Clinical trial NCT02922153
Conditions: Pain
Keywords: CryoAnalgesia Thoracotomy Forced Expiratory Volume (FEV1) Visual Analog Scale (VAS)
Sponsor: AtriCure, Inc.
Start date: 2016-06-13; Completion date: 2019-08-28
Enrollment: 84 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The investigators propose to assess whether intra-operative intercostal cryoanalgesia using the cryoICE® probe (AtriCure®, Inc., 7555 Innovation Way, Mason, Ohio) provides superior post-operative analgesic efficacy as compared to current pain management in patients undergoing unilateral thoracotomy cardiac procedures.

Detailed description:
Completion of the proposed study will for the first time demonstrate efficacy of intercostal cryoanalgesia in patients undergoing minimally invasive cardiac procedures. Furthermore, results of this study may have a pivotal role in supporting future clinical outcome trials for intercostal cryoanalgesia therapy.

Arms: arm 1: Cryoanalgesia in Conjunction with Standard of Care. Up to 5 sessions of cryoanalgesia for 120 seconds per session. arm 2: Institutional SOC for pain management will be followed. The use of local post-operative pain management techniques (i.e., intercostal, peri-vertebral, or any other acceptable method) is permitted for both treatment groups up to 24 hours post-operatively according to institutional standard of care.
Interventions: intervention 1: Cryoanalgesia intervention 2: Standard of Care
Intervention descriptions: intervention 1: AtriCure® cryoICE cryo-ablation system intervention 2: Institutional SOC for pain management will be followed.

Protocol documents:
Prot_SAP_001.pdf: 








 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 5 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
Patient Population: 
Patients undergoing unilateral thoracotomy cardiac procedures 
Inclusion Criteria: 
Patients satisfying the following criteria will be considered the screening population 
and will be eligible for participation: 
1. Age 18 - 85 years male or female 
2. Patients undergoing unilateral thoracotomy cardiac procedures (with the 
exception of Aortic Aneurysm repair as sole treatment) 
3. Acceptable surgical candidate, including use of general anesthesia 
4. Willing and able to provide written informed consent 
5. Willing and able to return for scheduled follow-up visits 
Exclusion Criteria: 
Patients satisfying the following criteria will not be eligible for participation: 
1. Cardiac valve surgical procedure via conventional full sternotomy 
2. Procedures that require a posterolateral thoracotomy 
3. Current pregnancy 
4. Current use of prescription opioids 
5. FEV1 < 40% predicted  
6. Documented myocardial infarction within 30 days of signing informed 
consent 
7. Documented psychiatric disease 
8. Documented chronic pain syndrome 
9. Documented history of substance abuse 
10. Patient currently enrolled in another research study that could directly affect 
results of either study 
11. Physical or mental condition that would interfere with patient’s self-
assessment of pain 
12. A medical condition that in the investigator’s opinion could adversely 
impact the patient’s participation or safety, conduct of the study, or 
interferes with the pain assessments 
 
Study Duration:  
Anticipated subject duration will be approximately 180 days post index procedure 


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 6 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
Study Endpoints: 
 
Endpoints: 
Co-Primary Endpoints: 
1. Forced Expiratory Volume (FEV1) at 48-hours post-surgery 
2. Visual Analogue Scale (VAS) pain in the surgical region at 48-hours post-
operative 
Secondary Endpoints: 
1. Spirometry assessments including: forced expiratory volume (FEV1), forced 
vital capacity (FVC) and slow vital capacity (SVC)  at 48-hours post-
extubation and other designated time points during hospital admission 
2. Pain in the surgical region assessed via a Visual Analogue Scale (VAS) pain 
at 72-, 96- and 120-hours (as long as patient remains in hospital up to 120-
hours) post-operative 
3. Allodynia at 3 and 6 months 
4. Duration of oral endotracheal intubation defined as hours until patient is 
extubated from time patient leaves the operating room  
5. Patient Controlled Analgesia (PCA) and oral opioid consumption up to each 
time point (24-, 48, -96 and 120-hours) and total PCA and oral opioid 
consumption after extubation 
6. ICU length of stay and hospital length of stay 
7. Ambulatory movement  
 
 
 
 
 


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 7 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
TABLE OF CONTENTS 
 
Page 
INVESTIGATOR SIGNATURE PAGE ................................................................................... 2 
SPONSOR SIGNATURES .................................................................................................... 3 
CLINICAL STUDY PROTOCOL SYNOPSIS ......................................................................... 4 
KEY PROTOCOL-SPECIFIC ACRONYMS AND ABBREVIATIONS ..................................... 9 
SCHEDULE OF ASSESSMENTS ....................................................................................... 10 
ETHICS ............................................................................................................................... 10 
STUDY ADMINISTRATIVE STRUCTURE .......................................................................... 13 
1.0 
INTRODUCTION .................................................................................................. 13 
2.0 
STUDY OBJECTIVES............................................................................................ 14 
3.0 
STUDY ENDPOINTS ............................................................................................. 14 
4.0 
INVESTIGATIONAL PLAN................................................................................... 15 
4.1 
Overall Study And Design – Subject Disposition Diagram ........................................ 15 
4.2 
Selection of Study Population .................................................................................. 16 
4.2.1 
Recruitment ............................................................................................................ 16 
4.2.2 
Enrollment ............................................................................................................. 16 
4.2.3 
Inclusion Criteria .................................................................................................... 17 
4.2.4 
Exclusion Criteria ................................................................................................... 17 
4.2.5 
Removal of Subjects from Study .............................................................................. 17 
5.0 
PROCEDURE ........................................................................................................ 19 
5.1 
General Description ................................................................................................ 19 
5.2 
Intercostal CryoAnalgesia (Index Procedure) ........................................................... 19 
5.2.1 
Control Arm – Surgery without Intercostal Cryoanalgesia + standard POPM ........... 19 
5.2.2 
Study Arm – Surgery with Intercostal Cryoanalgesia + standard POPM ................... 19 
5.2.3 
Pain Management for Both Treatment Groups ........................................................ 19 
6.0 
IDENTITY OF STUDY DEVICES .......................................................................... 20 
6.1 
Product Accountability............................................................................................ 21 
7.0 
SUBJECT VISITS .................................................................................................. 21 
7.1 
Visit 1 – Baseline ..................................................................................................... 21 
7.2 
Visit 2 – Index Procedure ........................................................................................ 21 
7.3 
Visit 3  24 hour Post-Operative Follow-Up Visit ....................................................... 22 
7.4 
4, 5, 6 and 7 –  48, 72, 96 and 120 Hour Post-Operative Follow-up Visits ................... 22 
7.5 
Visit 8 – Hospital Discharge ..................................................................................... 22 
7.6 
Visit 9 – 30 Day Post-Operative Follow-Up Visit ....................................................... 22 
7.7 
Visit 10 – 90 Day Post-Operative Follow-Up Visit (Phone call) .................................. 22 
7.8 
Visit 11 – 180 Day Post-Operative Follow-Up Visit (Phone call) ................................ 22 
7.9 
Study Exit ............................................................................................................... 23 
7.10 
Allodynia Visits ....................................................................................................... 23 
7.11 
Repeated Study Visit Tests ...................................................................................... 23 
8.0 
DATA MANAGEMENT AND INTEGRITY ............................................................ 24 
8.1 
Data Completion and Record Keeping ..................................................................... 24 
8.1.1 
Source Documents ................................................................................................... 24 
8.1.2 
Data Collection ....................................................................................................... 24 
8.1.3 
Data Correction ...................................................................................................... 25 
8.1.4 
Investigator Regulatory Binder ............................................................................... 26 


