduction 30%; 
p=0.31) and median left ventricular ejection fraction (LVEF) was 42% in the hypothermia 
group and 40% in the control group (absolute reduction 2.4%, relative reduction 6%; 
p=0.36). There were no statistically significant differences between the groups, in adverse 
events or serious adverse events.49 
 
Summary and Clinical Trial Rationale 
Previous clinical trials in patients experiencing acute myocardial infarction (AMI) have 
demonstrated that therapeutic hypothermia is safe, well tolerated and showed reductions 
in infarct size.19 Additionally, recent preclinical results (Stanford-ZOLL data) have shown 
that temperature at reperfusion of 32 °C is superior to 35 °C for reducing infarct size, 
confirming a dose response. Future clinical trials will require more powerful cooling 
devices, and more consistency in implementing 18 minutes of cooling before reperfusion 
across all study sites in order anterior infarctions. It is therefore the objective of the 
COOL-AMI EU PIVOTAL Trial to evaluate the actual effectiveness of therapeutic 
hypothermia as a protection strategy. 
Further clinical trials are needed to evaluate more powerful cooling devices, along with a 
refined therapeutic hypothermia protocol (target temperature of 32°C + 18 minutes of 
cooling prior to PCI). It will also be important to understand whether adequate cooling to 
32°C + 18 minutes of cooling prior to PCI can be implemented into existing STEMI 
treatment protocols with no significant delay in door-to-balloon times. This trial aims to 
address the need for a powered clinical evaluation assessing the safety and effectiveness 
of the Proteus IVTM for this refined therapeutic hypothermia protocol as an adjunct 
therapy for AMI patients undergoing PCI.  Among these refinements are: 1) A larger dose 
of cooling was achieved with the Proteus System (temp at PCI was 33.6°C as opposed to 
35°C for COOL MI), 2) Delivery of at least 18 minutes of cooling prior to PCI was 
possible (mean 20 minutes in the EU Pilot Study), 3) the anti-shivering protocol was 
refined and worked successfully, and 4) the use of report cards for every case to track : a) 
anti-shivering protocol impementation, b) infusion of 1 liter of cold saline prior to PCI, c) 
18 minutes of cooling prior to PCI, d) door to balloon time less than 90 minutes, e) total 
ischemic time less than 6 hours, and f) proper administration of dual antiplatelet therapy 
(DAPT) are all refinements ready to be implemented. 
  

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6 
CLINICAL TRIAL PLAN 
 
Trial Objective 
The objective of this randomized clinical trial is to evaluate the safety and effectiveness 
of therapeutic hypothermia, using the ZOLL Proteus IVTM System, as an adjunctive 
therapy for patients presenting with acute anterior myocardial infarction and undergoing 
PCI, in comparison with patients with acute anterior myocardial infarction and undergoing 
PCI only. Therapeutic Hypothermia may be initiated prior to arrival at the treating 
hospital. 
 
Trial Endpoints 
6.2.1 Primary Effectiveness Endpoint 
Relative reduction of 20% in mean anterior myocardial infarct size (IS), as determined by 
Cardiac Magnetic Resonance (cMR) imaging at 4-6 days post-infarct in the Test Arm 
(cooling + PCI) compared to the Control Arm (PCI only). Infarction Size (IS) is defined 
as % Left Ventricular Mass as measured by Cardiac Magnetic Resonance (cMR) imaging. 
Infarct Size (IS) will be assessed by Cardiac Magnetic Resonance (cMR) at 4 – 6 days 
following the index procedure. The trial is considered to have met the primary efficacy 
endpoint if the Test Arm demonstrates a 20% relative reduction in infarct size compared 
to the Control Arm. 
The ITT analysis set will be used for primary statistical analyses and summaries. The ITT 
population includes those subjects who have signed an informed consent and have been 
randomized to the Test Arm or the Control Arm of the trial. ITT subjects will be evaluated 
according to the group to which they were randomized. 
The PP analysis set will also be evaluated. The PP population includes those subjects who 
met inclusion and exclusion criteria, were randomized to either the Test or Control arm, 
received the treatment to which they were randomized, and complied substantially with 
the treatment timeline and steps of this protocol without major protocol violations. 
6.2.2 Primary Safety Endpoint 
Per-patient rate of composite Major Adverse Cardiac Events (MACE) subjects, defined 
as Cardiac Death (CD), All Myocardial Infarction (All MI) and Clinically-Indicated 
Target Lesion Revascularization (CI-TLR) at 30 day follow-up; non-inferiority to the 
control. 
6.2.3 Additional Assessments: Demographics and Other Parameters 
Subject demographics and various baseline characteristics will also be collected. 
Additional clinical data collected and evaluated will include the number of patients who 
can successfully be enrolled and randomized, the timing of subject presentation to 
hospital, the timing of therapeutic and adjunctive interventions, the timing of reaching the 

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target temperature zone, temperature at PCI, subsequent maintenance of hypothermia and 
temperature data from the IVTM System. Observations will be evaluated relating to the 
use of the ZOLL Proteus IVTM System and how it performs in relation to the induction 
of therapeutic cooling and follow-up cMR imaging. New York Health Association24 
(NYHA) Functional Class and Kansas City Cardiomyopathy Questionnaire25 (KCCQ)  
will be evaluated at 12 month follow-up. 
 
Trial Design 
This clinical trial is a multicenter, prospective, interventional, randomized-controlled trial. 
Randomization will be in a 1:1 ratio, Test Arm (PCI + Cooling) or Control Arm (PCI 
alone) in up to a total of 500 patients (250 subjects in each arm), at up to 70 clinical sites. 
 
To enhance each site’s ability to successfully integrate steps of the protocol and for 
training purposes prior to randomization, each site may enroll up to 4 Roll-In subjects in 
a non-randomized fashion. Roll-In subjects will be treated and followed as subjects in the 
Test Arm of the protocol (PCI + Cooling). Up to a total of 280 Roll-In subjects (up to 4 
per site) may be enrolled. Due to limited cMR data in patients with inferior MI who 
received an adequate dose of cooling prior to revascularization, Inferior MI subjects will 
be allowed to be included as Roll-Ins to further evaluate inferior MI infarct size by cMR 
imaging. Evaluation will be done of cMR imaging at 4-6 days following the index 
procedure. 
 
Patient Population 
Subjects will include those who meet the trial eligibility requirements and who can 
provide informed consent for cooling treatment. Subjects considered for enrollment in this 
trial will include adult patients presenting with an acute anterior myocardial infarction. To 
qualify, patients must have symptoms consistent with AMI (i.e., chest pain, arm pain, etc.) 
unresponsive to nitroglycerin, qualifying ST-segment elevation of ≥ 0.2 mV in two or 
more anterior contiguous precordial leads (V1-V4), with symptom onset greater than 30 
minutes, but less than 4.5 hours prior to arrival of the Emergency Medical Services or 
upon arrival to hospital, and be eligible for PCI.  This ensures that the overall ischemic 
time from symptom onset to time of wire crossing is less than 6 hours.   
Subjects randomized to the Test Arm, as well as all Roll-In subjects, will receive 
intravascular cooling with the Proteus IVTM device.  While undergoing temperature 
management, the Anti-shivering Protocol must be followed (see Attachment II).  
 
Selection Criteria 
Patients shall be screened to the following inclusion and exclusion criteria. Patients are 
qualified for participation only if all Inclusion Criteria have been met and all Exclusion 
Criteria have been confirmed not present. 

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Inclusion Criteria 
All Inclusion Criteria must be answered YES for subject to satisfy Inclusion Criteria: 
 
1. The patient is ≥ 18 years of age. 
2. The patient has symptoms consistent with AMI (i.e. chest pain, arm pain, etc.) and 
unresponsive to nitroglycerin, with symptoms beginning greater than 30 minutes but 
less than 4.5 hours prior to consent.. 
3. Qualifying Infarct Location: 
a. Roll-In subjects:  Evidence of Acute Anterior or Inferior MI with ST- 
segment elevation of ≥ 0.2 mV in two or more anterior or inferior 
contiguous precordial leads (V1-V4). 
b. Randomized subjects: Evidence of Acute Anterior MI only with ST- 
segment elevation of ≥ 0.2 mV in two or more anterior contiguous 
precordial leads (V1-V4). 
4. The patient is eligible for PCI. 
5. The patient is willing to provide written informed consent to participate in this clinical 
trial. 
 
 
Exclusion Criteria 
All Exclusion Criteria must be answered NO for subject to satisfy Exclusion Criteria: 
 
1. The patient has had a previous Myocardial Infarction. 
2. The patient is experiencing cardiogenic shock, systolic blood pressure [SBP] <100 
mmHg, HR>100 bpm and arterial oxygen saturation (pulse oximetry) <92% without 
additional oxygen.   
3. The patient is presenting with resuscitated Cardiac Arrest, Atrial Fibrillation, or 
Killip risk stratification class II through IV. 
4. The patient has an aortic dissection or requires an immediate surgical or procedural 
intervention other than PCI. 
5. The patient has known history of Congestive Heart Failure (CHF), Hepatic Failure, 
end-stage kidney disease or severe Renal Failure (clearance < 30ml/min/1.73m²).  
6. The patient is febrile (temperature > 37.5 °C) or has experienced an Infection with 
Fever in the last 5 days. 
7. The patient has a known previous CABG. 
8. The patient has a known recent Stroke within 90 days of admission.  
9. Cardio-Pulmonary Decompensation that has occurred prior to consent or, in the 
opinion of the physician, that is imminent or likely to occur following presentation to 
the clinical site. 

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10. Contraindications to hypothermia, such as patients with known Hematologic 
Dyscrasias which affect thrombosis (e.g., cryoglobulinemia, sickle cell disease, 
serum cold agglutinins) or Vasospastic Disorders (such as Raynaud’s or 
thromboangitis obliterans). 
11. Any contraindication to cardiac MRI, or any implants in the upper body which may 
cause artifacts on cardiac MRI imaging. 
12. The patient has a known hypersensitivity or contraindication to aspirin, heparin, or 
sensitivity to contrast media, which cannot be adequately pre-medicated. 
13. The patient has a known history of Bleeding Diathesis, Coagulopathy, 
Cryoglobulinemia, Sickle Cell Anemia, or will refuse blood transfusions. 
14. The patient has a height of <1.5 meters (4 feet 11 inches). 
15. The patient has a known hypersensitivity or contraindication to buspirone 
hydrochloride or Pethidine (Meperidine) and/or has been treated with a monoamine 
oxidase inhibitor in the past 14 days. 
16. Patient has a known history of severe hepatic or renal impairment, untreated 
hypothyroidism, Addison’s disease, benign prostatic hypertrophy, or urethral 
stricture that in the opinion of the physician would be incompatible with Pethidine 
administration. 
17. The patient has an Inferior Vena Cava filter in place (IVC). 
18. The patient has a pre-MI life expectancy of <1 year due to underlying medical 
conditions or pre-existing co-morbidities. 
19. The patient has a known, unresolved history of drug use or alcohol dependency, or 
lacks the ability to comprehend or follow instructions. 
20. The patient is currently enrolled in another investigational drug or device trial. 
21. The patient is apprehensive about or unwilling to undergo the required MRI imaging 
at follow-up, has a documented or suspected diagnosis of claustrophobia, or has 
Gadolinium allergy, or is in permanent Atrial Fibrillation. 
22. The patient has received thrombolytic therapy prior to consent 
23. The patient shows clinical evidence of spontaneous reperfusion as observed 
symptomatically and/or from baseline ECG findings (partial or complete ST 
resolution in ECG prior to informed consent and randomization). 
24. The patient is a vulnerable subject, for instance, a person in detention (i.e., prisoner 
or ward of the state). 
25. The patient is a female who is known to be pregnant. 
 
Clinical Trial Procedures 
6.8.1 Patient Screening 
Patients presenting with clinical signs and symptoms of AMI will be expeditiously triaged 
and offered the opportunity to participate in this clinical trial without regard to age, gender 
or ethnicity.  To ensure that patients are approached for potential trial participation without 

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bias, patient screening information will be maintained on a patient screening log at each 
site.  This log will track patients that were enrolled in the trial as well as patients who were 
excluded from participation and the reason(s) for their exclusion. The use of a patient 
screening log assures that all eligible subjects are given an opportunity to participate or 
decline participation in the trial. 
The subject’s eligibility for treatment with the Proteus IVTM System will be evaluated 
based on the medical and anatomical criteria outlined above in the inclusion/exclusion 
criteria section.  The Investigator will explain the elements of this clinical trial, including 
the risks, potential benefits and required interventional and follow-up procedures, to each 
subject prior to obtaining informed consent. 
If a subject is found to be ineligible during baseline screening and routine diagnostic tests, 
the subject shall be considered a screen failure and will be documented on the patient 
screening log.  Roll-In subjects are considered enrolled in the trial when all inclusion and 
exclusion criteria have been satisfied, and informed consent has been signed. Randomized 
subjects are considered enrolled in the trial when all inclusion and exclusion criteria have 
been satisfied, informed consent has been signed, and the patient is randomized to either 
Test or Control Arm of the trial. 
6.8.2 Informed Consent 
The reviewing Medical Ethics Committee (MEC) must review and approve an Informed 
Consent Form (ICF) specific to this study. The Sponsor will provide each study center 
with an example ICF. The study center, to meet specific requirements, may modify this 
example ICF; however, the ICF to be used for subject consent under this protocol must 
contain all of the elements required by the study Sponsor and the governing regulatory 
requirements for informed consent (21 CFR Part 50). Therefore, each investigational site 
will provide the Sponsor with a copy of the MEC approved ICF - as well as any 
amendments - for the duration of the study.  
Informed consent will be required from each subject.  The (MEC) approved Informed 
Consent document must be signed by the patient or by the  legal authorized representative 
(LAR)  prior to any related procedures (or according to the MEC’s approved guidelines), 
including the collection of data on case report forms (CRFs). Only subjects that have the 
appropriate informed consent form will be included in the trial. Consent may be obtained 
either at upon EMS arrival or at hospital admission. 
The informed consent process (including time and date of discussion), should be 
documented in the subject’s medical record and signed/dated by the individual 
(investigator or designee) who recorded it.  The original signed consent form must be filed 
in the subject’s medical record and a copy of the signed informed consent documentation 
given to the subject.  

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All subjects must sign, date and note the time on the Institutional Medical Ethics 
Committee (MEC) approved informed consent prior to any clinical trial/investigation-
specific procedures. Obtaining the consent with the documented date and time, and the 
provision of a copy to the subject will be documented in the subject’s medical record.  
Due to the emergent nature of treating acute myocardial infarction, patients who have been 
enrolled in the study may receive a subsequent consent which provides more detailed 
information about their participation in the trial (based on MEC requirements), which may 
be reviewed and signed after the acute phase of their treatment has been completed.  If the 
patient decides they no longer want to be included in the study, they will be withdrawn 
and their data will be included in the analysis up until the time of withdrawal. 
If in the course of the pre-study evaluations prior to consent, the patient is found not to be 
eligible for inclusion in the study, the patient should be notified and the reason for 
ineligibility documented on the appropriate Screening Log. 
All information pertinent to this clinical investigation (including at a minimum the 
description and purpose of the study, potential benefits, potential risks and 
inconveniences, active procedures, confidentiality, compensation, circumstances for 
termination and site contact persons) will be provided to the subjects in writing and in 
their native, non-technical, language by Investigator or designee, who has been trained on 
the protocol.   
If new information becomes available that can significantly affect a subject's future health 
and medical care, this information shall be provided to the affected subject(s) in written 
form. If relevant, all affected subjects shall be asked to confirm their continuing informed 
consent in writing. 
6.8.3 Roll-In Enrollment  
Prior to randomizing patients, each participating center may enroll up to 4 patients Roll-
In subjects in a non-randomized fashion. Roll-In subjects are treated and followed as 
patients in the Test Arm (PCI + Cooling) for training purposes. The justification for the 
number Roll-In patients in this study is based on ZOLL’s previous clinical trial experience 
in relationship to a site’s ability to successfully incorporate the cooling protocol including 
consent, anti-shivering regimen and an adequate dose of cooling without significantly 
delaying door-to-balloon time.  Successful implementation takes teamwork and often 
several cases to assure the cooling protocol is adhered to with consistent accuracy. 
In light of the fact that previous clinical trials (e.g., COOL-MI19, ICE-IT23 and CHILL-
MI37) have failed to provide an adequate dose of cooling prior to reperfusion, ZOLL has 
implemented a tool called a “Report Card”.  This Report Card notes the site’s success in 
achieving critical aspects of the protocol, called “Standards”, and is provided to the site 
after every patient is enrolled into the trial.  The objective of the Report Card is to report 

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back to the site their success in implementing a set of standards according to the protocol, 
and to encourage continuous improvement following each enrollment.  The Standards, as 
noted on the Report Card, include but are not limited to accuracy of antishivering regimen 
administration and 18 minutes of cooling delivered prior to the wire crossing the lesion. 
The Standard of 18 minutes of cooling has been demonstrated in previous ZOLL trials to 
be the amount of time required to deliver an optimal dose of cooling so the patient’s core 
body temperature is as close to target temperature as possible prior to reperfusion without 
significantly delaying door-to-balloon time. 
Consistent achievement of each standard allows sites to move from Roll-In to 
randomization and enables consistency in execution of the protocol. Feedback will be 
provided to the site after each enrollment to assure the standards have been met and an 
adequate dose of cooling has been achieved.  Use of the Report Card and Standards is 
intended to assist sites in ascending their learning curve as rapidly as possible.  All centers 
will transition from Roll-In to Randomization as soon as possible once they have 
demonstrated their ability to enroll patients while consistently meeting the standards, 
thereby minimizing the number of Roll-In patients but ensuring accurate, precise 
adherence to the investigational protocol. Based on the site’s performance with the Roll-
In patients, as determined by the Sponsor, the site will be notified of authorization to 
randomize patients in the trial. 
Additionally, Roll-In patients will undergo cMR as part of the cMR training process at 
each site.  This will allow the site to train and qualify acquisition of cMR images per cMR 
protocol and ensure high quality and consistent imaging throughout the study across sites.  
Roll-In patients will not be included in the primary endpoint analysis; however, they will 
be included in the safety endpoint analysis.  All performed activities on Roll-In subjects 
will be recorded as if performed in the Test Arm of the trial and hence documented in the 
Case Report Forms (CRF) for training and evaluation. 
Roll-In subjects will be considered to be enrolled when all inclusion and exclusion criteria 
have been met and the informed consent form has been signed. 
6.8.4 Approval to Randomize in the Trial 
It will be at the discretion of the sponsor to advance a site to Randomization.  Based on 
the site’s performance with the Roll-In patients, as determined by the Sponsor, the site 
will be notified of authorization to randomize patients in the trial. 
6.8.5 Randomization 
In the randomization phase, patients who meet eligibility criteria for participation will be 
randomly assigned to either the Test Arm (PCI + Cooling) or Control Arm (PCI alone) in 
a 1:1 ratio. 