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 8 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
8.1.5 
Study Correspondence ............................................................................................ 26 
8.1.6 
Data Privacy ........................................................................................................... 26 
8.1.7 
Record Retention, Inspection, and Custody .............................................................. 26 
8.1.8 
Medical Dictionary Coding ...................................................................................... 26 
8.1.9 
Data Quality Assurance ........................................................................................... 27 
8.1.10 
Investigator Training - Protocol Specific Training .................................................... 27 
8.1.11 
Monitoring ............................................................................................................. 27 
8.2 
Changes to Protocol, Protocol Deviations and Protocol Amendments ........................ 28 
8.2.1 
Changes to Protocol ................................................................................................ 28 
8.2.2 
Protocol Deviations ................................................................................................. 28 
8.2.3 
Protocol Amendments ............................................................................................. 28 
9.0 
STATISTICAL METHODS .................................................................................... 29 
9.1 
Clinical Study Objective .......................................................................................... 29 
9.2 
Study Endpoints ..................................................................................................... 29 
9.3 
Sample Size and Power............................................................................................ 29 
9.4 
Randomization ........................................................................................................ 30 
9.5 
Analysis Populations ............................................................................................... 30 
9.6 
Analysis of Study Endpoints .................................................................................... 30 
9.6.1 
Effectiveness and Health Economic Analysis ............................................................ 31 
9.6.2 
Safety Analysis ........................................................................................................ 31 
9.7 
Detailed Analysis Plan ............................................................................................. 31 
10.0 
Safety Monitoring ................................................................................................... 32 
10.1 
Adverse Events ....................................................................................................... 32 
10.1.1 
Definition of an Adverse Event ................................................................................ 32 
10.2 
Serious Adverse Events ........................................................................................... 32 
10.2.1 
Definition of a Serious Adverse Event ...................................................................... 32 
10.2.2 
Subject Death ......................................................................................................... 33 
10.2.3 
Adverse Event Classification ................................................................................... 33 
10.2.4 
Reporting Adverse and Serious Adverse Events ....................................................... 33 
11.0 
PRODUCT COMPLAINTS .................................................................................... 34 
11.1 
Medical Device Reporting and Product Complaints .................................................. 34 
11.2 
Source Of Product Complaint Data ......................................................................... 34 
12.0 
STUDY OVERSIGHT ............................................................................................ 34 
12.1 
Independent Oversight ............................................................................................ 34 
13.0 
Appendices ............................................................................................................. 36 
APPENDIX 1 -  VISUAL ANALOG SCALE .......................................................................... 36 
APPENDIX 2 – ALLODYNIA ASSESSMENT ...................................................................... 37 
APPENDIX 3  - RISK/BENEFIT ASSESSMENT .................................................................. 38 
 
 
 


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 9 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
KEY PROTOCOL-SPECIFIC ACRONYMS AND ABBREVIATIONS 
Acronyms/Abbreviation 
Terms 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
CBP 
Cardiopulmonary Bypass 
CRA 
Clinical Research Associate 
CTA 
Cotton Tip Applicator Test 
DLCO 
Diffusion Capacity for Carbon Monoxide 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume 
 
 
FVC 
Forced Respiratory Volume 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
IFU 
Information for Use 
ICH 
International Conference on Harmonization 
ICU 
Intensive Care Unit 
IRB 
Institutional Review Board 
LOS 
Length of Stay 
MDR 
Medical Device Reporting 
PI 
Principal Investigator 
PE 
Physical Exam 
PHI 
Protected Health Information 
POPM 
Post-operative Pain Management 
QS 
Quality Systems 
SAE 
Serious Adverse Event 
SAS 
Science Analysis System 
SOC 
Standard of Care 
SOP 
Standard Operating Procedures 
SVC 
Slow Vital Capacity 
VAS 
Visual Analog Scale 
VPS 
Verbal Pain Scale 
 
 
 
 
 




 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 11 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
The study will be conducted in accordance with the ethical principles that have their origins in the 
Declaration of Helsinki. 
The study protocol, any protocol amendments, Informed Consent Form (ICF), any ICF amendments, and 
if applicable, any other written information provided to the subjects e.g., subject recruitment advertising, 
will be reviewed and approved by an or Institutional Review Board (IRB) prior to implementation of any 
procedures required solely for the purposes of this study.  Each Investigator must obtain IRB approval 
prior to consent of the first subject. 
Prior to site initiation, a signed copy of the IRB approval letter identifying the study and site is required to 
be submitted to the sponsor signifying study approval. 
Each Investigator must also maintain continuous IRB approval.  Documentation of approval and renewals 
must be provided to the Sponsor, and filed on site in the Investigator’s Regulatory Binder.  Additionally, 
amendments to the protocol will be submitted for review before implementation except when necessary to 
eliminate apparent immediate hazards to a subject.  IRB approval is required to implement protocol 
amendments or to resume a suspended clinical investigation. 
The occurrence of serious or unanticipated Adverse Events (AEs) during the study must be reported to the 
IRB. 
 
Applicable Regulations 
Regulations are to be followed as applicable including: 21 CFR Parts 11 (Electronic Records; Electronic 
Signatures), 50 (Protection of Human Subjects), 56 (Institutional Review Boards), and 803 (Medical 
Device Reporting); All surgical products used in this study are commercially available and will be used 
within current labeling and indications for use.  Consequently, this study is not investigational and is 
exempt from 21CFR Part 54 (Financial Disclosure by Clinical Investigators) and 21CFR Part 812 
(Investigational Device Exemptions) with the exception of 21CFR812.119 (Disqualification of a Clinical 
Investigator); International Conference on Harmonization (ICH) Guideline E6 for Good Clinical Practice 
(GCP); Declaration of Helsinki; Health Insurance Portability and Accountability Act (HIPAA) 
regulations; and Applicable state and local laws and regulations. 
 
 
 
 
 
 


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 12 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
Subject Information and Consent 
This informed consent process applies to participation in the study only (i.e., this process does not include 
consent required for structural heart surgery).  The surgeon will obtain the Institution’s standard informed 
consent for surgery. 
In compliance with FDA regulations, no subject shall be enrolled in an investigation without provision of 
adequate informed consent.  The Principal Investigator is responsible for ensuring that each subject 
enrolled in the study is given adequate informed consent.  Failure to obtain and properly document this 
process is in violation of the US Code of Federal Regulations, the Declaration of Helsinki, and this study 
protocol. 
The ICF must have the approval of the IRB.  While some institutions may request for modification of the 
ICF to satisfy specific institutional requirements, the use of a modified or unique ICF is permitted if it 
meets the requirement of 21 CFR Part 50 and is approved by the Sponsor.  Informed consent of all 
subjects must be documented on an ICF in the primary language of the subject.  All translated consent 
forms need IRB approval.  Eligible U.S. subjects should also sign the Health Insurance Portability & 
Accountability Act form, if not combined with the ICF. 
The Investigator or designee shall carry out the Informed Consent process on those subjects meeting the 
eligibility criteria.  The informed consent process involves the following: giving a subject adequate 
information concerning the study, providing adequate opportunity (time) for the subject to consider all 
available options, responding to the subject’s questions, ensuring that the subject has comprehended this 
information and finally, obtaining the subject’s consent to participate in this study.  All subjects in this 
study should be completely informed about the purpose, risks, benefits, and other pertinent details of this 
study.  The informed consent process is careful to avoid the perception of any coercion or undue influence 
on, or inducement of, the subject to participate, and does not waive or appear to waive the subject's legal 
rights.  The ICF is presented in native, non-technical language that is understandable to the subject.  The 
ICF ensures important new information is provided to new and existing subjects throughout the clinical 
investigation.   
The Informed Consent process is finalized by completion of the ICF.  Following the explanation of the 
study intent, the Investigator or designee shall offer to answer any of the subject’s questions.  If the 
subject then agrees to participate, his or her willingness must be documented via signatures of the ICF. 
This document must be signed and dated by the subject prior to any study related procedures or 
enrollment.  No dates should be pre-populated, or completed by someone other than the person providing 
the signature.  The subject will be provided a copy of the signed informed consent document. 
During a subject's participation in the study, the subject will sign and date any amendment(s) to the 
informed consent document and a copy of the signed document will be provided to them. 
 