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Randomization will be applied using an internet based Interactive Web Response Systems 
(IWRS). In the trial, randomization will be done using random permuted blocks (based on 
procedure outlined in Pocock SJ. Clinical Trials: A Practical Approach. Wiley, 
Chichester, 1983), stratified by site, with 1:1 allocation ratio using a randomization list. 
At randomization, inclusion and exclusion criteria will be verified, and confirmation of 
informed consent signature will be done. 
Subjects will be considered to be enrolled in the Test Arm and Control Arms of the trial 
when all inclusion and exclusion criteria have been met, the informed consent form has 
been signed, and randomization assignment has been completed. 
6.8.6 Acute Care and Emergency Room Triage  
Prior to the initiation of this trial at each participating institution, training will be 
conducted by the Sponsor targeted toward the integrated care of each trial subject and 
emphasizing the shared responsibility between the Departments of Emergency Medicine 
and Interventional Cardiology, where applicable at each center, with the goal of rapid 
screening, enrollment and treatment of appropriate patients. 
Each center will clearly delineate departmental responsibilities for the following: 
• Assessment of patient clinical features, signs and symptoms 
• Administration of Informed Consent 
• Review of Inclusion/Exclusion Criteria 
• Assurance that diagnostic procedures mandated by the protocol are completed 
prior to randomization into this trial and are appropriately documented 
• Patient Randomization 
• Administration of pre-treatment medication(s) 
• Administration of Anti-shivering medications to subjects randomized to the Test 
Arm of the trial 
• Consensus on location in EMS ambulance and/or hospital where cooling using 
the Proteus IVTM System will be initiated 
• Set-up of Proteus IVTM System, including insertion of the Proteus Catheter into 
the femoral vein induction of cooling, initiation of re-warming, Proteus IVTM 
System shutdown and catheter extraction for Test Subjects. 
6.8.7 Standardized Care Prior to the Cooling Procedure 
It is anticipated that subjects may receive one or more of the following therapies as part 
of current clinical practice in the treatment of acute myocardial infarction: 
• Intravenous fluids and electrolytes 
• Oxygen  
• Antiplatelets and/or antithrombotics  
• Vasoactive agents and diuretics 

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Clinicians will be encouraged to manage the subject in a standardized manner with 
respect to oxygenation, anti-coagulation and/or anti-platelet medications.  
6.8.8 Documentation Procedures 
Trial procedures and treatment data will be documented on standardized Case Report 
Forms (CRFs) which may be on paper or via an electronic data capture system (EDC). 
The completion of the CRFs may be delegated to a member of the study team (e.g., the 
study coordinator) as long as that person is listed on the Delegation of Authority Log.  
However, the Principal Investigator retains responsibility for the accuracy and integrity of 
the data entered on the CRF.  The CRF will be monitored for accuracy and completeness 
per the source documents (medical records, charts, interventional systems, worksheets as 
applicable, etc.) at each clinical center.  Temperature data from the Proteus IVTM System 
will be downloaded and sent to Sponsor.  A flow diagram for the Test Arm is represented 
in Figure 10. 
It is anticipated that technology and/or techniques such as edit checks and double entry of 
data may be utilized to minimize the rate of error.  Additionally, ZOLL or its assignees 
may ask for data clarification or re-check of data for accuracy.  Monitoring visits and CRF 
completion logs will be used to track data entry in accordance with trial logistics and 
expectations.  
Any source documentation (procedure reports, imaging studies, lab reports, death 
certificates, etc.) that is sent to the Sponsor should have all patient identifiers removed and 
replaced with the subject’s trial ID, and processes ensuring patient privacy and clinical 
data confidentiality will be followed in accordance with local regulations and applicable 
laws. 
 

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6.8.9 Study Flow and Procedures 
  
Figure 8 Screening and Enrollment Flow 
 
 
 
 
 

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Figure 9 Control Arm Flow 
  
1:1 Randomization
CONTROL ARM
PCI Only
Perform PCI 
Procedure
Obtain Vital Signs 
and Core Body Temp 
at Baseline
Perform 12-lead ECG 
at Baseline
Record Troponin I or 
T at Baseline and 
until peak identified
Document All 
Medications and All 
Adverse Events
Post PCI

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Figure 10 Test Arm Flow 
 
 

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Figure 11 All Patient Procedures 
 
 

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6.8.10  
Pre-Cooling Assessment Procedures 
All required procedures and data collection from the time of subject screening (as from arrival of 
the Emergency Medical Services or hospital)) through the pre-cooling assessment period are given 
below in Table 11. 
 
Table 11:  Baseline / Screening and Enrollment Procedures/Evaluations and Data 
Collection for the Test & Control Arms of the Trial 
Procedures/ 
Evaluations  
Data 
Trial 
Eligibility 
At arrival of  Emergency Medical Services or upon arrival to hospital  
Informed 
Consent  
Obtain Consent from patient before any trial-related procedure is initiated 
(upon arrival of EMS or to the hospital). 
Trial 
Enrollment  
- 
Follow randomization process to assign patient to Roll-In, Test or 
Control Arms of the trial 
- 
Complete Enrollment Form, document randomization, and FAX  or 
email to ZOLL at 
 
+1 800.243.0360 or ami-eu@zoll.com to enter in the eCRF 
Temperature 
Document subject’s temperature using a tympanic thermometer 
Vital Signs 
Blood Pressure, Heart Rate, Respiratory Rate, BSAS measurement 
Physical Exam  
Complete Physical Examination 
Blood Studies 
RBC’s, WBC’s, Hct, Hgb, Platelets,  
Lab Studies 
BUN, Creatinine, sodium, potassium, calcium, phosphate, magnesium, 
chloride, lactic acid, glucose, amylase, lipase 
Cardiac 
Markers  
Baseline and peak Troponin I or Troponin T including upper limit of normal 
ECG 
12-lead baseline 
Medications 
Document as indicated on Case Report Form since STEMI onset 
Adverse 
Events 
Collect all adverse events as soon as patients are enrolled in the trial 
 

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6.8.11 Initiation, Maintenance, and Reversal of Cooling with Proteus IVTM System 
Procedures / Evaluations and Data Collection for Subjects Enrolled in the 
Test Arm 
6.8.12 Test Arm: Temperature Management Protocol and Data Collection Time 
Points 
Treatment with therapeutic hypothermia will begin with a forced infusion of up to 1 L of cold 
saline (4°C) (according to the guideline) using pressure bags, and at the time of administration of 
the anti-shivering medication according to the anti-shivering guidelines, then will continue with 
the Proteus IVTM System as soon as possible.  Cooling will be initiated with the Proteus IVTM 
System set at a temperature of 32.0 °C, and the subject’s temperature will be measured with the 
Proteus IVTM System immediately before PCI has occurred (measured as time the wire crosses 
the target lesion). Cooling will be maintained for 3 hours and will be followed with active 
rewarming to attain normothermia 36.0 °C (96.8°F).  
Cooling induction, maintenance of hypothermia, and rewarming are described in the following 
Table 12. The data collection schedule for Test Arm subjects is summarized in Section 6.8.13. 
Table 12:  Initiation, Maintenance, and Reversal of Cooling with Proteus IVTM System 
Procedures / Evaluations and Data Collection for Subjects Enrolled in the Test Arm 
Phase 
Task 
Immediately Upon 
Arrival of 
Emergency Medical 
Services or at  
Hospital 
1. Turn the Proteus Console on (in preparation for cooling with 
the device) 
2. Document time of occurrence of STEMI and ECG 
3. Document time of arrival of Emergency Medical Service 
EMS (Paramedics) 

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Phase 
Task 
Baseline / 
Enrollment 
4. Immediately after informed consent is obtained and patient is 
randomized to the Test Arm of the trial, initiate anti-shivering 
medication protocol using Guidelines outlined in Attachment 
II. 
5. Begin cooling induction by forced infusion with 25mL/kg of 4°C 
cold saline using pressure bags up to 1 L of cold saline (4°C) 
(according to the guideline) at the physician’s discretion. Use 
Bair HuggerTM (CE marked device) for patient comfort. 
6. Document the time the Proteus console is turned on. The 
device will begin cooling the patient immediately; however, 
optimal cooling is achieved in 5-10 minutes after it is turned on. 
7. Perform Physical Examination and obtain Vital Signs. 
8. Obtain Blood and Lab studies. 
9. Obtain Troponin I or Troponin T . 
10. Obtain 12-lead baseline ECG. 
11. Document all medication use since STEMI onset. 
12. Measure body temperature using an independent tympanic 
thermometer.  The independent measurement is to be used in 
addition to the core body temperature collected by the Proteus 
Temperature Probe (X-Probe). 
13. Document all Adverse Events. 

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Phase 
Task 
Initiation of Cooling  
14. Document the volume of cold saline, the time the cold saline 
infusion is started and the time the cold saline infusion is 
finished. 
15. Following the ZOLL Proteus IVTM System Instructions for Use 
(IFU), insert the Proteus Catheter into the Inferior Vena Cava via 
either femoral vein.  The Proteus Catheter is then connected to 
the Cassette that has been inserted into the Proteus Console. 
16. Following insertion of the Proteus Catheter, insert the Proteus 
Temperature Probe (X-Probe). 
Access site selection may vary by both operator preference and 
anatomical considerations; however, the function of the system is not 
dependent on which femoral vein is chosen. 
17. Once the Proteus System Catheter & Proteus Temperature Probe 
(X-Probe) have been inserted, enter set point temperature to 
32.0°C on the Proteus Console and perform cooling at maximum 
power as soon as the console is ready to cool.  
18. Document the time of Proteus Catheter & X-Probe 
(temperature probe) insertion. 
19. Document the time cooling is initiated with the Proteus 
IVTM System. 
20. Document vital signs (BP, HR, RR), and temperature 
measurements (Tympanic and Proteus Console 
measurements). 
21. Document all medication use. 
22. Document all adverse events since the time of enrollment. 
23. Use Bair HuggerTM warming blankets for counter-warming. 
If choosing to use low dose anticoagulation during the cooling phase, 
follow hospital’s guidelines for venous thromboembolism 
prophylaxis. 

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Phase 
Task 
Hospital arrival and 
transfer to 
catheterization lab 
24. Please refer to 6.8.19 Transferring Subject during Cooling.  
25. Please take all necessary steps to minimize the transfer time 

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Phase 
Task 
Immediately Prior to 
Reperfusion 
26. If clinically relevant shivering (Bedside Shivering Assessment 
Scale (BSAS) of 2 or greater) occurs at 32° (see Anti-Shivering 
Guidelines, Attachment II, and BSAS Attachment III), 
increase the dose of Pethidine (Meperdine) as indicated in 
shivering protocol and increase set point temperature on the 
Proteus IVTM System to 32.5°C. If clinically relevant shivering 
continues (BSAS ≥2), once again increase dose of Pethidine as 
indicated in Anti-Shivering Protocol and increase set point 
temperature on the Proteus IVTM System to 33°C.  Continue this 
process until a temperature is reached where there is no 
shivering. Follow sedation procedures using Anti-Shivering 
Guidelines, Attachment II, and the BSAS Attachment III. 
27. Perform *angiogram after the induction of hypothermia has been 
initiated and just prior to PCI. 
28. Obtain vital signs (BP, HR, RR), BSAS and temperature 
measurements (Tympanic and Proteus Console 
measurements) just prior to PCI. 
29. Document all medication use since the initiation of cooling. 
30. Document all adverse events since the initiation of cooling. 
CAUTION: Anticipate changes in electrolytes and laboratories 
values secondary to hypothermia. 
31. Document core body temperature at the time of PCI. 
32. If subject has not reached 32.0 ± 1.0°C (or temperature where 
shivering does not occur, as indicated above) at the time of PCI, 
continue cooling induction until target temperature has been 
reached. 
33. Document the time wire crossed the target lesion. 

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Phase 
Task 
Maintenance of 
Hypothermia Target 
Temperature 32 
±1°C 
34. Maintain the patient at the set target temperature of 32.0 (or 
temperature where shivering does not occur, as indicated above) 
for 3 hours ± 15 minutes from the initiation of cooling with the 
Proteus System.  
35. Obtain vital signs (BP, HR, RR), BSAS and temperature 
measurements (Tympanic and Proteus Console 
measurements) every 30 minutes during the 3 hours of 
cooling. 
36. Document all medication use since the angiogram/ PCI 
procedure. 
37. Document all adverse events since the angiogram/ PCI 
procedure. 
38. If clinically relevant shivering [Bedside Shivering Assessment 
Scale  (BSAS) of 2 or greater] occurs at 32.0°C (See Anti-
Shivering Guidelines, Attachment II, and BSAS, Attachment 
III), increase dose of Pethidine (Meperidine) as indicated in 
shivering protocol and increase temperature on the Proteus 
IVTM System console to 32.5°C. 
39. If clinically relevant shivering continues (BSAS ≥ 2), once again 
increase dose of Pethidine as indicated in shivering protocol and 
increase temperature on the Proteus IVTM System to 33°C.  
Continue this process until a temperature is reached where there 
is no shivering.  Follow sedation procedures using Anti-
Shivering Guidelines outlined in Attachment II and BSAS 
assessment in Attachment III. 

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Phase 
Task 
Rewarming 
40. After 3 hours of cooling with the Proteus IVTM System, begin 
active rewarming to normothermia.  Palliative care such as 
blankets, Bair Hugger patient warming systems, and warm 
liquids may be used. 
41. Using the Proteus System Console, press STOP and Increase 
target temperature to 36.0°C using the arrow touch buttons and 
then press Continue.  
42. Set rewarming rate to 1.0°C/hr using the arrow touch buttons and 
press Continue to start rewarming. 
43. Maintain the Pethidine infusion during rewarming using the 
Anti-Shivering Protocol outlined in Attachment II. 
44. Obtain blood studies, lab studies and record peak Troponin I or 
Troponin T including upper limit of normal for site. 
45. Document all medication use during the rewarming phase. 
46. Document all adverse events during the rewarming phase.  
CAUTION: Anticipate changes in electrolytes and laboratories 
secondary to re-warming 

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Phase 
Task 
Catheter Removal  
47. Document core body temperature at time of Proteus Catheter 
removal. 
48. Remove Proteus Catheter and X-Probe per IFU and document 
time of removal. 
49. Dispose of the Proteus Catheter, X-Probe and Proteus Cassette 
per institution’s guidelines (single-use). 
50. Assess catheter access site for signs of bleeding, access vessel 
trauma, or hematoma formation. 
 
51. Download temperature data from the Proteus Console after 
the cooling phase has been completed. Send downloaded data 
to amidatadownload@zoll.com immediately upon 
downloading.  Device data must be saved according to 
Section 16.1, Investigator Records.  
52. Document all medication use during the hypothermic phase. 
53. Document all adverse events during the hypothermic phase. 
DO NOT DISCARD SPLITTER CABLE (MULTI–USE  
TEMPERATURE CABLE) 
Normothermia 
54. Document all adverse events until patient is discharged from the 
hospital. 
Post-Procedure 
55. If required, provide additional Informed Consent document to 
patients who were consented with the short consent form (if 
required by MEC or country-specific regulations). 
NOTE:  All post-PCI times will be measured from the start of PCI, defined as time the wire 
crosses the target lesion. In the event that PCI is not performed, the time of the first 
cineangiogram of the infarct related artery will be referenced. If PCI is staged for the non-
culprit lesion, then the PCI will be performed after the 4-6 day cMR 
*Angiograms are to be uploaded for all adjudicable events.  
 