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 13 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
STUDY ADMINISTRATIVE STRUCTURE 
This study is sponsored by AtriCure, Inc. and will be conducted in the US, under a single protocol 
approved by an IRB for each site prior to implementation at the study site.   
The Principal Investigators (PI) at the study sites are qualified by education, experience and training to 
assume responsibility for the conduct of this study.   
An Electronic Data Capture (EDC) system will be utilized by study site personnel to transfer study data 
from source records (medical records and/or source document worksheets) onto common electronic case 
report forms (eCRFs). The EDC system is a web-based, secure electronic software and is compliant with 
national and international GCP data protection/data privacy and electronic record/electronic signature 
(e.g., 21 CFR Part 11) regulatory requirements. 
Serious Adverse Events (SAEs) and product quality problems (for products used during the index 
procedure), including potential and actual product use errors suspected to be associated with the use of a 
Food and Drug Administration (FDA) regulated drug, biologic, medical device or dietary supplement 
used during the course of this study will be reported by the PI to applicable authorities including the: 1) 
Sponsor (AtriCure); 2) IRB; 3) respective manufacturer(s); and/or 4) FDA via MedWatch Online 
Voluntary Reporting Process or Medical Device Reporting (MDR) as appropriate. 
1.0 INTRODUCTION 
Intercostal cryoanalgesia is shown to be a safe and effective strategy for post-operative pain management 
for patients undergoing intrathoracic procedures requiring thoracotomy.1,2  Right anterior mini-
thoracotomy has been advocated as an alternative approach for patients undergoing mitral and aortic 
valve surgery.3  Intercostal cryoanalgesia in post-unilateral thoracotomy patients undergoing cardiac 
procedures has not been evaluated compared to the current standard of postoperative pain management 
using oral or intravenous opioids. 
Post-thoracotomy pain is reported to be one of the most painful surgical incisions currently used,4,5 due to 
the combined factors of incisional pain with interruption of muscular, ligamentous, neurovascular 
bundles, and osseous structures.  The application of retractors used during the procedure, continuous 
pleural irritation and chest wall movements during respiration and coughing with indwelling chest tubes 
further adds challenges in the balance of optimal analgesia and the risk of side effects.6  This alters 
respiratory physiology that may lead to splinting, sputum retention, atelectasis, and chest infections.  It 
represents a major morbidity, because there is currently no single standard technique that can effectively 
eliminate the pain and associated complications.7  Adequate post-thoracotomy analgesia can improve 
respiratory function, improve pulmonary toilet, allow compliance with intensive physiotherapy and 
prevent some complications.8   
Several options are available for treatment of post-thoracotomy pain. Conventional analgesia involves 
intravenous opiates, which is not always completely effective and is associated with several side effects, 
including mental status changes and respiratory depression.8  Epidural analgesia is another commonly 
used form of pain control for post-thoracotomy pain, however full anticoagulation for cardiopulmonary 
bypass poses a potential risk for epidural hematoma. Also, postoperative patient mobility is reduced while 
the epidural is in place. Other techniques include intercostal nerve blocks for immediate postoperative 
pain control. However, intercostal blocks are rarely employed as the sole analgesic technique as they are 
short lived. In addition, intercostal nerve blocks can result in a high plasma concentration of local 
anesthetic per volume injection; therefore, care must be taken to avoid toxic levels.   


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 14 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
Recent studies have demonstrated the beneficial effect of cryoanalgesia for post-thoracotomy pain in 
reduction of opioid requirement, reduction in post-operative pain scores, superior hemodynamic recovery 
(optimization of systolic blood pressure and heart rate, optimization of the pH values of arterial blood 
gases, and superior pulmonary function (higher FEV1  and FVC values).1  Intercostal cryoanalgesia can 
produce temporary neurolysis for up to two months without long-term histological nerve damage.2   
We propose to assess whether intra-operative intercostal cryoanalgesia using the cryoICE® probe 
 provides superior post-operative analgesic 
efficacy as compared to current pain management in patients undergoing unilateral thoracotomy cardiac 
procedures.   
2.0 STUDY OBJECTIVES 
 
The objectives of this study are to: 
1. To demonstrate that intraoperative intercostal cryoanalgesia provides improved analgesic efficacy 
in patients undergoing unilateral thoracotomy cardiac procedures as compared to current 
intraoperative standard of care. 
2. Long-term goal is to elucidate complementary strategies for enhanced postoperative pain 
management of patients at risk for postoperative pulmonary complications from unilateral 
thoracotomy cardiac procedures.   
Completion of the proposed study will for the first time demonstrate efficacy of intra-operative intercostal 
cryoanalgesia in patients undergoing minimally invasive cardiac procedures.  Furthermore, results of this 
study may have a pivotal role in supporting future clinical outcome trials for intra-operative intercostal 
cryoanalgesia therapy. 
 
3.0 STUDY ENDPOINTS 
The following endpoints will be collected for this study: 
Co-Primary Endpoints: 
1. Forced Expiratory Volume (FEV1) at 48-hours post-surgery 
2. Visual Analogue Scale (VAS) pain in the surgical region at 48-hours post-operative 
Secondary Endpoints: 
1. Spirometry assessments including: forced expiratory volume (FEV1), forced vital capacity (FVC) 
and slow vital capacity (SVC) at 48-hours post-extubation and other designated time points during 
hospital admission 
2. Pain in the surgical region assessed via a  Visual Analogue Scale (VAS) pain at 72-, 96- and 120-
hours (as long as patient remains in hospital up to 120-hours) post-operative 
3. Allodynia at 3 and 6 months 
4. Duration of oral endotracheal intubation defined as hours until patient is extubated from time 
patient leaves the operating room  
5. Patient Controlled Analgesia (PCA) and oral opioid consumption up to each time point (24-, 48, -
96 and 120-hours) and total PCA and oral opioid consumption after extubation 
6. ICU length of stay and hospital length of stay 
7. Ambulatory movement 


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 15 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
4.0 INVESTIGATIONAL PLAN 
 
4.1 
Overall Study And Design – Subject Disposition Diagram 
 




 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 17 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
4.2.3 
Inclusion Criteria 
Patients satisfying the following criteria will be considered the screening population and will be eligible 
for participation: 
1. Age 18 - 85 years male or female 
2. Patients undergoing unilateral thoracotomy cardiac procedures  
3. Acceptable surgical candidate, including use of general anesthesia 
4. Willing and able to provide written informed consent 
5. Willing and able to return for scheduled follow-up visits 
4.2.4 
Exclusion Criteria 
Patients satisfying the following criteria will not be eligible for participation: 
1. Cardiac valve surgical procedure via conventional full sternotomy 
2. Procedures that require a posterolateral thoracotomy 
3. Current pregnancy 
4. Current use of prescription opioids 
5. FEV1 < 40% predicted  
6. Documented myocardial infarction within 30 days of signing informed consent 
7. Documented psychiatric disease 
8. Documented chronic pain syndrome 
9. Documented history of substance abuse 
10. Patient currently enrolled in another research study that could directly affect results of either 
study 
11. Physical or mental condition that would interfere with patient’s self-assessment of pain 
12. A medical condition that in the investigator’s opinion could adversely impact the patient’s 
participation or safety, conduct of the study, or interferes with the pain assessments 
4.2.5 
Removal of Subjects from Study 
In accordance with the Declaration of Helsinki and the Code of Federal Regulations, a subject has the 
right to withdraw from the study at any time for any reason without prejudice to his/her future medical 
care by the physician or the institution.  Should a subject (or subject’s legally authorized 
guardian/representative) decide to withdraw; all efforts will be made to collect and report the final visit 
observations as thoroughly and timely as possible.  Subjects who withdraw from the study will not be 
replaced. 
The primary reason for early termination and the date of termination will be recorded in the electronic 
case report form.  Reasons may include: 
 
 
 


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 18 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
 
Investigator Decision 
If the subject experiences an adverse event and the Principal Investigator or Medical Monitor 
believes it is in their best interest to discontinue participation in the study, they will be withdrawn 
from the study. 
Lost to Follow-up 
When contact with the subject has been lost without completing the final visit assessment, and 
every attempt to contact has failed, the subject will be considered lost to follow-up.  Attempted 
contact with the subject should include 2 attempted phone calls and the sending of a certified 
letter before the subject can be considered lost to follow-up.  Final documentation regarding all 
attempts to contact the subject requesting their return for the final visit should be documented. 
Withdrawal of Consent 
The subject withdraws consent for participation in the study.  Any method of contact with the 
subject in which they state they no longer want to participate in the study specific activities 
constitutes withdrawal of consent.  When possible the reason for withdrawal will be documented. 
Site Termination or Study Termination 
A site or study may be terminated.  When this occurs all subjects at the site will be withdrawn and 
documented as early termination.  Reasons for site or study termination may include, but are not 
limited to the following: 
• 
Administrative Concerns (e.g., inadequate subject enrollment, Investigator/institution non-
compliance, change of business strategy, etc.); 
• 
Safety Issues, including those due to non-compliance, which substantially affect the risk to 
benefit ratio of the study subjects at a site or for the study as a whole; 
• 
Regulatory Body Mandate(s) 
 
Other (which may include): 
• 
Protocol deviation, noncompliance or violation 
• 
Sponsor recommendation 
• 
Device/index procedure failure 
• 
Death 
 
Subjects that are not extubated or discharged from the hospital by Day 5 Post-Operative will continue to 
be followed for 180 days post procedure.      
 