 
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6.8.13 Trial Schedule for Test Arm Subjects 
Procedure/ Interval 
Baseline / 
Enrollment 
Initiation 
of Cooling  
Immediately 
prior to 
reperfusion 
(PCI) 
Maintenance 
of Target 
Temp  
32 ±1°C 
Rewarming to 36°C 
Catheter 
Removal 
Discharge 
Follow-Up 
@ 4-6 Days  
Follow-Up 
@ 30 Days 
(±7 days) 
Follow-Up 
@ 12 
months 
(±14 days) 
Unscheduled 
Visit 
Trial Eligibility & Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
X 
 
 
 
 
Anti-Shivering Protocol 
X 
 
 
X∞ 
 
 
 
 
 
 
 
Cold Saline Infusion 
 
X 
 
 
 
 
 
 
 
 
 
Catheter Insertion Time 
 
X 
 
 
 
 
 
 
 
 
 
Catheter Removal Time 
 
 
 
 
 
X 
 
 
 
 
 
Temperature Documented 
X 
X 
X 
every 30 min 
during 3 hr 
cooling 
every 60 min 
during 
rewarming 
 
 
 
 
 
 
Temperature Data Download   
 
 
 
 
 
X 
 
 
 
 
 
Vital Signs 
X 
X 
X 
every 30 min 
every 60 min 
 
 
 
 
 
 
Blood Studies (upon arrival at 
hospital) 
RBC’s, WBC’s, Hct, Hgb, 
Platelets,  
X 
 
 
 
X 
upon reaching 
normothermia 
 
 
 
 
 
 
NT-pro BNP 
 
 
 
 
 
 
 
 
 
X 
 
Lab Studies (upon arrival at 
hospital) 
BUN, Creatinine, Na, K, Ca, 
Mg, Cl, P, lactic acid, 
glucose, amylase, lipase 
X 
 
 
 
upon reaching 
normothermia 
 
 
 
 
 
 
Any Medication Use since 
AMI onset 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Troponin I or T(including 
ULN) during hospitalization 
X 
Perform Troponin until peak value identified 
 
 
 
 
 
12 lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
SAE only 
X** 
Catheter Access Site 
Assessment  
 
 
 
 
 
X 
X 
X 
 
 
 
Cardiac Magnetic Resonance 
(cMR) imaging 
 
 
 
 
 
 
 
X 
 
 
 
NYHA Assessment 
 
 
 
 
 
 
 
 
 
X 
 
KCCQ  
 
 
 
 
 
 
 
 
 
X 
 
∞For persistent clinically relevant shivering (BSAS ≥ 2), increase dose of Pethidine as indicated in shivering protocol and increase temperature on Proteus IVTM System console by 0.5°C.  Continue this process until a temperature is reached 
where there is no shivering.  Follow sedation procedure using Anti-Shivering Guidelines outlined in Attachment II and BSAS assessment in Attachment III Include BSAS measurement and temperatures from independent method. 
If unscheduled visit occurred within 30 days follow-up, report all AEs. However, if unscheduled visit occurred after 30 days follow-up within 12 months, report only SAEs. 

 
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6.8.14 Trial Schedule for Control Arm Subjects 
Procedure/ Interval 
Baseline / Enrollment 
Immediately prior to 
reperfusion 
(PCI)Post-PCI 
Discharge* 
Follow-Up @ 4-6 
Days  
Follow-Up @ 30 
Days 
(±7 days) 
Follow-Up @ 12 months 
(±14 days) 
Unscheduled 
Visit 
Trial Eligibility & Informed Consent 
X 
 
 
 
 
 
 
Physical Exam 
X 
 
X 
 
 
 
 
Catheter Insertion Time 
X 
 
 
 
 
 
 
Catheter Removal Time 
 
 
 
 
 
 
 
Temperature Documented 
X 
 
 
 
 
 
 
Vital Signs 
X 
 
 
 
 
 
 
Blood Studies  
RBC’s, WBC’s, Hct, Hgb, Platelets,  
X 
 
 
 
 
 
 
 
NT-pro BNP 
 
 
 
 
 
X 
 
Lab Studies  
BUN, Creatinine, Na, K, Ca, Mg, Cl, P, 
lactic acid, glucose, amylase, lipase 
X 
 
 
 
 
 
 
 
Any Medication Use 
X 
X 
X 
X 
X 
X 
X 
Troponin I or T(including ULN) 
X 
Perform Troponin 
until peak value 
identified 
 
 
 
 
 
12 lead ECG 
X 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
SAE only 
X 
Cardiac Magnetic Resonance (cMR) 
 
 
 
X 
 
 
 
NYHA Assessment 
 
 
 
 
 
X 
 
KCCQ  
 
 
 
 
 
X 
 
If unscheduled visit occurred within 30 days follow-up, report all AEs.  However, if unscheduled vist occurred after 30 days follow-up within 12 months, report only SAEs. 

 
 
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6.8.15 Control Arm Protocol and Data Collection Time Points 
The data collection schedule for Control Arm subjects is summarized in Section 6.8.14. For 
patients randomized to the Control Arm, i.e., PCI alone, the following procedures will be 
performed: 
i. 
Document time of occurrence of the STEMI & ECG results 
ii. 
Document time of arrival of Emergency Medical Service EMS (Paramedics) & 
time of arrival at hospital 
iii. 
Collect all adverse events as soon as patients are enrolled in the trial 
iv. 
Perform Blood Studies, Labs, and record Baseline and peak Troponin I or T  
v. 
Perform PCI. If PCI is staged for the non-culprit lesion, then the PCI will be 
performed after the 4-6 day cMR 
vi. 
Monitor and record the patient’s vital signs, temperature, blood pressure, heart 
rate and respiratory rate, at baseline  
vii. 
Obtain 12-lead baseline ECG  
viii. Monitor and record all pharmacological agents 
ix. 
Measure and record  baselineTroponin I or T including upper limit of normal, 
and when a peak is identified. 
x. 
Monitor and record all adverse events for the duration of 30 days follow-up and 
serious adverse events for the duration of 12 month follow-up. 
xi. 
Complete physical exam prior to discharge.  
6.8.16 Follow-up at 4-6 days and at 30 days following the PCI Procedure 
Subjects enrolled in the Test and Control Arms, and Roll-In patients, will undergo Cardiac 
Magnetic Resonance (cMR) to assess infarct size at 4-6 days In addition, the following procedures 
are to be performed at 4 - 6 days and at 30 days after the index procedure (PCI) for all patients: 
i. 
Monitor and record all adverse events for the duration of 30 days follow-up. 
ii. 
Review and record all medication changes since index. 

 
 
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6.8.17 Follow-up at 12 months following PCI 
Following completion of the 30 day follow-up and, all subjects will be followed through 12 months 
for the incidence of Serious Adverse Events, Death and Heart Failure (as assessed by NYHA and 
Kansas City Cardiomyopathy Questionnaire (KCCQ)). 
i. 
 Monitor and record all serious adverse events for the duration of 12 month follow-
up. 
ii. 
Collect NT-pro BNP value to assess clinical prognosis of Heart Failure. 
iii. 
Review and record all medication changes 
iv. 
Perform blinded NYHA Assessment and administer Kansas City Cardiomyopathy 
Questionnaire (KCCQ). 
6.8.18 Use of other Cooling Methods 
For the purposes of this trial, no other cooling methods may be used. 
6.8.19 Transferring Subject during Cooling 
Although interruption during the induction phase of hypothermia is not recommended, if subject 
transfer is required during any phase of the cooling, follow relevant instructions in the device 
Instructions for Use.   
 
For additional detail, refer to the Proteus IVTM System Instructions for Use. The console screen 
also provides prompts for entry of user-defined parameters and system start-up.  
6.8.20 Patient Withdrawal and Discontinuation 
The term “patient withdrawal” refers to the patient deciding to terminate their participation in the 
trial.  The term “discontinuation” refers to the physician deciding that the patient will not continue 
trial participation as defined below.   
A subject has the right to withdraw from the trial at any time and for any reason without prejudice 
to his or her future medical care by the physician or the institution. Trial withdrawal by a subject 
specifically means withdrawal of consent from further participation in the trial. Subjects who 
withdraw consent after enrollment will be evaluated to the time of withdrawal, and withdrawal of 
consent precludes any further trial related treatment or data collection. If possible, a complete, 
final physical examination should be performed on all subjects who withdraw from the trial. At a 
minimum, every effort should be made to document subject outcome at the time of trial 
withdrawal.   
A subject may withdraw from the clinical investigation for the following reason:  

 
 
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o 
Subjects may choose to withdraw from the clinical investigation under the terms 
of the Declaration of Helsinki and their consent documentation without having to 
give a reason;  
A subject may be discontinued from the clinical investigation for the following reasons: 
o 
Any unanticipated adverse reaction which is, in the opinion of the Investigator, 
related to the treatment and will endanger the well-being of the patient if treatment 
is continued;  
o 
Development of any illness(es), infection or condition(s) that might interfere with 
the Clinical Investigational Plan;  
o 
Non-compliance with the clinical investigation procedures deemed by the 
Investigator to be sufficient to cause discontinuation;  
o 
Any problem deemed by the Investigator to be sufficient to cause discontinuation.  
- Investigator will treat all subjects discontinued from the investigation due to an 
unanticipated adverse reaction, directly related to the investigation, until the reaction 
resolves.  
- Investigator will not replace subjects who have withdrawn from the clinical 
investigation if they have received the investigational device. If possible, Investigator 
will perform any procedures or assessments planned for the subject at the time of 
withdrawal.  
All subjects are expected to continue in the trial through the final follow-up assessment or until 
ZOLL notifies the Investigator in writing that further follow-up is no longer required, except in 
the event of death or upon the subject's request for early withdrawal from the clinical trial.  
6.8.21 Patient Lost to Follow-up  
The investigator will attempt to contact a subject at least three times prior to designating them as 
lost-to-follow-up subjects. The investigator will document the date and type of attempted 
communication. The investigator will complete and sign the Study Exit Form when a subject is 
lost to follow-up.  
6.8.22 Early Termination of a Clinical Investigation 
Both the Sponsor and Investigator reserve the right to terminate the clinical investigation at any 
time. If necessary, and after review and consultation with the Principal Investigator, the Sponsor 
will make a final determination on whether to terminate the study. 

 
 
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A clinical investigation or Investigator may be terminated at a clinical center for any of the 
following reasons, or for reasons not listed that affect patient safety or integrity of the trial: 
• Unsatisfactory rate of patient enrollment or compliance to eligibility criteria. 
• Repeated noncompliance with the investigational plan. 
• Inaccurate, incomplete, and/or untimely submission of data. 
• Inadequate accountability of the investigational device. 
 
The sponsor may terminate this trial if there are new, previously unknown adverse events related 
to device or cooling procedure, deaths, SAEs/AEs exceeding those reported as related to 
device/cooling procedures in previous trials, and/or if recommended by DMC (Data Monitoring 
Committee) to stop the trial. The sponsor will make the final determination on whether to terminate 
the study. 
The sponsor may terminate the trial for any other unforeseen circumstances. In case of premature 
termination/suspension, ZOLL will stop the enrollment, inform all investigators at all sites and all 
regulatory agencies governing the study. ZOLL will perform complete device accountability of all 
investigational devices and retrieve them from the clinical sites. All study subjects will be followed 
through the specified follow-up periods. ZOLL will issue a final report of the clinical study. 
6.8.23 Amendments and Protocol Deviations 
Investigator will not deviate from the CIP without prior written confirmation by Sponsor, or their 
designee, except as required in a medical emergency. In medical emergencies, Sponsor does not 
require prior confirmation for protocol deviations, but Investigator will notify Sponsor within 5 
days of the incident and will notify the EC according to local requirements. Investigator, or 
designee, will record deviations with an explanation for the deviation. Investigator will report to 
Sponsor who will analyze them and assess their significance.  Significant deviations from the CIP 
will be reported to the Competent Authority. 
 
Examples of protocol deviations may include those relating to: 
• Eligibility 
• Enrollment and randomization 
• Informed consent 
• Protocol adherence (e.g., tests and assessments done as required in Trial Schedule, etc.) 
 
Routine monitoring will assess Investigator compliance to the protocol.  
 

 
 
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Investigator must not modify the CIP without the prior and written permission from Sponsor. All 
modifications to the clinical protocol must be submitted to the Competent Authority (where 
required) to allow the Competent Authority review and approval.  
 
The Sponsor is responsible for management, processing and approval of any amendment to the 
Investigational Plan. Should the site consider an amendment necessary, the Sponsor will work with 
the site to make the appropriate changes. The Sponsor will manage documentation of such changes 
through the existing document control system. A history of changes and a redline version of the 
documentation will be maintained per the applicable quality system procedures. The proposed 
amendment will be submitted to the reviewing MEC/ IRB and government agency as applicable. 
Any necessary approvals will be received in writing before the requested change is implemented. 
 
This study will be conducted in compliance with ISO 14155, ICH E6 Consolidated Good Clinical 
Practice Guidance, 21 CFR 812, 21 CFR Part 50, and any requirements imposed by countries with 
participating clinical sites. The study will not commence until the necessary government and 
MEC/IRB approvals have been obtained. 
6.8.24 Trial Exit 
The Trial Exit Form (CRF) should be completed at the time a subject is exited from the trial.  A 
subject will be considered to have exited from the trial for any of the following reasons. 
• Subject completes follow-ups required by the investigational plan. 
• Subject dies. 
• Subject requests to be withdrawn. 
• Physician requests that patient be withdrawn to protect the welfare of the patient. 
• Patient is lost to follow-up. 
• Other (specify) 
6.8.25 Subject Confidentiality 
Subject confidentiality will be maintained throughout the clinical trial to the extent permitted by 
law.  That is, every attempt will be made to remove patient identifiers from clinical trial documents.  
For this purpose, a unique subject identification code (site number, subject number and subject 
initials) will be assigned and used to allow identification of all data reported for each subject.  This 
will also ensure that the information can be traced back to the source data.  
Trial data may be made available to third parties, e.g., in the case of an audit performed by 
regulatory authorities, provided the data are treated confidentially and that the subject’s privacy is 
guaranteed.  The identity of a subject will never be disclosed in the event that trial data are 
published. 

 
 
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Security and Unique usernames and passwords will be utilized by data entry, data verification and 
other personnel who have database access to insure confidentiality and protection of data. 
Trial sites must comply with Health Insurance Portability and Accountability Act (HIPPA) and/or 
the subject confidentiality provisions and privacy laws of each participating country, local 
regulations, and institutional requirements, whichever is stricter. 
6.8.26 Device Accountability 
ZOLL is responsible for the availability and traceability of all investigational products.  
Documentation is required at each step of the process via a device accountability log.  
Investigational product will be reconciled on a regular basis. 
The investigator also is required to maintain adequate records of the receipt and disposition of all 
investigational devices.  A device accountability log will be provided for this purpose. 
All unused product must be returned to ZOLL prior to the close of the trial. 
6.8.27 Return of Materials upon Trial Termination 
Sponsor will ship investigational devices only to qualified Investigators participating in this 
clinical investigation. Sponsor will not ship investigational devices to any site until evidence of 
EC approval has been provided to Sponsor, or designee.  
Investigator will control access to investigational devices, and will only use investigational devices 
in the clinical investigation and according to the CIP.  
Sponsor will keep investigational device records to document the physical location of each device. 
Record(s) will include information documenting devices shipped, devices at investigation sites, 
devices disposed of, and devices returned.  
Investigator, or designee, will keep records documenting the receipt, use, return and disposal of 
the investigational devices, which will include:  
• Date of receipt,  
• Identification of each investigational device (serial number or unique code),  
• Expiry date, if applicable,  
• Date or dates of use,  
• Subject identification,  
• Date on which the investigational device was returned, or explanted from subject, if 
applicable, and  
• Date of return of unused, expired or malfunctioning investigational devices, if applicable.  
 

 
 
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After the trial procedures have been completed, all unused devices must be accounted for and 
returned to ZOLL.  Instructions for device return to ZOLL will be reviewed at the site initiation 
visit. 
6.8.28 Trial Closure 
Trial closure can occur under the following circumstances: 
a. termination of site participation in the trial (i.e., closure that occurs prior to meeting 
defined endpoints) of the trial 
b. upon completion of the trial (i.e., when all patients enrolled have completed the follow-
up visits or previously exited the trial, and the CRFs and queries have been completed)  
Under any circumstance for closure of the trial at the site, ZOLL and/or its designees will notify 
the site of this occurrence in writing.  Trial closeout visits will be performed once a determination 
has been made that the trial is closed.  All unused trial devices and any unused trial materials and 
equipment will be collected and returned to ZOLL and/or its designees.  The monitors will ensure 
that the investigator’s regulatory files are current and complete and that any outstanding issues 
from previous visits have been resolved.  Other issues that will be reviewed at this visit include:  
discussing record retention requirements (refer to Section 14.1—Investigator Records), device 
accountability, possibility of site audits, publication policy, and notifying the Medical Ethics 
Committee and Competent Authorities of trial closure, etc., as applicable. 
 
Cardiac Magnetic Resonance (cMR) imaging Core Laboratory 
Cardiac Magnetic Resonance (cMR) imaging must be collected per the Manual of Operations 
provided by the sponsor. Images must be submitted to the core laboratory designated by the 
sponsor for analysis. 
7 
ADVERSE EVENTS & DEVICE DEFICIENCIES 
 
Definitions 
7.1.1 Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in subjects, users or other persons, whether or not related 
to the investigational medical device. 
NOTE 1- This definition includes events related to the investigational medical device or the 
comparator. 
NOTE 2- This definition includes events related to the procedures involved. 