 
 
 
 






 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 21 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
All medical devices used during this study are cleared for commercial distribution and are to be used in 
accordance with approved product labeling. 
6.1 
Product Accountability 
Product accountability will not be applicable as the investigator will use commercially available products 
for this study.  Devices will not be provided by the sponsor. 
7.0 SUBJECT VISITS 
Details for specific subject visit activities are found below and reflect the Schedule of Assessments grid. 
7.1 
Visit 1 – Baseline 
Subjects will be screened for study participation during the baseline visit.  The procedures required for the 
baseline visit may be conducted during more than one visit.  The following will be conducted and/or 
obtained:  Some baseline procedures may have been completed as patient standard of care and therefore 
may be completed prior to informed consent and do not need to be repeated after consent. 
The following procedures must be conducted within 30 days prior to the index procedure: 
• 
Informed Consent 
• 
Demographics 
• 
Medical and Surgical History 
• 
Targeted Physical Exam 
• 
Pregnancy Test, as required (within 7 days of procedure) 
• 
Vital Signs 
• 
Height and Weight 
• 
Spirometry 
• 
Concomitant Medication Review 
• 
Inclusion/Exclusion Criteria 
• 
Randomization  
• 
VAS 
• 
Ambulatory Movement 
7.2 
Visit 2 – Index Procedure  
• 
Targeted Physical Exam (prior to Index Procedure) 
• 
Vital Signs (prior to Index Procedure) 
• 
VAS (prior to Index Procedure) 
• 
Index Procedure (Study Arm - Intercostal Analgesia or Control Arm – SOC Pain 
Management) 
• 
Concomitant Procedure Type 
• 
Concomitant Medication Review 
• 
Adverse Events Assessment  
• 
Date and Time Subject Exits Surgical Suite 


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 22 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
7.3 
Visit 3  24 hour Post-Operative Follow-Up Visit 
• 
Vital Signs 
• 
Concomitant Medication Review 
• 
Adverse Event Assessment 
7.4 
4, 5, 6 and 7 –  48, 72, 96 and 120 Hour Post-Operative Follow-up Visits 
• 
Vital Signs 
• 
Spirometry 
• 
VAS  
• 
Ambulatory Movement 
• 
Concomitant Medication Review 
• 
Adverse Events Assessment  
7.5 
Visit 8 – Hospital Discharge 
• 
Vital Signs 
• 
Spirometry 
• 
VAS  
• 
Ambulatory Movement 
• 
Concomitant Medication Review 
• 
Adverse Events Assessment  
• 
Date and Time of Discharge from ICU 
• 
Date and Time of Extubation 
o Extubation is anticipated to occur during the first 24 - 36 hours post-op but may 
occur at any time during hospital stay. 
• 
Date and Time of Hospital Discharge 
7.6 
Visit 9 – 30 Day Post-Operative Follow-Up Visit 
• 
Vital Signs 
• 
Spirometry 
• 
Concomitant Medication Review 
• 
Adverse Events Assessment 
 
 
 
7.7 
Visit 10 – 90 Day Post-Operative Follow-Up Visit (Phone call) 
• 
Vital Signs required if subject is seen in the office for allodynia assessment 
• 
Allodynia Screening 
• 
Concomitant Medication Review 
• 
Adverse Events Assessment 
7.8 
Visit 11 – 180 Day Post-Operative Follow-Up Visit (Phone call) 
• 
Vital Signs required if subject is seen in the office for allodynia assessment 


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 23 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
• 
Allodynia Screening 
• 
Concomitant Medication Review 
• 
Adverse Events Assessment  
• 
Study Exit (See 7.9) 
7.9 
Study Exit 
At study exit the following must be collected. 
• 
Study Exit Date 
• 
Exit Reason 
7.10 
Allodynia Visits 
Allodynia screening questions will be included at the 90 and 180 day visits.  If the questions elicit a 
positive response, the subjects will be asked to make an office visit for a more thorough allodynia 
assessment. Vital signs will be collected along with the allodynia assessment. 
 
7.11 
Repeated Study Visit Tests 
All study procedures should be conducted at the investigational site.   
Targeted Physical Examination:  A targeted physical exam (PE) includes an assessment of the 
following body systems:  General Appearance, Cardiovascular, Respiratory, and Musculoskeletal.  A 
more thorough PE may be conducted according to institutional SOC.  If any findings are noted during the 
PE, the finding should be recorded in the source documents as medical history or as an adverse event, as 
appropriate.  The finding shall be recorded in the eCRF as required per the Safety section of the protocol. 
Vital Signs: Vital signs should be taken in accordance with institutional SOC and include pulse rate, blood 
pressure, temperature and respiration rate.   
Height/Weight: Height and weight should be taken in accordance with institutional SOC.  BMI will be 
calculated automatically by the EDC based on the height and weight taken at Visit 1.   
Spirometry: Spirometry assessments including: forced expiratory volume (FEV1) forced vital capacity 
(FVC) and slow vital capacity (SVC). To allow for consistency across study sites, these spirometry 
measurements will captured on a commercially available bedside device provided by AtriCure.  
Ambulatory movement: Ambulatory movement assessed by "Yes- Independently", "No" or "Yes - with 
assistance" responses to the following questions:  
 
Is patient able to sit up in bed?  
 
Is patient able to stand up? 
 
Is patient able to walk? 


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 24 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
Ambulatory movement will also be assessed via "shoulder flexion movement" of "Limited ROM", "Full 
ROM" or "Unable". Ambulatory movement will be collected individually for each shoulder.   
Visual Analog Scale (VAS): The Visual Analogue Scale and Mankoski Pain Scale Definitions are found 
in Appendix 1.  The subject should be asked to complete the scale to rate their current pain level for general 
pain intensity.  In addition, the subject should be asked to complete the scale to rate their current pain level 
for pain intensity related to the surgical region.  The person conducting the test at the site should be blinded 
as to treatment group.   
Concomitant Medication Review:  All medications, including vitamins or nutritional supplements 
currently prescribed to, or taken by, the subject shall be recorded in the subject’s source documents.  Only 
medications taken for pain management therapy need to be reported on the eCRFs. 
Adverse Event Assessment:  All adverse events shall be recorded in the subject’s source documents.  
Only adverse events that are related to the intercostal analgesia procedure or the AtriCure® cryoICE 
cryo–ablation system need to be reported on the eCRFs.  Refer to description of collection of Adverse 
Events for additional information. 
 
Allodynia Screening:  As part of the 90 and 180 day follow-up visit, a series of questions will be asked 
of the subject to determine if an in-office visit is necessary to further evaluate the presence of allodynia. 
 
Allodynia Assessment: Cotton Tip Applicator (CTA) Test. See Appendix 2 for instructions.  The same 
person at the site should administer the test at each time point and should be blinded as to treatment 
group.   
8.0 
DATA MANAGEMENT AND INTEGRITY 
8.1 
Data Completion and Record Keeping 
8.1.1 
Source Documents 
Source documents are documents on which information regarding subjects are first recorded. PI subject 
files or hospital records generally are the basis of source document information. This may include but is 
not limited to, original subject files, hospital/clinic records, original recordings/tracing, digital images 
from automated instruments, X-ray films, and laboratory results. 
 
 
Source documents must be retained by the PI as part of the subject’s permanent medical record. The 
information in the source documents is used to complete the eCRFs. All information captured on the 
eCRFs should be completely and accurately supported in source documentation.  Study Monitors will 
verify data reported on eCRFs with site source documents.  Any additional information relevant to the 
study should be included in the source documents. In particular, any deviations from the study protocol or 
procedures should be recorded in the source documents. The PI will retain originals of all source 
documents, subject consent forms, and study data. 
8.1.2 
Data Collection 
An EDC system will be utilized by study site personnel to transfer study data from source records 
(medical records and/or source document worksheets) onto common eCRFs. This system is a web-based, 


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 25 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
secure electronic software application This system is designed, developed, and maintained in a manner 
that is compliant with national and international GCP data protection/data privacy and electronic 
record/electronic signature (e.g., 21 CFR Part 11) regulatory requirements.  The platform software has 
been validated in accordance with 21 CFR Part 11, European Commission’s Directive on Data Protection 
and US Safe Harbor Certification.  Prior to being released for data entry, validation of the study level 
components (i.e. data entry screens, associated edit checks and work flow) will be conducted in 
accordance with approved user acceptance testing procedures. Access to this system will be controlled so 
that only authorized users will have the ability to enter into the system.  The system is considered a closed 
system according to 21 CFR Part 11 Electronic Records; Electronic Signatures. 
The EDC system will be used to facilitate the collection of all study data at the site. Designated site 
personnel will be responsible for entering subject data into the EDC system. All external and Sponsor 
internal users will be trained on the EDC application at a level dependent on their planned function.  
An EDC digital User Manual will be available under the help menu within the EDC website to assist in 
the collection and entry of source data into the electronic casebook. 
Investigative study sites will be asked to enter subject data into the eCRFs no later than 2 weeks from the 
time the subject was seen for their scheduled study visit. 
Detailed description of the eCRF components are included in the eCRF Completion Instructions. These 
will be provided to the Investigators prior to initiating subject enrollment.  The respective eCRFs must be 
fully completed for each subject and signed electronically. 
Data collected during the clinical investigation for each subject will be maintained as accurately and 
completely as possible with entries into an electronic data capture system provided by AtriCure.  The 
personal data recorded on all documents, including copy documents, and within the system will be 
regarded as confidential.  The Investigator will be responsible for the timing, completeness and accuracy 
of the details entered within the electronic data capture system.  All data entered in the database must 
have source documents in the subject’s medical records. 
Data will be entered into the electronic data capture system by members of the Investigational team who 
have received training in the use of the system.  The system will generate data queries at the point of data 
entry based on validation checks defined by AtriCure. Such validation checks will primarily be focused 
on validation of key variables including selected subject demographics, appropriate value ranges and date 
checks. Resolution of the queries will be the responsibility of the Clinical Investigator and investigation 
team members.  Following completion of all data queries on each eCRF, the Clinical Investigator will be 
responsible for reviewing and confirming agreement to the data within the system. 
The Investigator must record the subject’s participation in this clinical investigation in the subject’s 
hospital notes.  In addition, the Investigator must keep a separate list of all subjects entered into this 
clinical investigation showing each subject’s name, date of birth and assigned subject number (for 
identification purposes).  A subject Identification Log will be provided in the Investigator’s File for this 
purpose. 
8.1.3 
Data Correction 
Corrections to eCRFs will be prompted via automated electronic edit checks and queries manually created 
by reviewers.  The corrections and the individual making the correction(s) to the eCRF will be within 
EDC. 


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 26 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
8.1.4 
Investigator Regulatory Binder 
Each Investigator must maintain an accurate, complete, and current copy of the Investigator Regulatory 
Binder.  Upon receipt of copies of changes or revision updates to the Binder from the Sponsor, the 
Investigator will add the updated document to the Regulatory Binder.  If an Investigator holds multiple 
copies of the Regulatory Binder, then all copies must be updated with the current revisions. 
8.1.5 
Study Correspondence 
Each Investigator and all personnel from the investigational site will maintain records of all 
correspondence, electronic, written, and verbal, relating to any aspect of the clinical investigation.  The 
records are maintained in the Investigator regulatory Binder consisting of, but not limited to 
correspondence with other participating clinical investigators, the reviewing IRB, and the Sponsor.  The 
CRA will examine the contents of the correspondence. 
8.1.6 
Data Privacy 
Subjects will be made aware that their personal data will be collected and processed in accordance with 
data protection legislation including the Health Insurance Portability and Accountability Act of 1996 
(HIPAA). Subjects will be asked to sign an Authorization for Release of Personal Health Information 
(PHI) for the purpose of this investigation. This authorization may be combined with the ICF depending 
on local IRB preference.  Results from the Clinical Investigation may be published. However, subject 
confidentiality will be maintained at all times and it will not be possible to identify individual subjects 
from any data presented.  
8.1.7 
Record Retention, Inspection, and Custody 
The PI must maintain all documentation related to the study until notified by the Sponsor. The PI will 
allow representatives of the Sponsor, IRB, the FDA, or other government regulatory agencies to inspect 
all study records, eCRFs, and corresponding portions of the subject’s office and/or hospital medical 
records at regular intervals during the study. These inspections are to verify adherence to the protocol, 
integrity of the data being captured on the eCRFs, and compliance with applicable regulations. 
Subject medical records will be kept confidential.  Study reports will not identify subjects by name.  
These reports may be submitted to the FDA and/or regulatory authorities.  
If custody of the records is transferred, notice of such a transfer should be given to the Sponsor no later 
than ten (10) working days after the transfer occurs. 
The Investigator should retain copies of all documents pertaining to this clinical investigation (including 
source documentation, the informed consent document and any other documents to identify the subjects) 
for at least 2 years after this clinical investigation is completed.  In addition, if the Clinical Investigator 
moves/retires, etc., he/she should provide AtriCure Inc. the name and address of the person who will look 
after and be responsible for the subjects’ clinical investigation related records. 
8.1.8 
Medical Dictionary Coding 
Medical dictionary coding will be performed using a coding thesaurus algorithm.  The MedDRA will be 


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 27 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
used upon data entry and query resolution for AEs, SAEs, via automated and manual coding processes. 
8.1.9 
Data Quality Assurance 
Quality control and quality assurance processes implemented during this study to ensure subject safety 
rights, and welfare are protected and to foster data integrity are characterized below. 
8.1.10 Investigator Training - Protocol Specific Training 
Protocol training will be scheduled once IRB approval is obtained and the Clinical Study Agreement is 
executed.  AtriCure, Inc. will train the study site on the protocol and that training will be documented.  It 
is ultimately the responsibility of the Investigator to ensure all clinical site personnel participating in this 
study are trained. 
The index procedure may only be performed by qualified investigators, familiar with the study procedures 
and techniques.   
Investigators will also be required to complete training in the use of the AtriCure® cryoICE cryo–ablation 
system through didactic and hands on training, including review of an instructional video on the use of 
the AtriCure® cryoICE cryo–ablation system. 
8.1.11 Monitoring 
This study will be monitored by the sponsor to ensure: 
• 
The rights, safety and well-being of the subjects are protected; 
• 
The reported study data is accurate, complete, and verifiable from source documents; and 
• 
The conduct of the study is in compliance with the currently approved 
protocol/amendment(s), applicable GCPs, and with applicable local/regional regulatory 
requirements. 
AtriCure, as Sponsor of this study, will be responsible for monitoring this study.  The Clinical Research 
Associate (CRA) duties are to aid the Principal Investigator in the production and maintenance of 
complete, legible, well-organized and easily retrievable data.  In addition, the CRA will be responsible for 
assuring the Principal Investigator understands the protocol and all applicable regulations. Approaches to 
monitoring include on-site visits and may include a remote visit, as appropriate and the rationale and 
frequency for monitoring will be at the Sponsor’s discretion. The extent and nature of monitoring will be 
predetermined and based on considerations such as the objective, design, complexity, and endpoints of 
the study and mutually agreed to by the Sponsor. The frequency of monitoring will be determined for 
each site based on factors including:  the planned enrollment, the rate of enrollment, and the current study 
conduct.  Study conduct can be evaluated remotely based on compliance percentage, discrepancy rate and 
discrepancy type.  CRAs will be trained on and comply with established standard operating procedures as 
well as a written monitoring plan specified by the Sponsor. 
In order to perform the monitoring role effectively, the CRA must verify eCRF entries with source 
documents.  The CRA must be given access to primary subject data which supports the information 
recorded on the eCRF, i.e. hospital notes, appointment books, original laboratory records, etc.  Access to 
these documents must also be given should the regulatory authority in the instance of an external 
inspection.  Since a subject has the right to refuse access to these documents on the grounds of 