 
 
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NOTE 3- For users or other persons, this definition is restricted to events related to 
investigational medical devices.  
7.1.2 Serious Adverse Event (SAE) 
Adverse event that:  
a) led to a death, injury or permanent impairment to a body structure or a body 
function.  
b) led to a serious deterioration in health of the subject, that either resulted in:  
- a life-threatening illness or injury, or  
- a permanent impairment of a body structure or a body function, or  
- in-patient hospitalization or prolongation of existing hospitalization, or  
- in medical or surgical intervention to prevent life threatening illness  
c) led to foetal distress, foetal death or a congenital abnormality or birth defect.  
NOTE 1: Planned hospitalization for pre-existing condition, or a procedure required by the 
Clinical Investigation Plan, without a serious deterioration in health, is not considered a serious 
adverse event. 
7.1.3 Device Deficiency (DD) 
Inadequacy of an investigational medical device related to its identity, quality, durability, 
reliability, safety or performance. This may include malfunctions, use error, or inadequacy in the 
information supplied by the manufacturer. 
7.1.4 Adverse Device Effect (ADE) 
Adverse event related to the use of an investigational medical device. 
NOTE 1- This includes any adverse event resulting from insufficiencies or inadequacies in the 
instructions for use, the deployment, the implantation, the installation, the operation, or any 
malfunction of the investigational medical device. 
NOTE 2- This includes any event that is a result of a use error or intentional abnormal use of the 
investigational medical device. 
7.1.5 Serious Adverse Device Effect (SADE) 
A adverse device effect that has resulted in any of the consequences characteristic of a serious 
adverse event. 

 
 
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7.1.6 Unanticipated Serious Adverse Device Effect (USADE) 
Serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report. 
NOTE: Anticipated SADE (ASADE): an effect which by its nature, incidence, severity or 
outcome has been previously identified in the risk analysis report. 
 
Adverse Event Reporting 
7.2.1 Adverse Event Reporting from Site to Sponsor and MEC 
The collection of AEs will begin after the informed consent is signed. All AEs that occur through 
completion of the final follow-up visit, whether observed by the investigator or by the subject, and 
whether or not thought to be device related, will be reported in detail on the appropriate CRF and 
followed to resolution or the end of trial participation. 
The description of the AE will include the date and time of onset, seriousness, relationship to the 
device or procedure, the results of any diagnostic procedures or laboratory tests, any treatment 
recommended, and the outcome of the event.  In the circumstance that an AE has not resolved by 
the time of the subject’s completion of the trial, an explanation will be entered on the appropriate 
CRF. 
ZOLL will implement and maintain a system to ensure that the reporting of the reportable events 
by the investigator to ZOLL occur immediately, but no later than 3 calendar days after 
investigational site study personnel awareness of the event. 
7.2.2 Serious Adverse Event Reporting to Sponsor and MEC 
Serious adverse events (SAEs) and device deficiencies should be reported as soon as possible. 
Serious adverse events and device deficiencies must be reported no later than 3 calendar days from 
the site becoming aware of the event or as per the investigative site’s local requirements if the 
requirement is more stringent than those outlined. 
The date the site staff became aware of the SAE must be recorded in the source document. The 
Investigator will further report the event to the IRB/EC according to the institution’s IRB/EC 
reporting requirements. 
Serious adverse events that do not occur in the study subject but occur in the user or other persons 
need to be reported on the fax notification form titled SAE Notification Form. Serious adverse 
events that occur in the user or other persons other than the study subject should not be entered 
into the clinical database. 

 
 
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Serious adverse events should be reported on the SAE Notification Form in the occurrence that 
the clinical database is not available. This does not replace the electronic clinical database. All 
information must still be entered in the clinical database once the system is back to normal 
function. 
7.2.3 UADE/USADE Reporting to Sponsor and MEC 
ZOLL requires the Investigator to report any USADE to the sponsor within 3 calendar days of the 
investigator’s knowledge of the event and to the EC per EC requirements. 
7.2.4 Sponsor Reporting to NCAs (National Competent Authority) when European 
Sites Participate in the Trial 
7.2.4.1 What to Report 
The following events are considered reportable events: 
• any SAE, 
• any Device Deficiency that might have led to a SAE if: 
o suitable action had not been taken or 
o intervention had not been made or 
o if circumstances had been less fortunate 
• new findings/updates in relation to already reported events. 
7.2.4.2 Report to Whom 
Reportable events must be reported at the same time to all NCAs where the clinical investigation 
has commenced using the summary tabulation featured in the of MEDDEV 2.7/3. 
7.2.4.3 Reporting Timelines 
ZOLL must report to the NCAs where the clinical investigation has commenced: 
- for all reportable events as described in section 7.2.4.1 which indicate an imminent risk of death, 
serious injury, or serious illness and that requires prompt remedial action for other 
patients/subjects, users or other persons or a new finding to it: immediately, but not later than 2 
calendar days after awareness by ZOLL of a new reportable event or of new information in relation 
with an already reported event. 
- any other reportable events as described in section 7.2.4.1 or a new finding/update to it: 
immediately, but not later than 7 calendar days following the date of awareness by the ZOLL of 
the new reportable event or of new information in relation with an already reported event. 

 
 
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Device Relationship 
Determination of whether there is a reasonable possibility that an investigational product or device 
caused or contributed to an AE is to be determined by the Investigator and recorded on the 
appropriate CRF form. Determination should be based on assessment of temporal relationships, 
biologic plausibility, association (or lack of association) with underlying disease and presence (or 
absence) of a more likely cause. 
7.3.1.1 Causality Assessment 
The relationship between the use of the medical device (including the medical - surgical 
procedure) and the occurrence of each adverse event shall be assessed and categorized. 
The above considerations apply also to the serious adverse events occurring in the comparison 
group. 
The following definitions are used to assess the relationship of the serious adverse event to the 
investigational medical device or procedures. 
1) Not related: relationship to the device or procedures can be excluded when: 
• the event is not a known side effect of the product category the device belongs to or of 
similar devices and procedures; 
• the event has no temporal relationship with the use of the investigational device or the 
procedures; 
• the serious event does not follow a known response pattern to the medical device (if the 
response pattern is previously known) and is biologically implausible; 
• the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible – and reintroduction of its use (or increase 
of the level of activation/exposure), do not impact on the serious event; 
• the event involves a body-site or an organ not expected to be affected by the device or 
procedure; 
• the serious event can be attributed to another cause (e.g. an underlying or concurrent 
illness/ clinical condition, an effect of another device, drug, treatment or other risk 
factors); 
• the event does not depend on a false result given by the investigational device used for 
diagnosis, when applicable; 
• harms to the subject are not clearly due to use error; 
• In order to establish the non-relatedness, not all the criteria listed above might be met at 
the same time, depending on the type of device/procedures and the serious event. 

 
 
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2) Unlikely: the relationship with the use of the device seems not relevant and/or the event can 
be reasonably explained by another cause, but additional information may be obtained. 
3) Possible the relationship with the use of the investigational device is weak but cannot be ruled 
out completely. Alternative causes are also possible (e.g. an underlying or concurrent illness/ 
clinical condition or/and an effect of another device, drug or treatment). Cases were relatedness 
cannot be assessed or no information has been obtained should also be classified as possible. 
4) Probable the relationship with the use of the investigational device seems relevant and/or the 
event cannot reasonably explained by another cause, but additional information may be obtained. 
5) Causal relationship: the serious event is associated with the investigational device or with 
procedures beyond reasonable doubt when: 
• the event is a known side effect of the product category the device belongs to or of 
similar devices and procedures; 
• the event has a temporal relationship with investigational device use/application or 
procedures; 
• the event involves a body-site or organ that 
• the investigational device or procedures are applied to; 
• the investigational device or procedures have an effect on; 
• the serious event follows a known response pattern to the medical device (if the response 
pattern is previously known); 
• the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible); 
• other possible causes (e.g. an underlying or concurrent illness/ clinical condition or/and 
an effect of another device, drug or treatment) have been adequately ruled out; 
• harm to the subject is due to error in use; 
• the event depends on a false result given by the investigational device used for diagnosis 
17, when applicable; 
• In order to establish the relatedness, not all the criteria listed above might be met at the 
same time, depending on the type of device/procedures and the serious event. 
ZOLL and the investigators will distinguish between the serious adverse events related to the 
investigational device and those related to the procedures (any procedure specific to the clinical 
investigation). An adverse event can be related both to procedures and the investigational device. 
Complications of procedures are considered not related if the said procedures would have been 
applied to the patients also in the absence of investigational device use or application. 

 
 
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In some particular cases the event may be not adequately assessed because information is 
insufficient or contradictory or the data cannot be verified or supplemented. The ZOLL and the 
Investigators will make the maximum effort to define and categorize the event and avoid these 
situations. 
Particular attention shall be given to the causality evaluation of unanticipated serious adverse 
(device) events. The occurrence of unanticipated events related to the use of the device 
(USADE) could suggest that the clinical investigation places subjects at increased risk of harm 
than was to be expected beforehand. 
8 
MONITORING BY DATA MONITORING COMMITTEE 
The Data Monitoring Committee (DMC) is used to ensure safety by reviewing cumulative data 
from the clinical trial at pre-defined intervals for the purpose of safe-guarding the interest of trial 
participants. The DMC will serve in an advisory role in this trial. The composition, guiding 
policies, and operating procedures governing the DMC are described in a separate DMC charter. 
Based on safety data, the DMC may recommend a modification to the protocol or that the sponsor 
stops the clinical trial/investigation. All final decisions regarding clinical trial/investigation 
modifications, however, rest with the Sponsor. 
9 
ADJUDICATION OF EVENTS 
The Clinical Events Committee (CEC) is comprised of qualified physicians who are not 
investigators in the trial. The Clinical Events Committee is responsible for adjudicating specified 
clinical endpoints based on the specific criteria used for the categorization of clinical events in the 
trial. 
Periprocedural MI will be adjudicated according to the Clinically Relevant Myocardial Infarction 
After Coronary Revascularization (CRMI) definition.40 Death, Stent Thrombosis, Spontaneous 
MI, and Revascularization will be adjudicated per ARC definitions.27 
Hospitalization due to Heart Failure will be adjudicated per ACC/AHA definition.48 
The composition, guiding policies, and operating procedures governing the CEC are described in 
a separate CEC Manual of Operations. 
When applicable, sites will provide patients’ source documentation per request from the Sponsor 
and will aploade angiograms into AMBRA website through software service Dicom Grid, Inc., 
which will de-identify angiograms. 

 
 
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10 RECOMMENDATION FOR DAPT AND STENTS 
Control and intervention group patients should receive dual antiplatelet therapy (DAPT) and 
anticoagulation medication as recommended by the ESC Guideline for the management of acute 
myocardial infarction in patients presenting with ST-segment elevation. 
• This includes aspirin 162 or 325 mg po chewed as soon as feasible. 
• This should be followed by loading dose of ticagrelor (preferably crushed or chewed) 180 
mg before PCI. If ticagrelor not available, loading dose of prasugrel (60 mg) can be used. 
o Clopidogrel can be used only if the patient cannot take ticagrelor or prasugrel. 
• This also includes unfractionated heparin (UFH) given as an intravenous bolus as soon as 
feasible with subsequent boluses targeted to an activated clotting time of 200 to 250 
seconds. If Bivalirudin is used, the infusion should continue for 1-2 hours after PCI is 
finished. 
• Use of an intravenous GP IIb/IIIa inhibitor should be used according to the decision of 
interventional cardiologist. 
• In patients with STEMI in whom clopidogrel was initiated before coronary angiography, 
it is recommended to switch to either ticagrelor or prasugrel before, or during, or at latest 
immediately after PCI, if ticagrelor or prasugrel are not contraindicated. 
o Switching from clopidogrel to ticagrelor or prasugrel should include a loading dose 
of ticagrelor 180 mg (preferably crushed or chewed if before or during PCI) or 
prasugrel 60 mg if the patient is not at high risk of bleeding, irrespective of the prior 
dose of clopidogrel. 
• Recommended maintenance therapy consists of aspirin 81 mg once daily (or per local 
practice); ticagrelor 90 mg twice daily for at least 12 months. If ticagrelor not available, 
prasugrel 5 or 10 mg according to label recommendation can be used. 
• If needed, transition to clopidogrel can take place after 30 days post index PCI. 
o The recommended first dose of clopidogrel is 600 mg po 12 h after the last dose of 
ticagrelor or prasugrel. If maintenance therapy consists of aspirin and clopidogrel, 
the recommended doses are aspirin 81 mg once daily (or per local practice) and 
clopidogrel 75 mg once daily. 
• Use second or third generation DES. Do not use BMS or BVS or BRS such as Absorb in 
study patients. 

 
 
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11 RISK ANALYSIS 
 Risk Assessment Process 
 
ZOLL has a documented EN ISO 14971:2012 compliant Risk Management process, which 
includes the identification of risks, risk assessment, identification, implementation and verification 
of adequate controls (mitigations) to ensure that identified risks have been reduced as low as 
possible and to ensure the benefits of the intended use as compared to any residual risk is 
acceptable. 
The intent of the Risk Management process is to identify potential hazardous situations related to 
the design, manufacture, and use of the Proteus IVTM System, evaluate each risk and implement 
controls to reduce the risks as low as possible. 
Risks related to the IVTM System and Sub-Systems (Console, Catheter, Cassette and Temperature 
Probe) have been evaluated in a number of ways: 
• Hazard Analysis – The purpose of the Hazards Analysis is to identify, evaluate and 
control potential hazards to the patient, user and the environment. 
• Software Hazards Analysis - The Software Hazards Analysis is used to investigate 
potential device Software related hazards and control the potential hazards.  
• Design FMECA - The purpose of the Design FMECA is to evaluate failure modes 
of the device components, or subsystems, to identify potential design failure risk, 
then evaluate and control potential hazards. 
• Process FMECA - The purpose of the Process FMECA is to evaluate failure modes 
of the device manufacturing process steps to identify process failure risks, then 
evaluate and control potential hazards. 
The results of the Proteus IVTM System Risk Management process was reviewed, and concluded 
that the risk controls are effective to reduce the risks as low as possible. The ZOLL Proteus IVTM 
System presents an acceptable risk benefit ratio when used in accordance with its labeling for its 
proposed intended use: The Proteus IVTM System is intended for use in adult subjects with acute 
anterior myocardial infarction to induce and maintain hypothermia prior to percutaneous coronary 
intervention as an adjunctive therapy to reduce anterior infarct size.  
Note: See the Investigator Brochure for additional information on the Proteus IVTM System, as 
applicable. 

 
 
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 Expected Clinical Observations 
In subjects who have been treated for myocardial infarction, there are many sequelae of such an 
event that may be thought to be “normal” effects and not due to the treatment provided.  These 
events may be outside the range of what is considered to be “normal” (e.g., a high lab value such 
as a shift in potassium), but do not put the patient at risk for harm.  These events are therefore 
expected physiological responses to treatment with therapeutic hypothermia in all patients.  
Prospectively, these observations may include but are not limited to the following: 
• Shift in Potassium levels 
• High or low levels of glucose 
 
The expected clinical sequelae of patients treated with hypothermia include, but are not limited to, 
the following28: 
• Shivering 
• Prolonged ECG intervals 
• Bradycardia defined as a heart rate of 40 beats per minute and not requiring treatment 
(e.g., pacemaker, medications, etc.) 
• J wave (also called Osborne wave) can occur at any temperature < 32.3°C 
• Blood electrolyte shifts: Calcium, Phosphorus, Magnesium, Chloride 
• High or low levels of glucose: Decreased insulin sensitivity and insulin secretion 
• Asymptomatic shifts in serum amylase and lipase levels 
• Peripheral pulses may be difficult to detect 
Cold Diuresis: Increased resistance to ADH or Vasopressin resulting in decreased water or solute 
reabsorption. 
 Potential Clinical Risks 
Adverse events that are inherent to a PCI procedure and expected to occur in most subjects for a 
projected duration according to the opinion of the investigator may be considered unavoidable.  
Such events include, but are not limited to, those listed in Table 14.  These adverse events should 
not be reported during this trial. 
Table 14 Expected and unavoidable adverse events related to the PCI procedure 
Description of the Event 
Time Frame from the Index Procedure (PCI) 
Back pain related to laying on Cath lab table 
Within 48 hours 
Peripheral vasoconstriction  
Within 24 hours 
Thermal discomfort  
Within 24 hours 
Incisional pain (pain at access site) 
Within 72 hours 
Sleep problems or insomnia 
Within 72 hours 

 
 
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Mild to moderate bruising or ecchymosis 
Within 168 hours 
 
A list of potential (expected) risks that may be associated with use of the Proteus IVTM System is 
provided below.  Since this clinical study utilizes an investigational device, all risks may not be 
known.   However, they are believed to be similar to those associated with the existing intra-
vascular temperature management devices in clinical use or commercially available. 
The following potential adverse events may occur during the course of the clinical trial. 
11.3.1 Potential Adverse Events associated with the Proteus Catheter and Cooling 
System: 
Potential risks related to the Proteus Catheter are reasonably believed to be consistent with the 
common, known risks of central venous catheters and/or venous introducer sheaths.  Potential risks 
related to cooling, re-warming, and/or the Proteus IVTM System include but are not limited to the 
following: 
• Catheter related injury [embolism (air, thrombus, catheter fragment), clinically significant 
hematoma, vascular perforation or dissection, arteriovenous fistula, nerve injury, excessive 
bleeding, pseudoaneurysm] 
• Deep vein thrombosis (DVT) requiring treatment 
• Infection [local or systemic (pneumonia, sepsis, meningitis, visceral organ)] 
11.3.2 Potential Adverse Events associated with the cooling procedure include but 
are not limited to the following:   
• Acute renal failure  
• Acute renal insufficiency 
• Adverse drug reaction 
• Angina 
• Blood lysis 
• Congestive Heart Failure  
• Clinically relevant shivering (BSAS ≥ 2) that cannot be controlled by the antishivering 
medication regimen 
• Dysrhythmia [ventricular tachycardia, ventricular fibrillation or atrial fibrillation requiring 
intervention, bradycardia (HR ≤ 40 bpm, block)] 
• Hyperglycemia / Hypoglycemia 
• Hyperkalemia / Hypokalemia 

 
 
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• Hyperphosphatemia / Hypophosphatemia 
• Hypotension  
• Infection (local, systemic) 
• Liver Failure 
• Myocardial infarction 
• Multi-system organ failure 
• Overcooling (temperature <31.0°C for ≥ 20 continuous minutes) 
• Overwarming (temperature >38°C for ≥ 20 continuous minutes including dehydration, 
burns and neurological damage) 
• Pancreatitis 
• Pulmonary edema  
• Peripheral vascular insufficiency  
• Thrombocytopenia 
• Rebound hyperthermia 
• Respiratory failure during cooling or rewarming 
• Seizures 
• Stroke [Cerebral vascular Accident (CVA)] 
• Transient Ischemic Attack (TIA) 
• Unstable angina 
11.3.3 Risks Associated with Anti-shivering Medications 
In order to preserve patient comfort and suppress the shivering response during cooling, a 
combination of recommended buspirone, where available (or equivalent alternative) and required 
Pethidine (Meperidine) should be used (see Attachment II).  As identified in their labeling, the 
risks associated with the use of these pharmacologic agents in this trial population include the 
following:  
Buspirone (or equivalent alternative) 
• Interaction with MAO Inhibitors  
• Dizziness  
• Nausea  
• Headache  
• Nervousness  
• Lightheadedness  
• Excitement 
 

 
 
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Pethidine (Meperidine) 
• CNS Depression  
• Hypotension  
• Respiratory Depression  
• Circulatory Depression  
• Respiratory Arrest  
• Shock  
• Cardiac Arrest 
 
Other reported reactions:  
• Lightheadedness  
• Dizziness  
• Nausea  
• Vomiting  
• Sweating 
 Additional investigations due to the trial 
Participation in the clinical trial will involve extra blood sampling for laboratory markers 
(electrolytes, complete blood count, baseline and peak troponin including upper limit of normal), 
additional ECGs and the need for cardiac MRI imaging.  All of these are standard clinical 
procedures, and the risks to participants are low.  Sites will be carefully monitored for adherence 
to the protocol.  Patients will be screened for appropriateness for MRI prior to enrollment. 
11.4.1 Delay in PCI through the use of hypothermia therapy 
The probability for potential delay in PCI is considered Occasional.  In prior trials of hypothermia 
for STEMI, the increase in door to balloon time ranged from 9 minutes to 18 minutes.  It is 
noteworthy that this delay was not associated with an increase in infarct size hypothermia patients 
compared to controls.  In fact, patients with anterior STEMI with < 35°C at the time of reperfusion 
showed smaller infart size.  Sites will be trained to incorporate hypothermia into the cath lab 
workflow while minimizing delay.  Feedback will be provided for each case to help maintain 
efficiency. 