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 28 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
confidentiality, consent to access is included in the informed consent document, which the subject signs. 
The Principal Investigator will receive reasonable notification prior to each monitoring visit during the 
course of this clinical investigation.  At each visit, the Principal Investigator will be expected to co-
operate with the CRA for the review and verification of eCRFs and any additional records that may have 
been previously arranged between the Principal Investigator and the CRA. 
8.2 
Changes to Protocol, Protocol Deviations and Protocol Amendments 
8.2.1 
Changes to Protocol 
The Investigator should not implement any deviation from, or changes to the protocol without agreement 
by the sponsor and prior review and documented approval/favorable opinion from the IRB of an 
amendment, except where necessary to eliminate an immediate hazard(s) to study subjects, or when the 
change(s) involves only logistical or administrative aspects of the study (e.g., change in CRA(s), change 
of telephone number(s)). In the event of an emergency situation, the Investigator must notify the CRA or 
AtriCure immediately.  A full written report of the situation must be forwarded to the IRB who approved 
the original protocol and AtriCure within 10 working days of the event. 
8.2.2 
Protocol Deviations 
The Investigator agrees to conduct the study in accordance with this protocol; however, protocol 
deviations may occur during the course of the study.  Protocol deviations are events occurring during the 
conduct of the study which are not in compliance with the protocol and for which an amendment has not 
been granted. Protocol deviations can be committed by the Sponsor, the PI, or study subject. A deviation 
can be identified from a number of sources. Potential sources include, but are not limited to: a member of 
the PI’s staff, the CRA during monitoring visits, or a member of the data management or statistical groups 
when entering or analyzing data.  The PI or PI’s representative are encouraged to contact the CRA or 
AtriCure as soon as possible upon observing a protocol deviation.  Regardless of the source, it is crucial 
to document the deviation and record all corrective actions. Protocol deviations will be reported in the 
final report. 
The process for capturing deviations will be detailed in the monitoring plan.  The process will require that 
documentation describe the deviation, appropriate actions taken, and will be included in the study file for 
the respective PI and subject.  The study site representative will be advised to record the deviation and 
relevant discussion with the Sponsor about the deviation in subject source documents. 
Protocol deviations affecting the scientific soundness of the study or the rights, safety, or welfare of the 
subjects, will be reported by the PI, as required by the IRB. 
Protocol deviations will be summarized and grouped into relevant categories for analysis and may 
include, but not be limited to, subjects who: 
• 
Entered the study although they did not satisfy the eligibility criteria; or 
• 
Developed withdrawal criteria during the study, but not removed. 
8.2.3 
Protocol Amendments 
If it becomes necessary to amend the protocol then the nature of the amendment will be agreed between 
the Sponsor and the Principal Investigator(s) and this will be recorded with a justification for the 


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 29 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
amendment. The appropriate IRBs will be informed of amendments prior to implementation of the 
change. 
9.0 
STATISTICAL METHODS 
9.1 
Clinical Study Objective 
The objectives of this study are to: 
1. To demonstrate that intraoperative intercostal cryoanalgesia provides improved analgesic efficacy 
in patients undergoing unilateral thoracotomy cardiac procedures as compared to current 
intraoperative standard of care. 
2. Long-term goal is to elucidate complementary strategies for enhanced postoperative pain 
management of patients at risk for postoperative pulmonary complications from unilateral 
thoracotomy cardiac procedures.   
Completion of the proposed study will for the first time demonstrate efficacy of intercostal cryoanalgesia 
in patients undergoing minimally invasive heart valve surgery.  Furthermore, results of this study may have 
a pivotal role in supporting future clinical outcome trials for intercostal cryoanalgesia therapy. 
9.2 
Study Endpoints 
The following endpoints will be collected for this study: 
Co-Primary Endpoints: 
1. Forced Expiratory Volume (FEV1) at 48-hours post-surgery 
2. Visual Analogue Scale (VAS) pain in the surgical region at 48-hours post-operative 
Secondary Endpoints: 
1. Spirometry assessments including: forced expiratory volume (FEV1), forced vital capacity (FVC) 
and slow vital capacity (SVC) at 48-hours post-extubation and other designated time points during 
hospital admission 
2. Pain in the surgical region assessed via Visual Analogue Scale (VAS) pain at 72-, 96- and 120-
hours (as long as patient remains in hospital up to 120-hours) post-operative 
3. Allodynia at 3 and 6 months 
4. Duration of oral endotracheal intubation defined as hours until patient is extubated from time 
patient leaves the operating room  
5. Patient Controlled Analgesia (PCA) and oral opioid consumption up to each time point (24-, 48, -
96 and 120-hours) and total PCA and oral opioid consumption after extubation 
6. ICU length of stay and hospital length of stay 
7. Ambulatory movement 
9.3 
Sample Size and Power 
In a couple of previous studies10,11 of cyro-analgesia on patients undergoing thoracotomy the authors FEV1 
was collected at 48-hours post-procedure and at other specified time-points. The studies reported 48-hours 
FEV1 mean (SD) values of 1.5 (0.7) and 1.1 (0.47) in their standard of care (continuous analgesia and 


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 30 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
epidural fentanyl infusions) groups. We used a mean mid-point of 1.3 and a liberal standard deviation of 
0.39 as reasonable estimates for sample size calculation. The investigators participating in this trial agree 
that based on their prior experience a 20% improved FEV1 value (compared to SOC) is a reasonable 
expectation. Based on this assumption, the expected mean (SD) for the Study Group is 1.56 (0.39), 
assuming a common standard deviation. 
This is a prospective, multicenter, randomized (3:1). Group sample sizes of 75 (Study Group) and 25 
(Control Group) will achieve 80% power to reject the null hypothesis of equal means when the population 
mean difference is 0.26 with a standard deviation for both groups of 0.39 and with a significance level 
(alpha) of 0.05 using a two-sided two-sample equal-variance t-test. 
Also, in a previous preliminary observational study of six patients undergoing single cardiac valve surgical 
procedure via right anterior mini-thoracotomy comparing a Visual Analogue Scale (VAS of 0-10) pain was 
collected at 0, 24, and 48 hours post-procedure. Mean VAS pain differences of 1.5 and 1.8 between the 
intercostal Cryoanalgesia group and the SOC group at 24 and 48 hours were statistically significant with p-
values of 0.03 and 0.04, respectively. The common standard deviation at 48 hours post-procedure was 2.2.  
Group sample sizes of 75 (Study Group) and 25 (Control Group) will achieve 94% power to reject the null 
hypothesis of equal means when the population mean difference is 1.8 with a standard deviation for both 
groups of 2.2 and with a significance level (alpha) of 0.050 using a two-sided two-sample equal-variance 
t-test. 
9.4 
Randomization 
Upon enrollment, subjects will be assigned a sequential identification number at each site and a 
corresponding sealed envelope which will be opened prior to the procedure to reveal the treatment group. 
Subjects will be randomized 3:1 (3 intercostal Cryoanalgesia in conjunction with SOC and 1 SOC).  
Randomization sequences will be generated by AtriCure Statistician using SAS version 9.4 (SAS Institute 
Inc., Cary, North Carolina) and will be stratified by site.   
9.5 
Analysis Populations 
Intent-To-Treat (ITT) Population: The effectiveness, safety and health economics analyses will be based 
on the ITT population. The ITT Population is defined as all subjects randomized to either the Study Group 
or SOC Group and on whom the surgical index procedure is attempted (even if the index procedure is 
aborted). 
Per-Protocol (PP) Population: A PP population may be defined for effectiveness and health economics and 
analyses. This population is defined by ITT population but without any major protocol violations, that is, 
those that could potentially bias the results.  
9.6 
Analysis of Study Endpoints 
Study endpoints will be summarized by treatment group and overall as appropriate.  Continuous variables 
will be summarized by presenting the number of subjects, mean, standard deviation, median, minimum, 
maximum by procedure group (Study Group or SOC Group). Tabulation of categorical variables by group 
will include counts and percentages. 95% confidence intervals will be provided as appropriate.  
Since this is an exploratory study, additional analyses, additional analysis populations, covariates and 


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 31 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
summary tables and/or graphs will be generated as needed. 
In all analyses described below, the null hypothesis will be a two-sided test of no treatment group difference. 
All statistical tests will use a two-sided significance level of α=0.05.  
9.6.1 
Effectiveness and Health Economic Analysis 
A two-sided student’s t-test will be used to compare the FEV1 means between the two procedure groups at 
48-hours post-surgery. 95% CI will also be reported. A Shapiro-Wilk test of normality will be performed 
and if the normality assumption is not met, an approximate non-parametric model (e.g. Wilcoxon rank-sum 
test) may be performed. Similarly, a two-sided student’s t-test will be used to compare the VAS pain means 
between the two procedure groups at 48 hours post-surgery. 95% CI will also be reported. A Shapiro-Wilk 
test of normality will be performed and if the normality assumption is not met, an approximate non-
parametric model (e.g. Wilcoxon rank-sum test) may be performed.  
Hourly VAS pain at day of surgery, 72-, 96- and 120-hours post-surgery will be similarly analyzed. In 
addition, a repeated measures ANOVA model including sites (or clusters of sites), procedure (Study Group 
and SOC Group), time, and procedure group-by-time interaction will be used to analyze the mean pain over 
time. The compound symmetry, autoregressive order one, and unstructured will be used to model the 
covariance structure. The covariance structure producing the lowest Akaike’s Information Criterion (AIC) 
and Schwarz’ Bayesian Criterion (SBC) values will be selected. Effects with p-values < 0.05 will be 
removed from the model and the data will be reanalyzed.  
Other variables: duration of oral endotracheal intubation, PCA opioids, FVC, SVC, ICU length of stay 
(LOS) and overall hospital LOS, will be analyzed via ANOVA models taking as independent variables 
baseline characteristics, sites (or clusters of sites), sex, age, and other variables as seem appropriate.  
A Pearson’s Chi-Squared test will be used to compare the incidence of allodynia events between the two 
procedure groups at 3- and 6-months post-surgery. Alternatively, a Fisher’s Exact test will be used if 
justified by small cell counts (less than 5) and Clopper-Pearson (Exact) 95% CI will also be reported. 
Ambulatory movement will be similarly summarized and analyzed. 
Assumptions of hypothesis tests such as for normality and homogeneity of variance will be performed. In 
the event that the assumptions are severely violated, the nonparametric equivalent test may be reported 
along with the appropriate justification.  
9.6.2 
Safety Analysis 
AEs related to the CryoAnalgesia procedure or device will be reported on the eCRF.  These AEs will be 
listed and descriptively summarized for patients in the Study Group. No formal statistical hypothesis will 
be tested.  
9.7 
Detailed Analysis Plan 
Prior to looking at the data and database closure, if needed, a detailed statistical analysis  
plan will be prepared and finalized to completely specify the statistical procedures to be applied to the data 
by the statistician who will conduct the analysis. The plan will amplify on the methods discussed in this 
protocol, will address any protocol changes that would affect the analysis, and will provide a rationale for 
any changes to the analysis. 


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 32 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
10.0 
Safety Monitoring 
Subject safety will be monitored throughout the course of this study by monitoring for Adverse Events 
and Product Complaints related to the AtriCure cryoICE Probe (CRY02) used in conjunction with the 
cryoICE BOX (v6).  The AtriCure cryoICE Probe (CRY02) used during the index procedure for the 
clinical study has been cleared for marketing by the FDA and is being used within the current labeling 
and indications for use.  Any event that occurs that may have caused or contributed to a death or serious 
injury or that indicates the AtriCure cryoICE Probe (CRY02) device has malfunctioned and would be 
likely to cause or contribute to a death or serious injury if the malfunction were to recur will be reported 
in compliance with 21 CRF Part 803. 
In addition to general surgical risks, additional risks specifically associated with the AtriCure cryoICE 
Probe (CRY02) are as follows: 
• 
Skin injury due to cryoablation of skin  
• 
Intercostal muscle injury 
• 
Permanent peripheral nerve damage 
 
These risks could lead to symptoms that include: 
o Numbness around the incision lasting from 1 to 6 months 
o Neuralgia occurring 6 weeks after cryoanalgesia, lasting up to 2 months 
o Hyperesthesia 
There may also be other risks that are unforeseen at this time.  The complete Risk/Benefit Assessment 
is found in Appendix 3. 
10.1 
Adverse Events 
10.1.1 Definition of an Adverse Event 
Adverse Event (AE): any undesirable clinical occurrence or change from a patient’s baseline (pre-index 
procedure) condition, whether it is device related or not. 
 
Adverse Event Identification: a condition that is one of the following: 
a. A unique symptom or event that is a change from the subject’s baseline status 
b. A series of symptoms or events that can be categorized as a single entity based on definitions 
found herein 
c. A specific diagnosis responsible for a clinical change 
d. A worsening or exacerbation of a pre-existing condition 
10.2 
Serious Adverse Events 
10.2.1 Definition of a Serious Adverse Event 
Serious Adverse Event (SAE): any adverse event is considered serious if it results in death, is life 
threatening, requires hospitalization (initial or prolonged), results in disability or permanent damage, 
causes congenital anomaly/birth defect, requires intervention to prevent impairment or damage, or other 
serious (important medical events) which may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the above outcomes. 
Note:  “Death” should not be reported as an adverse event.  The cause of death should be reported as an 


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 33 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
adverse event.  The only exception is “Sudden Death” when the cause is unknown. 
10.2.2 Subject Death 
Subject death during the investigation must be reported by the Investigator (or designee) by submitting 
the Adverse Event eCRF to the Sponsor, within 24 hours of learning of the adverse event.  The electronic 
Adverse Event Form must be electronically signed by the Investigator.  A copy of the death records, death 
certificates and an autopsy report (if performed) are required to be sent to the AtriCure or designee within 
10 days following the death.  Any death must be reported to the FDA within 10 working days of AtriCure 
or designee’s knowledge of the death.  In addition, subject death must be reported to the IRB in 
accordance with IRB requirements.  
10.2.3 Adverse Event Classification 
The investigator is required to provide: 
• 
Time interval of the event – The time interval of the occurrence of the adverse event should be 
assessed in relationship to timing of the index procedure (Use of the AtriCure® cryoICE cryo–
ablation system) 
• 
Date of event onset and outcome of the event, or date of death 
• 
Severity of the event – (Mild, Moderate, Severe) 
• 
Action taken for medical management of the event 
Relationship of the event – it is the PIs responsibility to assess the relationship of an AE and provide 
primary cause.  Events will be categorized by relationship to the AtriCure cryoICE Probe (CRY02) 
device, the cryoICE BOX (v6), an ancillary device, the index procedure or other.   
• 
Adverse events will be assessed to determine if the event meets the definition of a serious adverse 
event.   
10.2.4 Reporting Adverse and Serious Adverse Events 
The investigator (or designee) will record all AEs (both serious and non-serious and regardless of 
relationship) in the source documents.  The Investigator at each site participating site is responsible for 
reporting AEs and SAEs to AtriCure only when they are related to the CryoAnalgesia index procedure or 
device.  AEs related to the CryoAnalgesia procedure or device will be reported on the eCRF.  The CRFs 
allow the investigator to indicate whether or not the adverse events are related to the device or index 
procedure. 
• 
Use a separate Adverse Event Form to document each event 
• 
The Adverse Event Form must be electronically signed by the Investigator 
Note: It is the responsibility of the Investigator to inform their IRB of SAEs as required by their 
IRB procedures and in conformance with FDA requirements. 
All Serious Adverse Events that are related to the CryoAnalgesia index procedure or device must be 
reported by the Investigator by submitting the AE eCRF to AtriCure within 10 days of becoming aware of 
the AE.  An event determined by the Investigator to be life threatening or to have led to death should be 
reported within 24 hours. 
The Investigator shall send a written report including a narrative description of the SAE to AtriCure 
within three (3) working days of the initial report.  The Investigator should follow all unresolved SAEs 




 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 35 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
REFERENCES 
 
1. Sepsas E, Misthos P, Anagnostopulu M, Toparlaki O, Voyagis G, Kakaris S. The role of intercostal 
cryoanalgesia in post-thoracotomy analgesia. Interactive cardiovascular and thoracic surgery 
2013;16:814-8. 
2. Moorjani N, Zhao F, Tian Y, Liang C, Kaluba J, Maiwand MO. Effects of cryoanalgesia on post-
thoracotomy pain and on the structure of intercostal nerves: a human prospective randomized trial and a 
histological study. Eur J Cardiothorac Surg 2001;20:502-7. 
3. Glauber M, Karimov JH, Farneti PA, et al. Minimally invasive mitral valve surgery via right 
minithoracotomy. Multimedia manual of cardiothoracic surgery : MMCTS / European Association for 
Cardio-Thoracic Surgery 2009;2009:mmcts 2008 003350. 
4. Loan WB, Dundee JW. The clinical assessment of pain. The Practitioner 1967;198:759-68. 
5. Papper EM, Brodie BB, Rovenstine EA. Postoperative pain; its use in the comparative evaluation of 
analgesics. Surgery 1952;32:107-9. 
6. Katz J. Cryoanalgesia for postthoracotomy pain. Ann Thorac Surg 1989;48:5. 
7. Cook TM, Riley RH. Analgesia following thoracotomy: a survey of Australian practice. Anaesth 
Intensive Care 1997;25:520-4. 
8. Simpson BR, Parkhouse J, Marshall R, Lambrechts W. Extradural analgesia and the prevention of 
postoperative respiratory complications. Br J Anaesth 1961;33:628-41. 
9. Maiwand MO, Makey AR, Rees A. Cryoanalgesia after thoracotomy. Improvement of technique and 
review of 600 cases. J Thorac Cardiovasc Surg 1986;92:291-5. 
10. Gough J.D., Williams, A.B., Vaughan, R.S. The control of post-thoracotomy pain. A comparative 
evaluation of thoracic epidural fentanyl infusions and cryo-analgesia. Anaesthesia, 1988;43:780-3. 
11. Gwak M.S., Yang M., Halm T.S., Cho H.S., Cho C.H., Song J.G. Effect of cyoanalgesia combined 
with intravenous continuous analgesia in thoracotomy patients. J Korean Med Sci, 2004;19:74-8. 
 