 
 
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11.4.2 Implementation of PCI in patients undergoing hypothermia (patient-related 
risks). 
Potential risks related to the use of hypothermia therapy in patients are outlined in sections  11.2.1 
and 11.2.2 above. These risks include: potential adverse events associated with the Proteus 
Catheter and Cooling System, potential adverse events associated with cooling, and potential risks 
associated with the anti-shivering medications. 
11.4.3 Implementation of PCI with concurrent use of endovascular hypothermia. 
The addition of hypothermia as adjunctive treatment of STEMI will potentially lead to more 
difficult conditions for the Investigator and other users.  The ability to integrate hypothermia into 
the cath lab workflow has been demonstrated successfully in prior clinical trials.  Again, thorough 
training, frequent monitoring, and rapid feedback will help mitigate the challenges of incorporating 
hypothermia into treatment for STEMI. 
11.4.4 The concurrent medication. 
Patients who have received medications such as monoamine oxidase inhibitor within a 14 day 
period will be excluded from the trial to prevent potential interaction with the anti-shivering 
medications.  In patients that receive morphine, the pethidine dose will be lowered to decrease the 
likelihood of respiratory depression. 
11.4.5 The supply of 4°C cooled saline solution 
The amount of cooled saline solution is limited to 1,000 ml, an amount shown to be well tolerated 
in the CHILL-MI trial, where the average amount of cooled saline was 1475 ml.  Again, careful 
training and monitoring will help to avoid unnecessary exposure to larger volumes of saline. 
11.4.6 Other procedures within the clinical trial 
The risk of adverse interaction or influence of other procedures within the clinical trial are deemed 
to be low.  In prior hypothermia trials in STEMI, there was no interference with the stenting 
procedure, with resuscitation efforts for arrhythmias or cardiogenic shock.  Hypothermia does 
inhibit the absorption and metabolism of clopidogrel, a anti-platelet inhibitor, given to reduce the 
risk of stent thrombosis.  This risk will be mitigated by calling for adherence to ESC guidelines 
which recommend either prasugrel or ticagrelor, both of which are less affected by hypothermia. 

 
 
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 Potential Clinical Benefits 
Although no assurances or guarantees can be made, there is a reasonable expectation that the use 
of this investigational device is safe within the context of the trial and may be beneficial.  Cooling 
using the device, for instance, may result in improved temperature control relative to the standard 
techniques already in use at the sites. 
The primary benefits of therapeutic hypothermia have been shown to be:  
• Improved patient survival 
• Improved heart tissue salvage after the ischemic event 
Additional potential benefits of therapeutic hypothermia with the Proteus System may include: 
• Faster cooling 
• More accurate control of the cooling procedure than with surface cooling 
• Further improved survival  
There is no guarantee that participation in this trial or use of hypothermia will benefit the trial 
subject.  However, collection of such trial data may provide added benefit for future myocardial 
infarction subjects. 
 Methods to Minimize Risk 
All efforts will be made to minimize risks by selecting investigators who are experienced and 
skilled in using minimally invasive catheter-based cardiovascular interventions and who have been 
adequately trained.  Also, risk minimization activities were performed during development and 
design verification tests of the device.  Activities intended to minimize risks include the following. 
• Investigator and trial personnel training will be conducted to share information regarding 
the design of the Proteus IVTM System, its application, pre-clinical results, and clinical 
trials on comparable intra-vascular cooling devices. 
• Adherence to eligibility criteria and screening procedures will ensure that appropriate 
patients are enrolled.   
• Adherence to the Proteus IVTM System Instructions for Use packaged with the device.  
• 
Corrective and preventative actions will be implemented by ZOLL, as necessary, if 
deviations from recommendations in the protocol or IFU are observed.  
• 
Clinical support by ZOLL representative will be provided during the enrollment in the 
study and thereafter if needed.  ZOLL representatives will only have advisory role.  
• The subjects will be carefully monitored throughout the trial period.   
• The investigator will evaluate the subject adverse events during the course of the trial. 
• Data submitted from the investigative centers will be monitored during the course of the 
trial.   

 
 
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• Monitoring visits will be conducted to evaluate protocol compliance and data quality. 
• Safety and effectiveness data obtained during the course of the trial will be shared with 
investigators in periodic reports to increase understanding of the device and potential 
adverse events. 
• An independent Data Safety Monitoring Board (DSMB) will monitor safety throughout the 
clinical trial. Stopping rules will be discussed with the DSMB and applied for subject safety 
through enrollment. 
 
Detailed trial procedures are provided in Section 6.8 - Clinical Trial Procedures. 
 Risk – Benefit Assessment 
To date, there have been five clinical trials that have reported on the safety and effectiveness of 
therapeutic hypothermia in AMI and one in Radio-Contrast nephropathy (COOL-RCN Trial), with 
a total of more than eleven hundred patients being enrolled in total with at least half of those treated 
with therapeutic hypothermia.  The rate of adverse events are well reported in these populations 
(see section 5, Prior Investigations), and the risks are clearly categorized for these trials.  In 
summary, the number of trials, patients enrolled, and low numbers of safety events reported 
indicate that therapeutic hypothermia in this patient population is at an acceptable risk level to 
engage in this trial. 
There is significant morbidity and mortality associated with the numerous clinical conditions 
outlined in this report, and therapeutic hypothermia has shown promise to greatly improve clinical 
outcomes in these patients.  In particular, patients with anterior STEMI have a higher incidence of 
congestive heart failure, cardiogenic shock, and cardiac mortality.  A significant reduction in 
infarct size in these patients, with therapeutic hypothermia, has the promise to reduce these adverse 
clinical outcomes.  Risks associated with the use of the Proteus IVTM system have been reduced 
via the Risk Management Process, and are deemed acceptable, considering the potential benefits.  
We conclude that the use of the Proteus IVTM system for medical practice is justified and 
warranted. 
 
Risk assessment of the Proteus IVTM System has been performed in accordance with the ISO 
14971:2012.30  The Proteus IVTM System is safe and presents an acceptable risk benefit ratio to 
provide cooling or warming of patients when: 
• Used by and under the supervision of a qualified medical practitioner 
• In patients for whom the risks of a central line are acceptable 

 
 
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• In intensive care environments equipped to handle clinical conditions warranting 
use of the device under this protocol 
• Used according to the Instructions For Use (IFU) 
12 RECORDS AND REPORTS 
Throughout the course of this clinical trial, ZOLL, the investigators, and reviewing MEC are 
responsible for the records and reports detailed in the following sections.  
 Investigator Records 
Investigators must retain all trial records required by ZOLL and by the applicable regulations in a 
secure and safe facility.  The investigator must consult a ZOLL representative before disposal of 
any trial records and must notify ZOLL of any change in the location, disposition, or custody of 
the trial files. 
Trial records are those that individually and collectively permit evaluation of the conduct of the 
trial and the quality of the data produced.  ZOLL’s SOP requires that all clinical trial data be kept 
for a minimum of 15 years and all data used in submissions be kept for the life of the corporation.  
It is the site’s obligation to inform ZOLL if their own policy does not comply with the sponsor’s 
requirement so necessary arrangements can be negotiated.  It is ZOLL’s responsibility to inform 
the investigator/institution as to when these documents no longer need to be retained. 
The investigator is responsible for the preparation (review and signature) and retention of the 
records cited below. 
• All correspondence with another investigator, MEC, ZOLL, a monitor, or FDA, including 
required reports and trial documents which pertain to the investigation. 
• Records of receipt, use, and final disposition of a device.    
• Records of each subject's case history and exposure to the device.  Case histories include 
the Case Report Forms (CRFs) and supporting source data (signed and dated informed 
consent forms, medical records, e.g., progress notes of the physician, patient’s hospital 
chart, nursing notes).   
• The clinical investigational plan, with documents showing the dates of and reasons for each 
deviation from the protocol.  
• Any other records that are required to be maintained by local regulations or by specific 
regulatory requirements for a category of investigations or a particular investigation. 
• Any other record that the reviewing MEC requires to be maintained for the subject 
investigation. 

 
 
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 Investigator Responsibilities 
The participating investigator is responsible for adhering to this Clinical Investigational Plan 
(CIP), FDA CFR,  ISO 14155 and Declaration of Helsinki  (Regulatory requirements of his/her 
country local law). 
Specifically, the Principal Investigator at each site shall: 
a) indicate his/her acceptance of the CIP in writing, 
b) conduct the clinical investigation in compliance with the CIP, 
c) create and maintain source documents throughout the clinical investigation and make 
them available as requested during monitoring visits or audits, 
d) ensure that the investigational device is used solely by authorized users as specified in 
6.2, and in accordance with the CIP and instructions for use, 
e) propose to the sponsor any appropriate modification(s) of the CIP or investigational 
device or of the use of the investigational device, 
f) refrain from implementing any modifications to the CIP without agreement from the 
sponsor, EC and regulatory authorities, if required, 
g) document and explain any deviation from the approved CIP that occurred during the 
course of the clinical investigation, 
h) ensure that an adequate investigation site team and facilities exist and are maintained 
and documented during the clinical investigation, 
i) ensure that maintenance and calibration of the equipment relevant for the assessment of 
the clinical investigation is appropriately performed and documented, where applicable, 
j) ensure the accuracy, completeness, legibility and timeliness of the data reported to the 
sponsor in the CRFs and in all required reports, 
k) maintain the device accountability records, 
l) allow and support the sponsor to perform monitoring and auditing activities, 
m) be accessible to the monitor and respond to questions during monitoring visits, 
n) allow and support regulatory authorities and the EC when performing auditing activities, 
o) ensure that all clinical-investigation-related records are retained as required by the 
applicable regulatory requirement(s), and 
p) sign the clinical investigation report, where applicable. 
 
The investigator is responsible for the preparation and submission of the reports cited in Table 15.  
Reports must be prepared in complete, accurate and timely manner.  These reports may be subject 
to regulatory inspection (and ZOLL) and copying, and the retention requirements described above 
for Investigator Records.  In addition to the reports listed in Table 15, the reviewing MEC may 
request reports pertaining to any aspect of the clinical trial. 

 
 
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Written approval from the Medical Ethics Committee (MEC) with authority for the participating 
site will be obtained prior to the start of the study. The investigator or if applicable, the Sponsor, 
is responsible for submitting all required documents to the MEC. At a minimum the following 
documents will be submitted: 
• Clinical Investigational Plan (CIP) 
• Patient Informed Consent documents in the local language 
• Any other written information to be provided to the subjects in the local language 
• Investigator Brochure (IB) (as required) 
• Other documents will be submitted as per local requirements 
After obtaining MEC approval, the investigator will submit the approval letter indicating the 
approved version of the CIP, Patient Informed Consent, IB and any other reviewed documentation 
to ZOLL. 
 
 

 
 
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Table 15 Investigator Reporting Responsibilities to Sponsor and MEC 
REPORT 
SUBMIT TO 
DESCRIPTION/CONSTRAINTS 
Withdrawal of 
MEC Approval 
Sponsor 
The investigator must report a withdrawal of the reviewing 
authority within 5 working days.  
Case Report Form  
(CRF)  
Sponsor & 
Monitor 
CRFs should be completed as soon as possible after any trial 
related procedure takes place. 
Deviation from 
Investigation Plan 
(Emergency) 
Sponsor & 
MEC 
Notification must be made within 5 working days if the 
deviation was made to protect the life or physical well-being of 
a subject. 
Deviation from 
Investigation Plan 
(Other – Non 
Emergency) 
Sponsor & 
MEC 
If the deviation may affect the scientific soundness of the plan 
or the rights, safety and welfare of the subjects (and is not an 
emergency), then the deviation must be approved by ZOLL, 
the MEC, and the reviewing authority prior to its 
implementation.  If the deviation does not affect these issues 
(trial soundness, rights, safety, etc.) then only ZOLL must 
approve it, (except in cases which are beyond the control of the 
investigator—see section on Protocol Deviations). 
Failure to Obtain 
Informed Consent 
Sponsor & 
MEC 
The Investigator must notify ZOLL and the reviewing authority 
within 5 working days after device use. The investigator must 
submit notification after device use or after the investigator 
first learns of the absence of informed consent. The report must 
include a brief description of the circumstances surrounding the 
failure to obtain informed consent and include written 
concurrence by a licensed physician not involved in the 
investigation. Failure to obtain informed consent must be 
reported to the MEC as required by local regulations. 
Final Report 
Sponsor & 
MEC 
This report must be submitted within 3 months after 
termination or completion of the investigation. 
 
 Sponsor Records  
All Sponsor documents and records shall be maintained as indicated by ZOLL’s Quality System. 
ZOLL will maintain the following trial -related records in accordance with ZOLL record 
retention policies and procedures following the completion of this investigational plan. Clinical 
data for regulatory submissions and publications will be retained for the life of the corporation. 
• All correspondence pertaining to the investigation with the sponsor, a monitor, an 
investigator, an MEC, regulatory agencies, including required reports.    

 
 
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• Records of shipment and disposition of the investigational device.  
• Signed investigator agreements including the financial disclosure information required to 
be collected and current signed and dated curriculum vitae.  
• Records of adverse events and device deficiencies.  
• List of participating institutions 
• Investigational product accountability reports including record of receipt, use, or 
disposition of the device(s) that relate to type, quantity, serial numbers of devices, and 
date of receipt, names of persons who received, used, or disposed of each device and why 
and how many devices have been returned to ZOLL or otherwise disposed 
• All signed and dated case report forms submitted by investigator, samples of patient 
informed consents, and other information provided to the subjects 
• Copies of all MEC approval letters and relevant MEC correspondence 
• Names and evidence of the institutions in which the clinical investigation will be 
conducted 
• Insurance certificates 
• Forms for reporting adverse events and device deficiencies  
• Names/contact addresses of monitors 
• Statistical analyses and underlying supporting data 
• Final report of the clinical investigation 
• The Clinical Investigational Plan, Clinical Monitoring Plan (CMP), Investigator Brochure 
(as applicable), and study related reports 
• Study training records for center personnel and ZOLL personnel participating in the trial 
• Any other records that MEC and /or competent authority requires to be maintained by 
regulation or by specific requirement for a category of investigation or a particular 
investigation. 
 Sponsor Reports 
ZOLL Circulation, Inc. is responsible for the classification and reporting of reportable adverse 
events and device deficiencies and ongoing safety evaluation of the clinical investigation in line 
with local regulatory requirements. 
ZOLL Circulation, Inc. will assure that all Serious Adverse Events and reportable Device 
Deficiencies are reported to the Competent Authorities in accordance with European Medical 
Devices directives and all applicable national regulations. 

 
 
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ZOLL Circulation, Inc. is responsible for the reports cited in Table 16.  These reports are subject 
to regulatory retention and inspection requirements.  Governing Regulatory Agencies or the 
reviewing MEC may request reports pertaining to any aspect of the clinical trial. 
Table 16:  ZOLL Reporting Responsibilities 
REPORT 
SUBMIT TO 
DESCRIPTION 
Unanticipated 
Adverse Device 
Effects; SAEs and 
Reportable DDs 
Relevant 
authorities and 
MECs 
Reporting timeframe as per local regulatory 
requirements. 
Investigators 
Notification throughout the course of the trial 
when appropriate (based on perceived risk) 
Premature 
termination or 
suspension of the 
Clinical 
investigation 
Investigators, 
MECs, Relevant 
Authorities 
Provide prompt notification of termination or 
suspension and reason(s). 
Subject 
enrollment 
Completed 
Investigators, 
MEC and 
Relevant 
regulatory 
Authorities upon 
request 
ZOLL will notify the investigators within 30 
working days of the completion of 
enrollment. Investigators will, in turn, inform 
their MECs, when required. 
Withdrawal of 
MEC approval 
Investigators, 
MECs 
Notification within five working days. 
Final Report 
Investigators, 
MECs, (and other 
relevant 
Authorities upon 
request) 
A final report will be submitted to 
investigators, and MECs within six months 
after completion or termination of this study. 
The investigators shall have the opportunity 
to review and comment on the final report. If 
a clinical investigator does not agree with the 
final report, his/her comments shall be 
communicated to the other investigators. The 
principal clinical investigator in each center 
shall sign the report. 

 
 
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13 MONITORING AND AUDITING PROCEDURES 
 Clinical Trial Sponsor and Monitors 
ZOLL is the Sponsor of the clinical trial.  It is the responsibility of the sponsor to ensure that proper 
monitoring of the investigation is conducted.  Clinical trial monitoring and auditing will be done 
by appropriately trained personnel appointed by the trial sponsor to ensure that the investigation 
is conducted in accordance with ZOLL’s requirements and applicable laws and regulations. 
A monitor is an individual designated by a sponsor or contract research organization to oversee 
the progress of an investigation.  The monitor may be an employee of a sponsor or a consultant to 
the sponsor, or an employee of or consultant to a contract research organization.  The monitor will 
be trained on the device, investigational plan, informed consent, instructions for use, applicable 
ZOLL procedures, electronic data capture system, and regulatory requirements.  The monitor will 
periodically check and report on the progress of the clinical trial at an investigational site or other 
data gathering organization or ZOLL facility.   
 Monitoring Methods 
Monitoring of the clinical trial will be a continuous, interactive process to ensure that high-quality 
data is obtained in compliance with the clinical investigational plan and regulatory requirements.  
Monitoring functions will be conducted by ZOLL, and/ or a contract research organization and/or 
other designees. Specific monitoring requirements are detailed in the Trial Monitoring Plan 
(maintained in the ZOLL COOL-AMI clinical trial project files).  Frequent communication will 
be maintained with each investigational site to keep both the clinical center and ZOLL up-to-date 
and aware of the trial progress.  Case Report Forms will be reviewed for completeness and 
accuracy.   
ZOLL will monitor sites in accordance with the monitor’s tasks set under Section 8.2.4 of Standard 
DIN EN ISO 14155:2012-01. These include visits to the clinical trial sites before the start of, 
during and at the end of the clinical trial. On-site monitoring of all trial centers will be frequent 
enough (at a minimum annually) to assure continued integrity and acceptability of the data.  
Accuracy of data reported on case report forms will be verified by comparison to source 
documents.  Reports of monitoring visits will be provided to the clinical trial personnel at each 
site.  Corrective action will be taken to resolve any issues of noncompliance.  If ZOLL finds that 
an investigator is not complying with the executed trial agreements, the investigational plan, the 
applicable national regulations, or the requirements of the reviewing MEC, then prompt action will 
be taken to secure compliance.  In addition, shipment of the device may be stopped or the 
participation of the investigator may be terminated.  Additional information is provided in Section 
6.30 – Trial Closure. 

 
 
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 Monitoring Visits 
Scheduled visits to the clinical investigational site will occur at the following times:  prior to the 
start of the clinical trial (pre- trial qualification visit), at initiation of the trial (during first index 
procedure or shortly thereafter), interim visits throughout the clinical trial as required, annually, 
and upon completion of the clinical trial. 
 Pre-trial Qualification Visit 
A pre- trial visit will be conducted by ZOLL personnel (or designees) to review the clinical 
investigational plan and regulatory requirements with the investigator and the trial personnel to 
assure that they:  
• Understand the investigational status of the device and the requirements for its use and 
accountability. 
• Understand the clinical investigational plan. 
• Understand the requirements for an adequate and well-controlled clinical trial. 
• Understand and accept the obligation to conduct the clinical investigation in accordance 
with the national regulations. 
• Understand and accept the obligation to obtain informed consent in accordance with the 
national regulations. 
• Understand and accept the obligation to obtain MEC approval before the clinical trial is 
initiated, ensure continuing review of the trial by the MEC, and keep ZOLL informed of 
MEC approval and actions concerning the clinical trial. 
• Have access to an adequate number of eligible patients to participate in the trial (at a 
minimum: 1 patient/center/month). 
• Have adequate facilities and resources to conduct the trial.  This includes resources 
appropriate for use of electronic data capture systems. 
• Have sufficient time from other obligations to carry out the responsibilities of the clinical 
trial. 
• Sign the Investigator Agreement and trial contracts (prior to enrollment of patients). 
A report of the pre- trial qualification visit will be completed.  Resolution of any concerns or 
completion of any appropriate follow-up activities stemming from the pre- trial visit also will be 
documented. 
 Initiation Visit 
ZOLL clinical personnel (or designees) will provide assistance for both technical concerns and 
trial management issues during the initiation visit.  Enrollment of the first patient at each clinical 

 
 
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site may or may not coincide with this visit.  Any observations will be documented and issues 
requiring follow-up will be identified on a monitoring report.  Training of trial personnel also will 
be documented. 
 On-Site Interim Monitoring Visits 
On-site monitoring visits will be made on an as-required basis (and at least annually) to assess 
adherence to the clinical investigation plan, MEC review of trial progress, maintenance of records 
and reports, and selected review of source documents for accuracy, completeness, legibility, and 
omissions.  The monitors will acquire information to assess the progress of the trial (toward 
meeting trial objective) and identify any concerns that stem from observation of device 
performance and/or review of the investigator's patient records, trial management documents, and 
patient informed consent documents.  Monitoring reports will be generated along with 
communications to the investigator, which document the result of the monitoring visit and any 
recommended actions.  Resolution of concerns and completion of assigned tasks will be 
documented. 
 Audits 
An on-site audit may be completed periodically throughout the trial at each clinical site by an 
independent group.  The purpose of the audit will be to ensure compliance to the investigational 
plan and regulatory requirements, e.g., written informed consent was documented, information 
recorded on the case report forms is complete and accurate as compared to source documentation, 
protocol deviations are noted, and device accountability is accurate and complete.  A randomly 
selected number of patient records and other supporting documents will be compared to the case 
report forms.  A record of the findings and recommended actions to correct deficiencies will be 
documented on the audit report. 
 Final Monitoring Review 
Depending upon the status of the trial at each center, a close-out or final visit may be conducted.  
Any ongoing responsibilities will be discussed with the investigator and the trial center 
coordinator.  A final monitoring report, which includes, at a minimum, disposition of any unused 
devices, will be completed. 
14 DATA MANAGEMENT PROCEDURES 
 
ZOLL will oversee all data management functions.  ZOLL will be responsible for database 
development, system maintenance, user training, data queries, and report generation. 

 
 
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 Case Report Forms 
ZOLL will use an electronic data capture (EDC) system to collect patient data.  The electronic case 
report forms (eCRFs) are the primary component of EDC and are based on the sample forms that 
will be provided in a separate document.  Training on use of the system will be provided to the 
trial site personnel.  Instructions for completion of the eCRFs also will be provided. 
The eCRFs must be completed, saved, and locked via electronic signature by the Investigator using 
a unique ID and password.  This ID and password are for the use of the investigator only and may 
not be used by any other person.  Because of the potential for errors or inaccuracies in transcribing 
data into eCRFs, source documentation must be maintained in each subject’s hospital chart and/or 
electronic medical record.  The eCRFs and source documentation must be available at all times for 
inspection by the trial monitors or regulatory inspectors. 
Changes made to eCRFs will be electronically recorded in a complete audit trail that cannot be 
changed, but can be accessed by authorized personnel at any time.  All data are transmitted via the 
Internet in an encrypted fashion.  When received at the server site, the data are decrypted and 
stored.  Data can be extracted for ZOLL review and analysis at any time. 
 Source Documentation 
Regulations require that an investigator maintain information in the trial subject’s medical records 
to corroborate data collected on the eCRF.  To comply with these regulatory requirements, the 
following information will be maintained and made available as required by ZOLL and/or its 
designees and/or regulatory inspectors.  Shadow charts are not appropriate or adequate source 
documentation.  Complete medical (clinical and hospital) records include the following 
documentation.   
• Medical history/physical condition of the patient before involvement in the trial sufficient 
to verify clinical protocol eligibility criteria. 
• Description of cooling procedure (material used, drugs administered during the procedure, 
device identification information and disposition, date, time, angiographic and clinical 
findings, etc.).  
• Electronic data downloaded from the ZOLL Proteus IVTM System. 
• Signed notes in the subject’s medical record on the enrollment day that identify and 
include:  the subject’s date of enrollment, procedure date, the trial sponsor (ZOLL), clinical 
site name, the subject-assigned identification number, the subject- assigned enrollment 
number, and documentation and confirmation that the appropriate informed consent was 
obtained. 
• Dated and signed notes for each subject’s trial visit. 

 
 
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• Lab results.   
• Baseline ECG, angiogram, and MRI reports, etc.   
• Dated printouts or reports of special assessments (ECG baseline report, imaging report, 
etc.). 
• Adverse event reporting and follow-up of the adverse events.  Information in the medical 
chart should include at a minimum the following:  event description, severity, seriousness, 
onset date, date site became aware of event, duration, relation to trial device, treatment, 
and outcome of the adverse event. 
• Trial subject’s condition upon completion of or withdrawal from the trial. 
• Trial subject’s medical status, including all SAEs out to 1 year following trial enrollment. 
• All notes related to trial subject’s KCCQ and the New York Heart Association Functional 
Class questionnaires. 
 Transmission of Data 
Required data will be recorded on the appropriate eCRF at the time of or as soon as possible after 
the patient visit.  The eCRFs and any requested supporting source documents must be sent to ZOLL 
and/or retrieved from the investigator during monitoring visits.  Questions about completion of the 
eCRFs may be directed to the ZOLL COOL AMI clinical team at Clin-safety@zoll.com 
 Data Queries  
During monitoring visits, the Monitor will perform a 100% review of all variables, i.e., 
demography, inclusion/exclusion criteria, safety, effectiveness, on the eCRFs with each subject’s 
source documents. Any discrepancies will be queried by ZOLL or its designee and must be 
resolved by the investigational site staff and investigator in a timely manner.  Queries also will be 
generated by ZOLL data management personnel during routine review of the data on the electronic 
data capture system. 
15 STATISTICAL ANALYSIS PLAN 
The objective of this trial is to evaluate the safety and effectiveness of therapeutic hypothermia, 
using the ZOLL Proteus IVTM System, as an adjunctive therapy for patients presenting with acute 
anterior myocardial infarction (AMI) and undergoing percutaneous coronary intervention (PCI). 
An analysis summarizing outcomes for the Primary Effectiveness Endpoint and the Primary Safety 
Endpoint will be created after the last randomized subject has completed the 30 day follow-up 
interval. The results of the primary endpoints will be summarized in the final clinical study report. 
Two interim analyses are planned to be performed at approximately 50% and 75% of 
randomization, once subjects have completed 4-6 day cMR follow-up. At the interim stage, the 

 
 
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trial will be stopped to reject the null hypothesis of no difference or continue enrolling. Another 
report will be issued summarizing all endpoints after all subjects have completed 12 month follow-
up.  
 
 Data Analysis 
Analysis Data Sets 
The Intention-to-Treat (ITT) analysis set will be used for primary statistical analyses and 
summaries. The ITT population includes subjects who have signed an informed consent and have 
been randomized to the Test Arm or the Control Arm of the trial. ITT subjects will be evaluated 
according to the group to which they were randomized. 
The Per-Protocol (PP) analysis set will also be evaluated. The PP population includes those 
subjects who met inclusion and exclusion criteria, were randomized to either the Test or Control 
arm, received the treatment to which they were randomized, and complied substantially with the 
treatment timeline and steps of this protocol without major protocol violations. 
The Safety Analysis Set will be used to evaluate safety endpoints. These will be all of the subjects 
included in the study as defined by the ITT analysis set and will include Roll-In subjects. For the 
safety analysis, subjects will be followed for all adverse events for 30 days post procedure. 
Additionally, all subjects will be followed for 12 months for the incidence of Serious Adverse 
Events (SAEs), Death and Heart Failure (as assessed by NYHA and Kansas City Cardiomyopathy 
Questionnaire (KCCQ)). 
Infarction Size (IS) is defined as % Left Ventricular Mass as measured by Cardiac Magnetic 
Resonance (cMR) imaging. Infarct Size (IS) will be assessed by Cardiac Magnetic Resonance 
(cMR) at 4 – 6 days following the index procedure. Infarct Size will be assessed in subjects in the 
ITT analysis set and also in the Per-Protocol analysis set. 
 
The Safety Analysis Set will be used to evaluate safety endpoints. These will be all of the subjects 
included in the study as defined by the ITT analysis set and will include the following clinical 
components evaluated at 30 day follow-up visit (30 day ± 7 days): 
Secondary Endpoint Analysis: 
The following clinical components of MACE will be evaluated at 30 day follow-up visit (30 day 
± 7 days): 

 
 
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o Death (Cardiac, Vascular, Non-Cardiovascular) 
o Myocardial Infarction (MI) 
 Attributable to target vessel (TV-MI) 
 Not attributable to target vessel (NTV-MI) 
o Target Lesion Revascularization (TLR) 
 Clinically-indicated TLR (CI-TLR) 
 Not clinically-indicated TLR (NCI-TLR) 
o Target Vessel Revascularization (TVR non TLR,) 
 Clinically-indicated TVR non TLR 
 Not clinically-indicated TVR non TLR 
o Non-Target Vessel Revascularization (NTVR,) 
 Clinically-indicated NTVR 
 Not clinically-indicated NTVR 
o All coronary revascularization 
In addition, Stent Thrombosis will be evaluated at 30 day follow-up visit (30 day ± 7 days): 
 Evidence (Definite and Probable) 
 
 Timing (Acute, Sub-acute) 
Additional Observational and Descriptive Analysis:  
In addition to the secondary endpoint, safety of the trial is also analysed by the following 
observational and descriptive analysis.  These events are not endpoints for the study: 
o the following serious adverse events will be evaluated at 30 day follow-up visit (30 day 
± 7 days): 
 Stroke 
 Cardiogenic shock 
 Pulmonary embolism 
 Pulmonary edema 
 Atrial fibrillation 
 Ventricular fibrillation 
 Vascular complications requiring intervention 
 Bleeding requiring transfusion of 2 units or greater 
 Cooling catheter access site infection 
 Systemic infection 
 Deep Venous Thrombosis (DVT) 
 Bradycardia 
 Hypotension 

 
 
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o The following serious adverse events will be evaluated at 12 month follow-up visit 
(12 month ± 14 days): 
 Death (Cardiac, Vascular, Non-Cardiovascular) 
 Stent Thrombosis 
• Timing (Acute, Sub-acute) 
• Evidence (Definite and Probable) 
 Hospitalizations due to Heart Failure 
 
 Statistical Methods 
Baseline demographic and clinical characteristics will be summarized for each arm using 
descriptive statistics. Continuous variables will be reported with mean, standard deviation, median, 
and range. Discrete variables will be reported as frequency and proportion. A χ2 test or Fisher 
exact test (for small frequencies) will be used to compare discrete variables; t-test or Wilcoxon test 
(for non-normal data) will be used to compare the 2 arms with continuous variables for randomized 
subjects in the trial. 
 
The primary effectiveness endpoint is to detect a 20% reduction of mean infarct size in the Test 
Arm compared to Control Arm where infarct size (%LV Mass) is measured by cMR at 4-6 days. 
The mean, median, standard deviation, and range will be presented for infarct size. A two sample 
t-test will be used to test the null-hypothesis of no difference in average infarct size test and control 
arm P-value will be reported with p<0.05 considered statistically significant. Infarct size will 
further be evaluated in subgroups and with ANOVA models. 
 
For the primary safety endpoint of MACE (as defined by CD, All MI, and CI-TLR) at 30 days, all 
events will be tabulated and reported. Per-patient rate of composite MACE will be compared 
between the two arms with 1-sided Fisher’s exact test. 
Two interim analyses are planned to be performed at approximately 50% and 75% of 
randomization, once subjects have completed 4-6 day cMR follow-up. At the interim stage, the 
trial will be stopped to reject the null hypothesis of no difference or will continue enrolling. Based 
on the Lan-DeMets method for group sequential trials using O’Brien-Fleming boundaries, the 
levels of significance for the interim analyses are alpha=0.00305 (50% information fraction), 
alpha=0.01832 (75% information fraction), and alpha=0.044 (final analysis).  
 
All analyses for effectiveness will be conducted in intent-to-treat and per-protocol analyses set. 
All analyses for safety will be conducted in the safety dataset. Imputation will be made for missing 
infarct size (LV%) in intent-to-treat analyses set per Intention-to-Treat principle; details are 
described in the Statistical Analysis Plan.  

 
 
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 Sample Size Justification 
The primary effectiveness analyses is designed to detect a relative reduction of 20% in mean 
anterior myocardial infarct size (IS), as determined by Cardiac Magnetic Resonance (cMR) 
imaging at 4-6 days post infarct in the Test Arm (cooling + PCI) compared to the Control Arm 
(PCI only). The absolute magnitude of a relative reduction of 20% depends on the mean IS in the 
control arm, which is assumed to be approximately 17 %LV.  Therefore, the treatment effect of 
interest is an absolute difference of 3.5 %LV.  
 
The hypothesis for the primary effectiveness endpoint is the following for patients randomized 1:1 
in Treatment Arm vs Control Arm: 
H0:  µT = µC   
HA: µT ≠ µC  
 
Null hypothesis:  
 
The null hypothesis is that the mean infarct size in the Test Arm is equal to the mean IS in the 
Control Arm.   
 
Alternative hypothesis:  
 
The mean infarct size in the control arm is not equal to mean infarct size of control arm. 
This 20% relative reduction is defined as absolute value 3.5 %LV and accounted for in our sample 
size calculation as minimally detectable effect. This assumption is based on previous studies with 
anterior infarct size measured with cMR reporting between 17-20% absolute %LV in anterior 
infarct (Tables 17 & 18). Therefore, a relative reduction of 20% can vary depending on the mean 
infarct size of the control arm. Assuming a representative mean infarct size of ~17% in controls, 
we assume absolute difference of 3.5 %LV is equivalent to 20% mean anterior infarct size would 
be an adequate detection limit for effect. 
Based on these assumptions--standard deviation of 12.0 %LV, two-tailed t-test of difference 
between means, a normal distribution, 80% power (beta=0.2), with the final analysis will be 
conducted using a two-sided test at the alpha=0.044 level of significance (adjusted for the two 
interim analyses)-- the required total sample to detect a mean difference of 3.5 %LV with 80% 
power is 384 subjects (192 subjects per group).  Assuming 24% loss to follow-up, the trial plans 
for an enrolment up to 500 randomized subjects (250 in each arm) for 4-6 days cMR imaging 
follow-up. 
 
 

 
 
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Table 17: Clinical trials reporting anterior mean infarct size measured by cMR 4-6 days in 
PCI trials (Control Group Only) and calculated 20% relative reduction  
Study name 
Anterior n 
Mean 
infarct size 
Standard 
Deviation 
20% relative 
reduction 
APEX-AMI41 
60 
16.6 
10.7 
3.3 
LIPSIAABCIXIMAB42 
63 
25.3 
16.1 
5.1 
LIPSIA-STEMI43 
38 
18 
16.0 
3.6 
CRISP-AMI 44* 
142 
37.5 
20.1 
7.5 
INFUSE-AMI45 
172 
17.3 
10.2 
3.5 
RAPID-MI ICE1 
7 
19.7 
8.5 
3.9 
CHILL-MI37 
21 
26.5 
10.9 
5.3 
AMI EU PILOT  
21 
23.3 
12.0 
4 
*>60% are large proximal infarcts 
 
A range of standard deviation in the table expected is represented by anterior infarct data 
measured with cMR from separate and pooled analyses of previous hypothermia trials with AMI 
patients cooled below 35°C: RAPID-MI ICE (2009), CHILL-MI (2013), AMI EU Pilot 
(ongoing) as described below in Table 18. 
Table 18: Hypothermia trials using cMR measured infarct size as primary outcome 
RAPID-MI 
ICE (2009) 
CHILL-MI 
(2013) 
AMI EU 
Pilot (2017) 
Pooled  
AMI EU Pilot, RAPID-
MI-ICE, CHILL-MI 
n (Control vs 
Cooled) 
7 vs 5 
21 vs 15 
21 vs 19 
49 vs 39 
Control Mean 
LV% 
19.7 
26.5 
23.3 
24.5 

 
 
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RAPID-MI 
ICE (2009) 
CHILL-MI 
(2013) 
AMI EU 
Pilot (2017) 
Pooled  
AMI EU Pilot, RAPID-
MI-ICE, CHILL-MI 
20% reduction 
in infarct 
3.94 
5.3 
4.7 
4.9 
Std Dev 
(control) 
8.5 
10.9 
12.0 
10.5 
Std Dev (cooled) 
6.5 
9.3 
10.3 
11.0 
 
The potential impact of variations in control infarct size and variability is presented in Table 19.  

 
 
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Table 19: Sample size estimates with alternative standard deviation and detection limit 
Mean Difference 
in infarct size for 
detection (%) 
 Standard Deviation Estimated Sample Size 
Total Enrollment 
(with 24% drop-out) 
3.0 
 
9 
288 
380 
3.0 
 
10 
355 
468 
3.0 
 
11 
430 
566 
3.0 
 
12 
506 
666 
3.5 
 
9 
212 
280 
3.5 
 
10 
260 
342 
3.5 
 
11 
314 
414 
3.5 
 
12 
374 
500 
4.0 
 
9 
162 
214 
4.0 
 
10 
200 
264 
4.0 
 
11 
240 
316 
4.0 
 
12 
286 
376 
 
The primary safety endpoint is a composite endpoint. For the sample size calculation, expected 
incidence is based on a literature review of acute MI hypothermia trials that combined six 
studies: Dixon et al, COOL MI, ICE-IT, RAPID MI-ICE, CHILL-MI, VELOCITY46 which 
resulted in a 30-day MACE rate of 6.6% in the Control patients and 7.5% in treatment patients. 
Previously, AMIHOT II trial defined 30-day MACE rate comprised of death, reinfarction, target 
vessel revascularization, and stroke used a non-inferiority hypothesis with a 6% equivalence 
delta and 7% in the Control patients47. 
The hypothesis for the primary safety endpoint is the following:  

 
 
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H0: πT ≥ πC + 6%  
HA: πT < πC + 6%  
πT and πC are the underlying proportion of patients having a MACE event.  
An enrollment of 500 patients would be able to demonstrate 91% power and 95% 1-sided 
significance. The safety endpoint will be considered to have been met if there is a high posterior 
probability of non-inferiority [i.e. P (πt < πc + 6% >95%)]. With a drop-out rate of 20%, the 
power is calculated to be 86%. 
 
16 PUBLICATION 
At the conclusion of the trial, a multi-center manuscript will be prepared for publication. 
Publications will be managed by the Sponsor, its designee and the Advisory board. Additional 
publications from any single site will be considered but only after the multi-center publication. 
17 INTELLECTUAL PROPERTY 
In all documents the company name of ZOLL Circulation® will be referred to in short hand as 
ZOLL.  ZOLL® is a registered trademark of ZOLL Medical Corporation.  The Proteus IVTM 
System is a trademark of ZOLL Circulation, Inc.  Proteus Catheters, Cassettes and Temperature 
Probes (X-Probe) are registered trademarks of ZOLL Circulation, Inc. 
18 STATEMENT OF COMPLIANCE 
1. Sponsor and Investigator will conduct the clinical investigation in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki. 
2. Sponsor and Investigator will comply with ISO 14155:2011 and any regional or national 
regulations, as appropriate. 
3. Investigator will not begin the clinical investigation until Investigator obtains the required 
written approval or favorable opinion from the MEC or regulatory authority, if 
appropriate.  
4. Investigator will follow any additional requirements imposed by the MEC or regulatory 
authority, if appropriate. 

 
 
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ATTACHMENT I – REFERENCES 
  
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Endovascular Cooling Before Reperfusion in Patients with ST-Elevation Myocardial 
Infarction.  Circulation: Cardiovascular Interventions.  2010; 3: 400-407. 
2. Good Clinical Practice Guidelines 
3. EN ISO 14155:2011, Clinical investigation of medical devices for human subjects – Good 
Clinical Practice (ISO 14155:2011). 
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357(11):1121-1135. 
5. Negovsky VA.  Postresuscitation disease.  Crit Care Med 1988; 16:942-946. 
6. Bolli R.  Does Lethal Myocardial Reperfusion Injury Exist? A Controversy that is Unlikely 
to Be Settled in our Lifetime.  J Thromb Thrombolysis 1997; 4(1):109-110. 
7. Yellon DM, Hausenloy DJ: Myocardial reperfusion injury. N Eng J Med. 2007;357:1121. 
8.  Haunseloy DJ, Yellon DM: Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J 
Clin Invest. 2013;123:92-100.  
9.  Hausenloy DJ, Botker HE, Engstrom T, Erlinge D, Heusch G, Ibanez B, Kloner R, Ovize M,  
Yellon DM, Garcia-Dorado G: Targeting reperfusion injury in patients with ST-segment 
elevation myocardial infarction: trials and triblations. Eur Heart J. 2017;38:935-941. 
10. Colbourne F, Sutherland G, Corbett D.  Postischemic hypothermia.  A critical appraisal with 
implications for clinical treatment.  Mol Neurobiol 1997; 14(3):171-201. 
11. Duncker DJ, Klassen CL, Ishibashi Y, Herrlinger SH, Pavek TJ, Bache RJ.  Effect of 
temperature on myocardial infarction in swine.  Am J Physiol 1996; 270(4 Pt 2):H1189-
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12. Miki T, Liu GS, Cohen MV, Downey JM.  Mild hypothermia reduces infarct size in the 
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15. Hale SL, Dae MW, Kloner RA.  Hypothermia during reperfusion limits 'no-reflow' injury in 
a rabbit model of acute myocardial infarction.  Cardiovasc Res 2003; 59(3):715-722. 

 
 
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16. Gotberg M, Olivecrona GK, Engblom H et al.  Rapid short-duration hypothermia with cold 
saline and endovascular cooling before reperfusion reduces microvascular obstruction and 
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of myocardial infarct size in dogs. J Mol Cell Cardiol 1997; 29:1577-1583. 
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20. Montalescot G, Barragan T, Wittenberg O, et al for the ADMIRAL Investigators. Platelet 
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Guagliumi, G, Stuckey, T, Turco, M, Fahy, M, Lansky, A, & Mehran, R.   Benefits and Risks 
of Abciximab Use in Primary Angioplasty for Acute Myocardial Infarction:  The Controlled 
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Mauri L, Vranckx P, McFadden E, Lansky A, Hamon M, Krucoff MW, Serruys PW; 

 
 
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Academic Research Consortium. Clinical end points in coronary stent trials: a case for 
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32. Piazza G, Goldhaber SZ. Acute pulmonary embolism: part I: epidemiology and 
diagnosis. Circulation. 2006; 114(2):e28–32. 
33. K. A. Wlodzimirow, S. Eslami, A. Abu-Hanna, M. Nieuwoudt, R. A. F. M. Chamuleau. 
Systematic Review: Acute Liver Failure — One Disease, More Than 40 Definitions. Aliment 
Pharmacol Ther. 2012;35(11):1245-1256. 
34. The Criteria Committee of the New York Heart Association. (1994 (9th ed)). Nomenclature 
and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. Boston: Little, Brown 
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35. Kidney International Supplements (2012) 2, 8–12; doi:10.1038/kisup.2012.7 
36. Thoeni RF. The revised Atlanta classification of acute pancreatitis: its importance for the 
radiologist and its effect on treatment. Radiology. 2012 Mar; 262(3):751-64. doi: 
10.1148/radiol.11110947. 
37. Erlinge, David MD PhD et al. “Rapid Endovascular Catheter Core Cooling Combined With 
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38. Nichol, Graham, MD, MPH, et al.. Prospective, Multicenter, Randomized, Controlled Pilot 
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39. Dixon, Simon R, MBCHB, FRACP, et al. Induction of Mild Systemic Hypothermia With 
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40. Issam D. Moussa, et al., 2013. Consideration of a New Definition of Clinically Relevant 
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41. Patel MR, Worthley SG, Stebbins A, et al. Pexelizumab and infarct size in patients with 
acute myocardial infarction undergoing primary percutaneous coronary intervention: a 
delayed enhancement cardiac magnetic resonance substudy from the APEX-AMI trial. J Am 
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42. Thiele H, Schindler K, Friedenberger J, et al. Intracoronary compared with intravenous bolus 
abciximab application in patients with STelevation myocardial infarction undergoing primary 
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Circulation 2008;118:49–57. 
43. Thiele H, Eitel I, Meinberg C, et al. Randomized comparison of pre-hospital-initiated 
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myocardial infarction). J Am Coll Cardiol Intv 2011;4:605–14. 
44. Patel MR, Smalling RW, Thiele H, et al. Intraaortic balloon counterpulsation and infarct size 
in patients with acute anterior myocardial infarction without shock: the CRISP AMI 
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45. Stone GW, Maehara A, Witzenbichler B, et al. Intracoronary abciximab and aspiration 
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46. Villablanca PA, Rao G, Briceno DF, et al. Therapeutic hypothermia in ST elevation 
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47. Stone GW, Martin Jack L., de Boer Menko-Jan, et al. Effect of supersaturated oxygen 
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48. Karen A.Hicks et all. 2014 ACC/AHA Key Data Elements and Definitions for 
Cardiovascular Endpoint Events in Clinical Trials. JACC, Vol  66, NO 4, 2015. 
49. Noc M1, Erlinge D, Neskovic AN, et al.(COOL AMI EU pilot trial: a multicentre, 
prospective, randomised controlled trial to assess cooling as an adjunctive therapy to 
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presenting with ST-segment elevation. European Heart Journal (2017) 00, 1–66. 
 
 

 
 
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ATTACHMENT II – ANTI-SHIVERING PROTOCOL  
Shivering Suppression Guidelines 
Turn on IVTM System console to initiate system and begin cooling of coldwell 
↓ 
Obtain Informed Consent (EMS arrival/at hospital) 
↓ 
Administer Buspirone 60 mg PO/NG x 1 immediately 
↓ 
Place Bair Hugger on upper body; set to “high”; forced-air cover should be adjacent to skin.   
Put one blanket on top. 
↓ 
Closer to the time of device deployment, Pethidine 1 mg/kg IV (up to 100 mg)  
 
***Morphine and/or other sedatives are often administered in the setting of an acute MI 
Morphine and Pethidine (Demerol) are both opiate narcotics and if possible, morphine should 
be held as the combination may cause over-sedation.  Consider 0.5 mg/kg Pethidine 
IV, if Morphine has been administered. 
↓ 
At 15 minutes, Pethidine 0.5mg/kg IV should be administered. 
 
Then a 25 mg/hr IV infusion of Pethidine (up to 80 kg patient) or 35mg/hr (> 80 kg 
patient) should be initiated and maintained for the duration of device deployment. 
***Make sure the patient has a respiratory rate ≥ 10 breaths/minute. 
 
What to do if shivering occurs: 
First, try repositioning the Bair Hugger or changing its settings to increase the heat delivered to 
the patient’s surface. 
 
Second, consider increasing dose of Pethidine.  Prior to giving additional Pethidine, look for 
signs of respiratory depression (i.e. decreased Respiratory Rate, decreased O2 Saturation by 
Pulse Ox.)  If it is decided that the patient can tolerate additional Pethidine the following may be 
tried: 
1. An IV dose of 25 mg x 1 may be given 
2. If Infusion rate is 25mg/hr, the rate may be increased to a maximum of 35 mg/hr 

 
 
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If the shivering persists following the above measures, consider raising the target temperature 
on the Proteus Console by 0.5°C (i.e. from 32.0°C to 32.5°C).  If this does not work after 5-10 
minutes at the new target temperature, then the process can be repeated until a temperature where 
no shivering is obtained. 
 

 
 
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ATTACHMENT III – BEDSIDE SHIVERING ASSESSMENT SCALE (BSAS) 
SCORE 
SEVERITY 
DEFINITION 
0 
None 
No shivering noted on palpation of the masseter, neck or chest 
wall 
1 
Mild 
Shivering localized to the neck and/or thorax only 
2 
Moderate 
Shivering involves gross movement of the upper extremities in 
addition to neck and thorax 
3 
Severe 
Shivering involves gross movements of the trunk, upper and lower 
extremities 
SCORE 
SEVERITY 
DEFINITION 
0 
None 
No shivering noted on palpation of the masseter, neck or chest 
wall 
1 
Mild 
Shivering localized to the neck and/or thorax only 
2 
Moderate 
Shivering involves gross movement of the upper extremities in 
addition to neck and thorax 
3 
Severe 
Shivering involves gross movements of the trunk, upper and lower 
extremities 

 
 
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ATTACHMENT IV – SPECIFIC NEW-ONSET ADVERSE EVENT DEFINITIONS 
SPECIFIC NEW-
ONSET ADVERSE 
EVENT  
DEFINITION 
1. All-Cause  
Mortality 
Deaths will be classified as cardiac, vascular or 
noncardiovascular as defined by the Academic Research 
Consortium.27 
 
All deaths are considered cardiac unless an unequivocal non-
cardiac cause can be established. Specifically, any 
unexpected death even in patients with coexisting potentially 
fatal non-cardiac disease (e.g. cancer, infection) should be 
classified as cardiac.  
 
Cardiac death (CD):  
Any death due to proximate cardiac cause (e.g. MI, low-
output failure, fatal arrhythmia), unwitnessed death and 
death of unknown cause, all procedure related deaths 
including those related to concomitant treatment.  
 
Vascular death:  
Death due to non-coronary vascular causes such as 
cerebrovascular disease, pulmonary embolism, ruptured 
aortic aneurysm, dissecting aneurysm, or other vascular 
cause.  
 
Non-cardiovascular death:  
Any death not covered by the above definitions such as 
death caused by infection, malignancy, sepsis, pulmonary 
causes, accident, suicide or trauma. 
2. Recurrent MI 27,31 
Recurrent MI or re-infarction may be diagnosed when 
cardiac biomarker levels are stable on 2 samples that are >6 
hours apart or are in decline if a subsequent value 3 to 6 
hours after the procedure is increased by > 20% from the 
baseline sample. If the baseline value is not stable, then 
insufficient data exists to recommend biomarker criteria for 
diagnosis, and the Academic Research Consortium27,31 
recommends that the event be considered as pre-procedure 
MI.  Periprocedural MI is that which occurs within the first 
48 hrs after PCI or within the first 72 hrs after coronary 
artery bypass grafting (CABG). 
 

 
 
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Q wave MI:  
Development of new, pathological Q wave on the baseline 
ECG (≥ 0.04 seconds in duration and ≥ 1 mm in depth) in ≥ 
2 contiguous precordial leads or ≥ 2 adjacent limb leads)  
 
Non-Q wave MI:  
Those MIs which are not Q-wave MI. 
3. Need for 
revascularization of 
the target vessel 
(TVR)27 
TVR is defined as any repeat percutaneous intervention or 
surgical bypass of any segment of the target vessel. The 
target vessel is defined as the entire major coronary vessel 
proximal and distal to the target lesion, which includes 
upstream and downstream branches and the target lesion 
itself.  
4. Stroke 
Development of a new neurological deficit that persists > 24 
hours, or worsening of previous neurological symptoms that 
persist > 24 hours. 
5. Cardiogenic shock 
Systolic blood pressure of less than 90 mmHg for at least 30 
minutes which is secondary to myocardial dysfunction, 
leading to decreased cardiac output and evidence of tissue 
hypoxia in the presence of adequate intravascular volume.  
6. Pulmonary 
embolism 
Sudden onset of pleuritic chest pain, cough, hemoptysis, 
hypoxia, tachycardia, and a positive ventilation/perfusion 
scan or a CT scan. 
7. Ventricular 
Fibrillation (V-  
Fib) 
Rapid uncoordinated fluttering contractions of the heart 
ventricles recognized by the occurrence on the 
electrocardiogram of coarse and irregular oscillations 
without discernible QRS complexes or T waves 
8. Vascular 
complications 
requiring intervention 
Complications arising from the use of the Proteus Catheter 
including the development of a vessel tear, hematoma, 
pseudoaneurysm, arteriovenous (AV) fistula, or 
retroperitoneal bleeding which require an additional surgical 
intervention for treatment. 
9. Bleeding requiring 
transfusion of 2 units 
or greater 
Any periprocedural bleeding which occurs as a result of the 
PCI and/ or cooling procedure which requires transfusing > 
2 units. 
10. Systemic Infection  Sepsis with confirmed positive blood cultures. 
11. Cooling Catheter 
Access Site Wound 
infection 
Infection and inflammation of the incision or puncture site 
requiring drainage and/or debridement in addition to 
antibiotic therapy, e.g., cellulitis. 
12. Pulmonary Edema Abnormal accumulation of fluid in the lungs 

 
 
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13. Deep Venous 
Thrombosis 
(DVT)32 
Formation of one or more blood clots in one of the body’s 
large veins, most commonly in the lower limbs. The clot(s) 
can cause partial or complete blocking of circulation in the 
vein, which in some patients leads to pain, swelling, 
tenderness, discoloration, or redness of the affected area, and 
skin that is warm to the touch.  As many patients enrolled in 
the trial will have pre-existing DVT, for the purposes of this 
trial DVT is defined as the de novo onset of DVT following 
enrollment which required treatment or worsening of pre-
existing DVT. 

 
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ATTACHMENT V – ADVERSE EVENT DEFINITIONS 
Adverse Event Definitions 
In addition to the definitions provided in Attachment IV– Specific New Onset Serious 
Adverse Event Definitions, the following definitions apply to expected adverse events 
that may occur and must be reported throughout this clinical trial.  Events reported should 
represent a new onset or increase in the severity of the condition from the time of 
enrollment. 
A. CARDIAC  
COMPLICATIONS 
DEFINITION 
Recurrent 
Myocardial 
ischemia 31 
Recurrent Myocardial Ischemia : is evidenced through baseline 
ECG changes identified during continuous multilead baseline 
ECG–ischemia monitoring (or Holter monitoring) which may 
be accompanied by the development of new clinical symptoms 
suggesting an ischemic cardiac episode.  
Arrhythmias 
The development of a new atrial and/or ventricular arrhythmia, 
significant increase in the severity of a preexisting arrhythmia, 
or any episode of cardiac arrest. 
Congestive Heart 
Failure34 
Defined as patients with defined or presumed cardiac disease 
and one of the following: Class I: without limitations of 
physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, or dyspnea. Class II: slight 
limitation of physical activity. They are comfortable at rest. 
Ordinary physical activity results in fatigue, palpitation, or 
dyspnea. Class III: marked limitation of physical activity. They 
are comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, or dyspnea. Class IV: inability to carry on 
any physical activity without discomfort. Symptoms are 
present even at rest or minimal exertion. 
 
B. PULMONARY 
COMPLICATIONS 
DEFINITION 
Pneumonia 
Clinical evidence as determined by physical, radiographic, and 
laboratory findings requiring treatment with antibiotics, 
inhalation therapy, intubation, or suctioning. 
Atelectasis 
Clinical evidence as determined by physical, radiographic, and 
laboratory findings requiring treatment with antibiotics, 
inhalation therapy, intubation, or suctioning. 

 
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Respiratory Failure 
Need for mechanical ventilation for > 24 hours 
postoperatively, or reintubation for any reason. 

 
 
 
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C. RENAL 
COMPLICATIONS 
DEFINITION 
Acute Kidney 
injury (AKI)35 
AKI is defined as any of the following:  
Increase in SCr by ≥.3 mg/dl (≥26.5 µmol/l) within 48 hours; 
or Increase in SCr to ≥ 1.5 times baseline, which is known or 
presumed to have occurred within the prior 7 days; or Urine 
volume < 0.5 ml/kg/h for 6 hours.  
 
D. VASCULAR 
COMPLICATIONS 
DEFINITION 
Arteriovenous 
Fistula 
Formation of an abnormal connection between the lumens of 
an artery and a vein as documented by CT, ultrasound, 
angiography, or direct observation. 
Embolism 
The obstruction of a blood vessel by a blood clot or foreign 
substance, e.g., air, fat, bacteria. 
Vessel perforation 
Defined as perforation of the access vessel wall or vena cava 
confirmed by extravasation of contrast under fluoroscopy, 
angiography, CT scan, and/ or direct observation at surgery or 
autopsy.  
Hematoma 
An abnormal localized collection of blood (clotted or partially 
clotted) and situated within an organ or a soft tissue space, 
such as within a muscle.  Development of an incisional or 
retroperitoneal hematoma requiring surgical intervention, 
evacuation, transfusion or prolonged hospitalization. 
Hemorrhage 
Post-procedural bleeding requiring transfusion of ≥ 2 units. 
Hypotension 
Abnormally low systolic blood pressure that is < 80 mm Hg 

 
 
 
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D. VASCULAR 
COMPLICATIONS 
DEFINITION 
Peripheral vascular 
insufficiency (PVI) 
Inadequate peripheral blood flow resulting from the occlusion 
of vessels by atherosclerotic plaques, thrombi, or emboli; 
damaged, diseased, or intrinsically weak vascular walls; 
arteriovenous fistulas; hematologic hypercoagulability; and 
heavy smoking. Signs of vascular insufficiency include pale, 
cyanotic, or mottled skin over the affected area; swelling of an 
extremity; absent or reduced tactile sensation; tingling; 
diminished sense of temperature; muscle pain, such as 
intermittent claudication in the calf; and, in advanced disease, 
ulcers and atrophy of muscles in the involved extremity.  
As many patients enrolled in the trial will have pre-existing 
Peripheral Vascular Insufficiency (PVI), for the purposes of 
this trial PVI is defined as the de novo onset of PVI following 
enrollment which requires treatment or worsening of pre-
existing PVI. 
Pseudoaneurysm 
Enlargement of the aorta, iliac, or femoral arteries, which 
contain some or all of the medial layer, the adventitia, and 
periaortic tissue most commonly associated with previous 
aortic operative procedures, trauma, and/or infection.  
Pseudoaneurysms typically present as a well-defined collection 
of blood outside the vessel wall from contained rupture.  
Stenosis 
A reduction in the diameter of the vessel lumen when 
compared to the reference diameter, as documented by 
angiography, which requires intervention and is related to the 
procedure, e.g., access vessel.  
Thrombosis  
Clotting within a blood vessel which may cause infarction of 
tissues supplied by the vessel; it may be occlusive or attached 
to the vessel or heart wall without obstructing the lumen. 
Transient Ischemic 
Attack (TIA) 
A brief episode of neurological dysfunction caused by focal 
brain or retinal ischemia with clinical symptoms typically 
lasting 1 - 24 hours and without evidence of acute infarction. 
 
E. WOUND 
COMPLICATIONS 
DEFINITION 

 
 
 
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Hematoma 
An abnormal localized collection of blood (clotted or 
partially clotted) and situated within an organ or a soft tissue 
space, such as within a muscle.  Development of an 
incisional or retroperitoneal hematoma requiring surgical 
intervention, evacuation, transfusion or prolonged 
hospitalization. 
Arteriovenous Fistula 
Formation of an abnormal connection between the lumens 
of an artery and a vein as documented by CT, ultrasound, 
angiography, or direct observation. 
Nerve 
Injury/Peripheral 
Neuropathy 
Direct damage to nerves surrounding the access site, 
operative field, or catheter deployment site, and the resultant 
signs and/or symptoms of such damage which may include 
pain and numbness in the affected area associated with 
muscle weakness and decreased patellar reflex lasting > 1 
month after treatment. 
 
F. SYSTEMIC 
COMPLICATIONS 
DEFINITION 
Coagulopathy 
The development of an abnormal bleeding disorder, e.g., 
disseminated intravascular coagulopathy or thrombocytopenia, 
documented by appropriate laboratory studies and requiring 
therapy with medication or transfusion. 
Anesthetic 
Complications 
Reaction or complication caused by administration of an 
anesthetic. 
Liver failure33 
Acute liver failure is defined as the rapid development of 
hepatocellular dysfunction, specifically coagulopathy and 
mental status changes (encephalopathy) in a patient without 
known prior liver disease.  
 
 
 

 
 
 
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F. SYSTEMIC 
COMPLICATIONS 
DEFINITION 
Pancreatitis36 
Evidenced on two of the following three conditions: 1) 
abdominal pain suggestive strongly of acute pancreatitis 
(epigastric pain often radiating to the back), 2) serum amylase 
and/or lipase activity at least 3 times greater than the upper 
limit of normal, (imaging is to be used if the elevated values 
are <3 times normal); and 3) characteristic findings of acute 
pancreatitis on transabdominal ultrasound or on Contrast 
Enhanced Computed Tomography (CECT) 32 
 
 
 
 
 
 
 

 
 
 
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ATTACHMENT VI – INVESTIGATOR LIST 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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ATTACHMENT VII – LIST OF ABBREVIATIONS 
AAR 
Area at Risk 
ACC 
American College of Cardiology 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AHA 
American Heart Assocation 
AKI 
Acute Kidney Injury 
AMI 
Acute Myocardial Infarction 
ASADE 
Anticipated Serious Adverse Device Effect 
AV 
Arteriovenous 
BSAS 
Bedside Shivering Assessment Scale 
CABG 
 Coronary Artery Bypass Grafting  
CD 
Cardiac Death 
CEC 
Clinical Events Committee 
CHF 
Congestive Heart Failure 
CIP 
Clinical Investigation Plan 
CI-TLR 
Clinically-Indicated Target Lesion Revascularization 
CMP 
Clinical Monitoring Plan 
cMR 
Cardiac Magnetic Resonance 
CNS 
Central Nervous System 
CRO 
Clinincal Research Organization 
CRF 
Case Report Form 
CRMI 
Clinically Relevant Myocardial Infarction 
CVA 
Cerebral Vascular Accident 
CVP 
Central Venous Pressure 
DAPT 
Dual Antiplatelet Therapy 
DD 
Device Deficiency 
DES 
Drug Eluting Stent 
DMC 
Data Monitoring Committee 
DP 
Dorsalis Pedis        
DSMB 
Data Safety Monitoring Board 
DTB 
Door-to-Balloon 
DVT 
Deep Vein Thrombosis 
EC 
Ethics Committee 

 
 
 
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ECG 
Electrocardiography 
EDC 
Electronic Data Capture 
ED 
Emergency Department 
ER 
Emergency Room 
ESC 
European Society of Cardiology 
EU 
European Union 
Fr 
French 
FMECA 
Failure Mode, Effects and Criticality Analysis 
FEP 
Fluorinated Ethylene Propylene 
GLP 
Good Laboratory Practice 
HDPE 
High-density Polyethylene 
HIPPA 
Heath Insurance Portability and Accountability Act 
HTN 
Hypertension 
ICF 
Informed Consent Form 
IEC 
International Electrotechnical Commission 
IFU 
Instructions for Use 
IQR 
Interquartile Range 
IRB 
Institutional Review Board 
IRI 
Ischemia Reperfusion Injury 
IS 
Infarct Size 
ISO 
International Organization for Standardization 
ITT 
Intention-to-Treat 
IVC 
Inferior Vena Cava 
IVTM 
Intravascular Temperature Management 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LAL 
Limulus Amebocyte Lysate 
LED 
Light-emitting Diode 
LV 
Left Ventricular 
LVEF 
Left Ventricular Ejection Fraction 
MACE 
Major Adverse Cardiac Events 
MAO 
Monoamine Oxidase 
MaR 
Myocardium at Risk   
MEC 
Medical Ethics Committee 

 
 
 
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MEM 
Minimum Essential Medium 
MI 
Myocardial Infarction 
MRI 
Magnetic Resonance Imaging 
NCA 
National Competent Authority 
NYHA 
New York Health Association 
OD 
Outer Diameter 
PCI 
Percutaneous Coronary Intervention 
PETG 
Polyethylene Terephthalate - Glycol modified 
PP 
Per-protocol 
PVI 
Peripheral Vascular Insufficiency 
PVP 
Polyvinylpyrrolidone 
RCN 
Radio-Contrast Nephropathy 
RF 
Radiofrequency 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Events 
SBP 
Systolic Blood Pressure 
SOP 
Standard Operating Procedure 
SPECT 
Single-photon Emission Computed Tomography  
STEMI 
ST-segment Elevation Myocardial Infarction 
SVT 
Supraventricular Tachycardia 
TIA 
Transient Ischemic Attack 
TIMI 
Thrombolysis In Myocardial Infarction 
TH 
Therapeutic Hypothermia 
TVR 
Target Vessel Revascularization 
UADE 
Unanticipated Adverse Device Effect 
UFH 
Unfractioned Heparin 
USADE 
Unanticipated Serious Adverse Device Effect 
USP 
United States Pharmacopeia 
UTI 
Urinary Tract Infection 
 
 

 
 
 
 
 
 
APPENDIX E 
 
Change Log (2 pages) 
 
 
 

COOL AMI EU PIVOTAL PROTOCOL (EDC-3135)  
SUMMARY OF CHANGES* 
 
Page 1 of 2 
 
Section 
Summary of Changes 
Rationale  
Cover Page 
Deleted text: 
Appendix A 
 
Deleted text for clarification 
Footer 
Revised text In the Footer: 
Appendix A, Rev 5, 12-Feb-2018 
Revised text for clarification 
Sponsor Approval 
Signature page 
Added page #2  
 
CLINICAL INVESTIGATION PLAN APPROVAL PAGE 
Added clarification per advisory board 
recommendation in response to questions 
regarding qualifying Infarct location. 
 
Synopsis 
 
 
Updated Clinical Trial Sponsor’s Contact: 
Renee Kochevar, PhD, AL M  Philippa Hill 
Vice President  Senior Director, Clinical Affairs 
ZOLL Circulation, Inc. 
2000 Ringwood Ave. 
San Jose, CA 95131 
Main:    +1 (408) 541-2140 
Fax:  +1 (408) 541-1030 
PHill@zoll.com rkochevar@zoll.com 
 
Updated with current Sponsor Contact 
Information  
6.8.9 
Revised text in Figure 11. All Patient Procedures: 
Collect NT-pro BNP 
Added text for clarification 
6.8.13 
6.8.14 
Revised text in Trial schedule for Test and Control Arm: 
NT-pro BNP 
Added text for clarification 
6.8.17 
Revised text: 
ii. Collect NT-pro BNP value to assess clinical prognosis of Heart Failure  
iv. Perform blinded NYHA Assessment and administer blinded Kansas City 
Cardiomyopathy Questionnaire (KCCQ). 
Revised for clarification. 

COOL AMI EU PIVOTAL PROTOCOL (EDC-3135)  
SUMMARY OF CHANGES* 
 
Page 2 of 2 
 
16 
Added a new section 16: 
16 PUBLICATION 
At the conclusion of the trial, a multi-center manuscript will be prepared for publication. 
Publications will be managed by the Sponsor, its designee and the Advisory board. 
Additional publications from any single site will be considered but only after the multi-
center publication. 
Added a publication section for ISO 
14551 compliance 
            *The Summary of changes applies to COOL AMI EU Pivotal Protocol (EDC-3135) revisions listed below: 
1. Pivotal Protocol (EDC-3135) from Rev 5. to Rev 6. - For sites that don’t require specific Dual Anti-Platelet Therapy details 
2. Pivotal Protocol (EDC-3135) from Rev 5. to Rev 6. – For Germany Only 
3. Pivotal Protocol (EDC-3135) from Rev 5. to Rev 6. - For sites that require specific Dual Anti-Platelet Therapy details 
4. Pivotal Protocol (EDC-3135) from Rev 2. to Rev 3. – For France Only