 
 
 
 
 


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 36 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
13.0 
Appendices 
APPENDIX 1 -  Visual Analog Scale  
 
 
Mankoski Pain Scale Definitions 
 
0- 
Pain Free 
1- 
Very minor annoyance- occasional minor twinges.  No medication needed. 
2- 
Minor annoyance- occasional strong twinges.  No medication needed. 
3- 
Annoying enough to be distracting.  Mild painkillers take care of it. (Aspirin, Ibuprofen.) 
4- 
Can be ignored if you are really involved in your work, but still distracting.  Mild painkillers remove pain for 3-4 hours. 
5- 
Can’t be ignored for more than 30 minutes.  Mild painkillers ameliorate pain for 3-4 hours. 
6- 
Can’t be ignored for any length of time, but you can still go to work and participate in social activities.  Stronger 
painkillers (Codeine, narcotics) reduce pain for 3-4 hours. 
7- 
Makes it difficult to concentrate, interferes with sleep.  You can still function with effort.  Stronger painkillers are only 
partially effective. 
8- 
Physical activity severely limited.  You can read and converse with effort.  Nausea and dizziness set in as factors of 
pain. 
9- 
Unable to speak.  Crying out or moaning uncontrollably- near delirium. 
10- Unconscious.  Pain makes you pass out. 


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 37 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
APPENDIX 2 – ALLODYNIA ASSESSMENT  
 
Allodynia and hyperpathia are terms used to describe the hypersensitivity that occurs with neuropathic 
pain. Many different techniques have been used to assess skins sensitivity, including alcohol pads, Von 
Frey fibers, and camel hair brushes (https://www.youtube.com/watch?v=-eRSx0Cbxks).  Recently, the 
use of a cotton tip applicator (CTA) has been described to test skin sensitivity to evaluate abdominal wall 
allodynia due to chronic pelvic pain (1). This simple test has been validated as a reproducable screening 
method to identify cutaneous allodynia in women with or without chronic pelvic pain (2), and we propose 
to use this same simple test to evaluate neuropathic pain following chest wall surgery. For a video of the 
technique used to evaluate chronic pelvic pain, please see 
http://www.jove.com/video/1232/demonstration-cutaneous-allodynia-association-with-chronic-pelvic.  
1. An explanation of the test is undertaken and permission to proceed is obtained. 
2. The patient exposes the chest wall at the surgical site. 
3. A disposable sterile cotton-tipped applicator is shown to the patient and brushed against the patient’s 
hand to demonstrate how the light pressure will feel. 
4. The cotton-tipped culture stick is then lightly drawn down the chest wall in the anterior axillary line, 
the mid axillary line, and the posterior axillary line, as well as the anterior and posterior extents of the 
incision. The patient is asked to note the point at which light pressure applied to the skin becomes sharp 
as the cotton-tipped culture stick is drawn down the chest wall, starting approximately 2 rib interspaces 
above the surgical incision, and continuing at least 3 interspaces below the surgical site.  
5. The patient will either note the presence of normal sensation or will note a sudden and discrete 
sharpness in sensation. A positive test is defined by the presence of this sudden sharp sensation. A small 
mark with a marking pen will be used to map the border of the area of sensitivity. The process should be 
repeated until the entire area of cutaneous allodynia has been identified. The furthest “north, south, east 
and west” points will be marked around the incision.  A photograph of the area of sensitivity may be 
taken to document increasing or decreasing areas of allodynia, but is not required.  
6.  The north south east and west points will be measured for height and width in centimeters (cm). 
7. In some cases the areas are large but in others they will be small. Some areas may encompass the entire 
length of the incision, while others may involve only a very small, specific site. 
 
1. 
Jarrell J. Demonstration of cutaneous allodynia in association with chronic pelvic pain. J 
Vis Exp. 2009(28). 
2. 
Nasr-Esfahani M, Jarrell J. Cotton-tipped applicator test: validity and reliability in 
chronic pelvic pain. Am J Obstet Gynecol. 2013;208(1):52.e1-5. 
 
 
 


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 38 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
 
APPENDIX 3  - RISK/BENEFIT ASSESSMENT 
 
Clinical Risk/ Benefit Assessment 
 
SUMMARY 
 
The cryoICE™ CryoAnalgesia study is being undertaken to examine pain management in post thoracic 
procedures via intercostal cryoanalgesia. Subjects meeting the inclusion/exclusion criteria and undergoing 
unilateral thoracotomy cardiac procedures will participate in this study. The risks of participation are 
offset by the significant potential for clinical and functional benefits. 
 
POTENTIAL BENEFITS 
 
The potential benefit to study subjects outweighs the risks of participation in this study. 
The benefits may include but are not limited to, the following: 
• 
Clinical improvement - patients may experience improved post-operative pain control following 
minimally invasive heart valve surgery 
• 
Functional improvement - patients may experience less post-operative pulmonary complications, 
less mental status changes, improved blood pressure and heart rate 
• 
Overall advancement of medical and scientific knowledge - Information obtained from this study 
may further our understanding of peri-operative pain control following this surgical procedure 
and improve patient post-operative experience. 
 
There may also be other benefits that are unforeseen at this time. 
 
POTENTIAL RISKS 
 
Risk Category: Minimal 
 
Independent from this research study, the participant is already scheduled to undergo a minimally 
invasive heart valve surgical procedure via right mini-thoracotomy. All risks for this procedure will have 
been discussed with the surgeon and surgical consent will have been signed. Similarly, common 
anesthetic risks will have been discussed, and anesthetic consent will have been signed. The participant 
will be fully informed of the risks of this study. Possible adverse events may include, but are not limited 
to, the following. 
 
Risks of Intercostal Cryoanalgesia with the cryoICE® probe: 
 
Most frequent (occurring more than 10% of the time): 
• 
Device Breakage 
• 
Skin injury due to cryoablation minor damage of skin that would heal over time 
• 
Intercostal muscle injury 
• 
Permanent peripheral nerve damage resulting in difference in sensation not evident prior to surgery 
• 
Failure to ablate peripheral nerve may result patient requiring pain management 


 
Study Number: CP2015-4 
CONFIDENTIAL 
Page 39 of 39 
Record: Clinical Study Protocol 
 
 
Version date: 31May2016 / Rev: D 
 
Less frequent (occurring 1-10% of the time): 
• 
Tissue perforation 
• 
Tissue freezing 
Rare (occurring less than 1% of the time):  
• 
Injury to user 
• 
Nitrous gas exposure to patient 
 
There may also be other risks that are unforeseen at this time. 
 
MINIMIZATION OF RISKS 
Measures which will be taken to minimize risks related to the study include: 
• 
Investigators will be chosen that are qualified to complete study index procedures and are experienced 
in use of cryoICE cryo-ablation system. 
• 
Well defined clinical study protocol, including specific inclusion/ exclusion criteria to enroll 
appropriate subjects in the trial. 
• 
Close patient monitoring during the surgical procedure and follow-up period. 
 
Alternative to Participation:  
Patients may decline and would be treated with the same standard of care.   
 
CONCLUSION 
 
This clinical study is justified because the study sponsor and clinical investigators believe the potential 
benefits outweigh the potential risks. 
 

ICF_000.pdf: