Conditions: Pectus Excavatum Funnel Chest
Keywords: Nuss Nuss Procedure pectus excavatum cryoanalgesia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 20
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether cryoanalgesia provides better pain control for minimally invasive pectus excavatum repair (the Nuss procedure) than thoracic epidural.

Detailed description:
Pain control is a major challenge for physicians, who must ensure appropriate and effective pain control for their patients, while remaining mindful of the many negative effects of opioid dependence and addiction. Nowhere is there a more pressing need than in children and young adults, who are at high risk for drug abuse, and in post-operative care, since post-operative opioid use can be a starting point for long-term pain issues. Postoperative pain control in the Nuss procedure, minimally invasive repair of the congenital chest wall deformity known as pectus excavatum, remains a significant problem for the 3000 patients who undergo this procedure each year, mostly adolescents and young adults. Many multimodal analgesic regimens have been tried, but optimal treatment remains unknown.

This study will test a novel and promising strategy of using intra-operative cryoanalgesia during the Nuss procedure. Cryoanalgesia is the localized, temporary freezing of peripheral nerves, which is performed at the time of the Nuss procedure. The study is a 20-subject prospective, randomized pilot trial comparing cryoanalgesia to thoracic epidural analgesia for post-operative pain control in patients undergoing the Nuss procedure. Subjects will be recruited from patients already scheduled for a Nuss procedure at our institution, and will undergo 1:1 randomization to either cryoanalgesia or thoracic epidural analgesia for perioperative pain control. During their hospitalization, patients' opiate usage will be prospectively recorded, and pain will be assessed twice per day. Upon discharge, patients will maintain a log of their opiate use, and will return to clinic at 2 weeks, 1 month, 3 months, and 1 year after Nuss procedure for post-operative assessment. Primary outcome is length of perioperative hospitalization, an objective measure that synthesizes many different aspects of a procedure and its subsequent post-operative course, including pain control. Secondary outcomes are post-operative narcotic usage and direct cost of perioperative hospitalization. Side effects of both interventions will also be assessed.

This will be the first systematic investigation of cryoanalgesia for local nerve block in a thoracoscopic procedure, and the first study involving its use in adolescents and young adults. The results will have direct application for those undergoing the Nuss procedure to repair pectus excavatum. Investigators will also delineate a reproducible protocol for delivering cryoanalgesia thoracoscopically, to ensure others can safely and effectively use this method if it proves beneficial. Although the focus is on the small subset of patients who undergo the Nuss procedure, if a standardized approach to cryoanalgesia delivery in a thoracoscopic procedure has a positive effect on patient outcomes and cost of hospitalization, the technique could be applied to a variety of surgical procedures, as well as for other neuropathic pain.

Arms:
arm 1: Cryoanalgesia performed thoracoscopically under general anesthesia by the patient's surgeon at the time of the Nuss procedure arm 2: Thoracic epidural (ropivicaine, fentanyl).

Interventions: intervention 1: Cryoanalgesia intervention 2: Thoracic epidural (ropivicaine, fentanyl)
Intervention descriptions: intervention 1: None intervention 2: Epidural infusion was begun with with 0.1% ropivicaine and 2 mg/cc fentanyl.

Protocol document:
Prot_SAP_000.pdf: 
15-18202 
 
 
Version 1 
Version Date: 12/7/15 
Page 1 of 25 
Protocol Template Effective: 07 JAN 2015  
 
 
 
 
 
 
Cryoanalgesia vs. Epidural in the Nuss Procedure 
Clinical Trial Number: NCT02721017 
Document Date: December 7, 2015 
Uploaded: 8/27/2019 


15-18202 
 
 
Version 1 
Version Date: 12/7/15 
Page 2 of 25 
Protocol Template Effective: 07 JAN 2015  
TABLE OF CONTENTS 
 
1 
BACKGROUND ................................................................................................................. 4 
1.1 
Overview of Non-Clinical Studies .............................................................................. 9 
1.2 
Overview of Clinical Studies ...................................................................................... 10 
2 
STUDY RATIONALE ........................................................................................................ 10 
2.1 
Risk / Benefit Assessment ........................................................................................... 10 
3 
STUDY OBJECTIVES ....................................................................................................... 10 
3.1 
Primary Objective ....................................................................................................... 11 
3.2 
Secondary Objectives .................................................................................................. 11 
4 
STUDY DESIGN ................................................................................................................. 11 
4.1 
Study Overview ........................................................................................................... 11 
5 
CRITERIA FOR EVALUATION ..................................................................................... 11 
5.1 
Primary Efficacy Endpoint .......................................................................................... 11 
5.2 
Secondary Efficacy Endpoints .................................................................................... 11 
5.3 
Safety Evaluations ....................................................................................................... 12 
6 
SUBJECT SELECTION .................................................................................................... 12 
6.1 
Study Population ......................................................................................................... 12 
6.2 
Inclusion Criteria ......................................................................................................... 12 
6.3 
Exclusion Criteria ....................................................................................................... 12 
7 
CONCURRENT MEDICATIONS .................................................................................... 12 
7.1 
Allowed ....................................................................................................................... 12 
7.2 
Prohibited .................................................................................................................... 12 
8 
STUDY TREATMENTS .................................................................................................... 13 
8.1 
Method of Assigning Subjects to Treatment Groups .................................................. 13 
8.2 
Blinding ....................................................................................................................... 13 
8.3 
Test and Control Products
 
Error! Bookmark not defined. 
8.4 
Supply of Study Medication at the Site
 
Error! Bookmark not defined. 
8.5 
Study Medication Accountability ............................................................................... 14 
8.6 
Measures of Treatment Compliance ........................................................................... 14 
9 
STUDY PROCEDURES AND GUIDELINES ................................................................. 14 
9.1 
Clinical Assessments ................................................................................................... 14 
10 EVALUATIONS BY VISIT ............................................................................................... 15 
10.1 Visit 1 (Day/Week/Month #) ...................................................................................... 15 
10.2 Visit 2 (Day/Week/Month # include visit window) .................................................... 15 
10.3 Visit 3 (Day/Week/Month # include visit window) .................................................... 16 
10.4 Visit 4 (Day/Week/Month # include visit window) .................................................... 16 
10.5 Visit 5 (Follow-up or Day/Week/Month # include visit window) .............................. 16 
10.6 Early Withdrawal Visit ............................................................................................... 16 


15-18202 
 
 
Version 1 
Version Date: 12/7/15 
Page 3 of 25 
Protocol Template Effective: 07 JAN 2015  
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION ........................ 17 
11.1 Adverse Events ........................................................................................................... 17 
11.2 Serious Adverse Experiences (SAE) ........................................................................... 18 
11.3 Protocol Defined Important Medical Findings Requiring Real Time Reporting
 
Error! Bookmark not defined. 
11.4 Medical Monitoring .................................................................................................... 19 
11.5 Safety Management Plan............................................................................................. 4 
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS................................... 19 
12.1 Withdrawal of Subjects ............................................................................................... 19 
12.3 Replacement of Subjects ............................................................................................. 19 
13 PROTOCOL VIOLATIONS ............................................................................................. 20 
14 STATISTICAL METHODS AND CONSIDERATIONS ............................................... 20 
14.1 Data Sets Analyzed ..................................................................................................... 20 
14.2 Demographic and Baseline Characteristics ................................................................. 20 
14.3 Analysis of Primary Endpoint ..................................................................................... 20 
14.4 Analysis of Secondary Endpoints ............................................................................... 20 
14.5 Interim Analysis
 
Error! Bookmark not defined. 
14.6 Sample Size and Randomization ................................................................................. 21 
15 DATA COLLECTION, RETENTION AND MONITORING ....................................... 21 
15.1 Data Collection Instruments ........................................................................................ 21 
15.2 Data Management Procedures ..................................................................................... 21 
15.3 Data Quality Control and Reporting ........................................................................... 21 
15.4 Archival of Data .......................................................................................................... 21 
15.5 Availability and Retention of Investigational Records ............................................... 22 
15.6 Monitoring .................................................................................................................. 22 
15.7 Subject Confidentiality................................................................................................ 22 
16 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS .................. 22 
16.1 Protocol Amendments ................................................................................................. 22 
16.2 Institutional Review Boards and Independent Ethics Committees ............................. 23 
16.3 Informed Consent Form .............................................................................................. 23 
16.4 Publications ................................................................................................................. 24 
16.5 Investigator Responsibilities ....................................................................................... 24 
 


15-18202 
 
 
Version 1 
Version Date: 12/7/15 
Page 4 of 25 
Protocol Template Effective: 07 JAN 2015  
LIST OF ABBREVIATIONS 
AE 
adverse event 
CFR 
Code of Federal Regulations 
CRF 
case report form 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
intravenous 
mEq 
milliequivalent 
PI 
Principal Investigator 
SAE 
serious adverse experience 


15-18202 
 
 
Version 1 
Version Date: 12/7/15 
Page 5 of 25 
Protocol Template Effective: 07 JAN 2015  
PROTOCOL SYNOPSIS 
TITLE 
Cryoanalgesia vs. Thoracic Epidural for Post-operative Pain Control 
following the Nuss Procedure 
SPONSOR 
UCSF Department of Surgery, Division of Pediatric Surgery 
NUMBER OF SITES 
1: UCSF Benioff Children’s Hospital 
RATIONALE 
Pectus excavatum is the most common congenital chest wall 
deformity, affecting approximately 1 out of every 1000 live births.  It 
presents as a depression of the anterior chest wall, which can compress the 
heart and lungs, causing symptoms such as shortness of breath, exercise 
intolerance, and chest pain. The minimally invasive pectus excavatum 
repair, known as the Nuss procedure, is a common corrective procedure. It 
uses an implanted, thoracoscopically-guided convex metal bar to 
immediately reshape the chest wall. The benefits of this method compared to 
open repair include smaller incisions, no cartilage resection or osteotomy, 
and reduced operative times. However, the immediate reshaping of the chest 
wall results in significant post-operative pain, which can be challenging for 
patients, families, and clinicians. The ability to adequately control this post-
operative pain is the primary determining factor for length of hospitalization 
following the procedure. 
      There is no standardized protocol for the management of pain following 
the Nuss procedure.  Epidural analgesia and patient controlled analgesia 
(PCA) are the two most commonly used techniques, employed either 
independently or together. While epidural analgesia has been shown to be 
more effective than PCA alone for the first few postoperative days, it carries 
significant risks and is limited to the first two to three post-operative days, at 
which time patients must be transitioned to alternate methods. Cryoanalgesia 
is a means of long-term local nerve blockade, which has previously been 
used in adults for acute pain control following thoracotomy, as well as for 
treatment of chronic thoracic pain due to surgery or post-herpetic neuralgia. 
Anecdotally, cryoanalgesia has been effective at controlling acute post-
operative pain following the Nuss procedure.  The procedure is particularly 
well-suited to the application of cryoanalgesia, as the operative exposure 
directly visualizes the intercostal nerves. However, no randomized trials 
have been performed to more rigorously evaluate this treatment.  We 
therefore propose a randomized, prospective trial to evaluate cryoanalgesia 
compared to epidural analgesia for the Nuss procedure. 
 
STUDY DESIGN 
This study is a prospective, randomized trial to compare cryoanalgesia to 
standard epidural analgesia for post-operative pain management in patients 
undergoing minimally invasive pectus excavatum repair (the Nuss 
procedure). 20 subjects will be randomized in 1:1 ratio to receive 
cryoanalgesia or epidural analgesia prior to their procedure. 
PRIMARY OBJECTIVE 
To compare post-operative length of stay in patients receiving cryoanalgesia 
vs. thoracic epidural analgesia for the Nuss procedure 


15-18202 
 
 
Version 1 
Version Date: 12/7/15 
Page 6 of 25 
Protocol Template Effective: 07 JAN 2015  
SECONDARY 
OBJECTIVES 
To compare post-operative pain scores, pain medication usage, side effects, 
and total cost of hospital stay in patients receiving cryoanalgesia vs. thoracic 
epidural analgesia for the Nuss procedure 
NUMBER OF 
SUBJECTS 
20 
SUBJECT SELECTION 
CRITERIA 
Inclusion Criteria: Otherwise healthy male or female patients with pectus 
excavatum deformity, scheduled for Nuss procedure for chest wall 
correction, at least 13 years of age at time of Nuss procedure.  
 
Exclusion Criteria:  
• 
Age less than 13 years at time of surgery 
• 
Pre-op pain medication usage 
• 
Pectus carinatum 
• 
Poland’s syndrome or other complex chest wall anomaly 
• 
Previous repair of Pectus Excavatum by any technique 
• 
Previous thoracic surgery 
• 
Congenital heart disease 
• 
Bleeding dyscrasia 
• 
History of previous problems with anesthesia or major 
anesthestic risk factors 
• 
Pregnancy 
• 
Non-English speaker 
TEST PRODUCT, DOSE, 
AND ROUTE OF 
ADMINISTRATION 
AtriCure cryosurgical system (AtriCure, Inc., West Chester, Ohio) 
The cryoprobe will be applied to the intercostal nerve under thoracoscopic 
visualization at the level of the incision and 2 interspaces above and below, 
bilaterally.  The temperature and duration of cryoablation therapy is pre-set 
by the probe and cryosurgical system at 2 minutes to -60°C. Each nerve will 
receive one cycle of cryoablation. 
CONTROL PRODUCT, 
DOSE AND ROUTE OF 
ADMINISTRATION 
Thoracic epidural catheter will be placed by the pediatric anesthesia team 
prior to Nuss procedure. Catheters will be placed using sterile technique at 
approximately T5-6 or T6-7 interspaces; procedure specifics are dependent 
on the attending anesthesiologist’s patient-dependent preference.  Whether 
the patient will be awake or asleep for epidural placement will be at the 
discretion of the attending anesthesiologist.  After placement, epidural 
infusion will begin with 0.1% ropivicaine and 2mcg/cc fentanyl.  No bolus 
doses will be used. 


15-18202 
 
 
Version 1 
Version Date: 12/7/15 
Page 7 of 25 
Protocol Template Effective: 07 JAN 2015  
DURATION OF 
SUBJECT 
PARTICIPATION AND 
DURATION OF STUDY 
Subjects will be on study for 1 year 
Screening:  1 week (prior to initial consultation) 
Treatment:  3-7 days (subjects to be admitted to the hospital) 
Follow-up:  1 year 
The total duration of the study is expected to be 1.5 years.  6 months for 
subject recruitment and 1 year following final recruitment for subject 
follow-up. 
CONCOMMITANT 
MEDICATIONS 
Allowed: all deemed necessary by primary team or pediatric pain service 
 
Prohibited: none 
EFFICACY 
EVALUATIONS 
 
PRIMARY ENDPOINT 
• 
Post-operative hospital length of stay 
SECONDARY 
ENDPOINTS 
• 
Post-operative pain scores 
• 
Pain medication usage 
• 
Side effects 
• 
Total hospitalization cost 
SAFETY 
EVALUATIONS 
Incidence of adverse events 
PLANNED INTERIM 
ANALYSES  
Serious adverse events will be monitored by the committee on an ongoing 
basis throughout the study.  
STATISTICS 
Primary Analysis Plan 
Patient baseline characteristics will be analyzed with descriptive statistics 
(ie. mean age, % male, mean pectus severity index, etc.). 
Our primary outcome will be post-operative length of stay, which will be 
analyzed using a two-tailed unpaired t test, with results considered 
statistically significant for p< 0.05. 
Secondary outcomes include post-operative pain scores, pain medication 
usage, and side effects.  Pain scores will be analyzed with Mann-Whitney 
rank sum tests (to compare between groups at each time point) and 
Wilcoxson signed-rank test (to compare scores within groups over time), 
with results considered statistically significant for p< 0.05..  Pain medication 
usage between the two groups will be analyzed with two-tailed unpaired t 
test, again with results considered statistically significant for p< 0.05.   
Given our small sample size and the low rate of complications with both 
analgesic methods, we expect very limited side effect data. A descriptive 
overall side effect rate will be calculated for each arm of the study, and the 
individual side effects will be listed in a table. 
A cost analysis will be performed, comparing the total cost of hospitalization 
between the cryoanalgesia and epidural groups.  Difference in total cost will 
be assessed with two-tailed unpaired t test.   


15-18202 
 
 
Version 1 
Version Date: 12/7/15 
Page 8 of 25 
Protocol Template Effective: 07 JAN 2015  
Rationale for Number of 
Subjects 
We used the UCSF Clinical & Translational Science Institute web-based 
sample size calculator (http://www.sample-size.net/sample-size-means/) to 
determine study size.  Based on previous Nuss procedures over the past 2 
years at our institution, we determined the mean length of hospitalization 
was 7 days, with a standard deviation of 1.3 days.  From anecdotal data from 
our prior experience, as well as from speaking with other surgeons utilizing 
cryoablation, we expect patients in the cryoanalgesia group to have 
approximately 2 days shorter hospital stay.  With type 1 error rate of 0.05 
and type II error rate of 0.1 (yielding 90% power), our study would need 18 
patients total.  Allowing for some dropout, we will plan to enroll 20 patients 
to the study. 
 


15-18202 
 
 
Version 1 
Version Date: 12/7/15 
Page 9 of 25 
Protocol Template Effective: 07 JAN 2015  
1 
BACKGROUND 
  Pectus excavatum is the most common congenital chest wall deformity, affecting approximately 
1 out of every 1000 live births.  It presents as a depression of the anterior chest wall, which can 
compress the heart and lungs, causing symptoms such as shortness of breath, exercise intolerance, 
and chest pain.1,2 The minimally invasive pectus excavatum repair, known as the Nuss procedure, 
is a common corrective procedure. It uses an implanted, thoracoscopically-guided convex metal 
bar to immediately reshape the chest wall.1,3,4 The benefits of this method compared to open repair 
include smaller incisions, no cartilage resection or osteotomy, and reduced operative times. 3 
However, the immediate reshaping of the chest wall results in significant post-operative pain, 
which can be challenging for patients, families, and clinicians.5,6 The ability to adequately control 
this post-operative pain is the primary determining factor for length of hospitalization following 
the procedure.7 
      There is no standardized protocol for the management of pain following the Nuss procedure.  
Epidural analgesia and patient controlled analgesia (PCA) are the two most commonly used 
techniques, employed either independently or together. 5-8 Thoracic epidural analgesia has been 
shown, with limited data, to be more effective than PCA alone for the first few postoperative days, 
but carries significant risks, including nerve damage, infection, and respiratory depression. 6,9 
Epidural analgesia also reduces post-operative mobility, and often necessitates the use of urinary 
catheters, which can increase risk of urinary tract infections.10 The use of epidural analgesia is 
limited to the first two to three post-operative days, at which time patients must be transitioned to 
alternate methods.11 This may increase length of stay, as it introduces an intermediate step prior to 
home oral regimen. 
      Thus, there is significant room for improvement in post-operative pain management in the 
Nuss procedure. One possible solution is the addition of a local nerve block with cryoanalgesia. 
The use of cold to numb pain is one of the oldest forms of analgesia, dating back at least to 
Hippocrates (460-377 BC), who described the use of ice and snow packs for relieving surgical 
pain.12 Today, the term “cryoanalgesia” refers to the localized freezing of peripheral nerves.  
Freezing occurs through application of a “cryoprobe,” which releases high-pressure carbon 
dioxide or nitrous oxide that rapidly expands, causing cooling via the Joule-Thomson effect to 
temperatures of -50 to -70 °C.  This sudden freezing causes the formation of intra-and 
extracellular ice crystals, which disrupt the cell wall and alter cellular osmolality.  When nerve 
axons are frozen, Wallerian degeneration occurs, preventing the transmission of pain signals and 
providing analgesia.  However, the fibrous neural structures, including the perineurium and 
epineurium, are able to resist damage and remain intact, which facilitates axonal regeneration. 10,12-
14 The rate of this axonal regeneration is approximately 1-3 mm/day. Animal studies of 
cryoanalgesia have demonstrated that repair and regeneration of the axon and myelin sheath 
following cryoanalgesia is complete by approximately 4-6 weeks.10,15 
      Cryoanalgesia has previously been used in adults for acute pain control following 
thoracotomy, as well as for treatment of chronic thoracic pain due to surgery or post-herpetic 
neuralgia.10,11,16-25 Anecdotally, cryoanalgesia has been effective at controlling acute post-operative 
pain in young adult and adult patients following the Nuss procedure.  The procedure is particularly 
well-suited to the application of cryoanalgesia, as the operative exposure directly visualizes the 
intercostal nerves. However, no randomized trials have been performed to more rigorously 
evaluate this treatment.  We therefore propose a randomized, prospective trial to evaluate 
cryoanalgesia compared to epidural analgesia for the Nuss procedure. 
1.1 
Overview of Non-Clinical Studies 
Scientists have been investigating the effect of cold on the nervous system since 
approximately 400 BC.  Since the 1970s, “cryoanalgesia” systems have been in use, which deliver 


15-18202 
 
 
Version 1 
Version Date: 12/7/15 
Page 10 of 25 
Protocol Template Effective: 07 JAN 2015  
high-pressure carbon dioxide or nitrous oxide that rapidly expands, causing cooling via the Joule-
Thomson effect to temperatures of -50 to -70 °C.  This sudden freezing causes the formation of 
intra-and extracellular ice crystals, which disrupt the cell wall and alter cellular osmolality.  When 
nerve axons are frozen, Wallerian degeneration occurs, preventing the transmission of pain signals 
and providing analgesia.  However, the fibrous neural structures, including the perineurium and 
epineurium, are able to resist damage and remain intact, which facilitates axonal regeneration. 10,12-
14 The rate of this axonal regeneration is approximately 1-3 mm/day. Animal studies of 
cryoanalgesia have demonstrated that repair and regeneration of the axon and myelin sheath 
following cryoanalgesia is complete by approximately 4-6 weeks.10,15 
1.2 
Overview of Clinical Studies 
There is no published literature on cryoanalgesia in pectus excavatum repair. Studies 
investigating pain control following the Nuss procedure shown, with limited data, thoracic 
epidural analgesia to be more effective than PCA alone for the first few postoperative days. 
However, this method carries significant risks, including nerve damage, infection, and respiratory 
depression.6,9 Epidural analgesia also reduces post-operative mobility, and often necessitates the 
use of urinary catheters, which can increase risk of urinary tract infections.10 The use of epidural 
analgesia is limited to the first two to three post-operative days, at which time patients must be 
transitioned to alternate methods.11 This may increase length of stay, as it introduces an 
intermediate step prior to home oral regimen. 
Cryoanalgesia has previously been used in adults for acute pain control following 
thoracotomy, as well as for treatment of chronic thoracic pain due to surgery or post-herpetic 
neuralgia.10,11,16-25 Anecdotally, cryoanalgesia has been effective at controlling acute post-operative 
pain in young adult and adult patients following the Nuss procedure and has led to shorter post-
operative length of stay.   
2 
STUDY RATIONALE 
As above, there is significant room for improvement in post-operative pain management in 
the Nuss procedure.  The procedure is particularly well-suited to the application of cryoanalgesia, 
as the operative exposure directly visualizes the intercostal nerves. The majority of patients who 
undergo the Nuss procedure are teens and young adults. This is because patients often become 
symptomatic from pectus excavatum at this age.  Moreover, the younger the patient, the more 
compliant the chest wall, allowing for effective remodeling. Because this procedure is most 
commonly performed in this age-group, it is important for this study to include these patients to 
ensure the data is applicable to the pertinent patient population. 
2.1 
Risk / Benefit Assessment 
We believe that cryoanalgesia may provide better post-operative pain control following the 
Nuss procedure than the current standard therapy, thus allowing patients to return home sooner 
after surgery.  This randomized study will demonstrate whether this hypothesis is valid.  If so, it 
will provide convincing data to encourage other surgeons to adopt this new method, benefitting 
future patients who undergo the Nuss procedure by decreasing the significant pain associated with 
the procedure. Furthermore, the post-operative pain and long hospital stay are often frightening for 
patients considering the procedure, and knowing that the post-operative course is less arduous may 
make patients more comfortable prior to surgery.  Shortening the post-operative hospital stay 
following Nuss procedure may benefit society by reducing the resources allocated to this 
procedure; the cost analysis included in the study will further define the possible cost savings. 
Even if this study shows there is no benefit with cryoanalgesia, and, in fact, the current 
standard thoracic epidural analgesia is preferred, this is also important information for physicians 


15-18202 
 
 
Version 1 
Version Date: 12/7/15 
Page 11 of 25 
Protocol Template Effective: 07 JAN 2015  
performing the procedure or caring for these patients post-operatively, as well as for patients 
themselves.  
There are few additional risks to patients specifically from taking part in the study. The risks 
above, with the exception of the risk of randomization, are all associated either with the procedure 
itself, or one of the methods of pain control, both of which are being offered outside of this study.  
By systematically studying these two methods, we hope to provide definitive data on the preferred 
post-operative pain control that can inform future patient and physician decisions. 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
In performing this study, we hope to determine whether cryoanalgesia can help patients recover 
more quickly from the Nuss procedure than standard epidural analgesia. 
3.2 
Secondary Objectives 
We also hope to see if there is a difference in post-operative pain, medication usage, side effects, 
and total hospitalization cost between the two anesthetic methods.  
4 
STUDY DESIGN 
4.1 
Study Overview 
This study is a prospective, randomized trial to compare cryoanalgesia to standard epidural 
analgesia for post-operative pain management in patients undergoing minimally invasive pectus 
excavatum repair (the Nuss procedure). Approximately 20 subjects will be randomized in 1:1 ratio 
to receive cryoanalgesia or epidural analgesia at the time of their procedure. Post-operative care 
and analgesic protocol will be identical for all patients with the exception of continuous epidural 
infusion (no bolus or PCEA). Upon discharge, patients will return to clinic for 4 total follow-up 
appointments: 2 weeks, 1 month, 3 month, and 1 year from the date of their surgery.  
Screening data will be reviewed to determine subject eligibility.  Subjects who meet all inclusion 
criteria and none of the exclusion criteria will be entered into the study.  
Total duration of subject participation will be 1 year.  Total duration of the study is expected to be 
1.5 years. 
5 
CRITERIA FOR EVALUATION 
5.1 
Primary Efficacy Endpoint 
Hospital length of stay, measured from time of surgery to time of discharge  
5.2 
Secondary Efficacy Endpoints 
• 
Post-operative pain scores 
• 
Post-operative pain medication usage 
• 
Side effects 
• 
Total cost of hospitalization 


15-18202 
 
 
Version 1 
Version Date: 12/7/15 
Page 12 of 25 
Protocol Template Effective: 07 JAN 2015  
5.3 
Safety Evaluations 
• 
Incidence of adverse events, including intractable pain, analgesic failure, infection, respiratory 
depression, need for further intervention, or anything else deemed by the study team to fit the 
description of an adverse event. Adverse events will be assessed in terms of relationship to 
anesthetic method, relationship to procedure, severity, subsequent treatment/intervention 
required, and resolution status. 
6 
SUBJECT SELECTION 
6.1 
Study Population 
Subjects with a diagnosis of pectus excavatum, undergoing Nuss procedure who meet the 
inclusion and exclusion criteria will be eligible for participation in this study.   
6.2 
Inclusion Criteria 
1. 
Male or female ≥ 13 years of age at time of surgery. 
2. 
Documentation of a pectus excavatum as evidenced by Haller index > 3.25. 
3. 
Written informed consent (and assent when applicable) obtained from subject or subject’s 
legal representative and ability for subject to comply with the requirements of the study. 
6.3 
Exclusion Criteria 
• 
Pre-op pain medication usage 
• 
Pectus carinatum 
• 
Poland’s syndrome or other complex chest wall anomaly 
• 
Previous repair of Pectus Excavatum by any technique 
• 
Previous thoracic surgery 
• 
Congenital heart disease 
• 
Bleeding dyscrasia 
• 
History of previous problems with anesthesia or major anesthestic risk factors 
• 
Pregnancy or active breastfeeding 
• 
Non-English speaker 
7 
 CONCURRENT MEDICATIONS 
All subjects should be maintained on the same medications throughout the entire study period, as 
medically feasible, with no introduction of new chronic therapies. 
7.1 
Allowed Medications and Treatments 
Standard therapy is allowed. Patients on pain medication prior to procedure will be excluded, as 
stated above. 
Prohibited Medications and Treatments: none 
 


15-18202 
 
 
Version 1 
Version Date: 12/7/15 
Page 13 of 25 
Protocol Template Effective: 07 JAN 2015  
8 
STUDY TREATMENTS 
8.1 
Method of Assigning Subjects to Treatment Groups 
Prior to enrollment, the patients will be randomly assigned to cryoanalgesia or thoracic epidural 
groups in a 1:1 ratio using a computerized random sequence generator (http://www.random.org/). 
The values 1-20 are entered in the system, which creates a random sequence of the integers, 
formatted in 2 columns of 10 integers each.  Column 1 is assigned to cryoanalgesia, and column 
two is assigned to thoracic epidural.  The assignments are placed in closed envelopes with the 
integers on the outside of the envelopes.  The study surgeons are blinded to the randomization. As 
patients are enrolled in the study, they are assigned an integer in order of enrollment (the first 
patient enrolled is patient 1, the next patient 2, etc.).  The envelope associated with each patient 
number is opened on the morning of surgery, revealing their group assignment. 
8.2 
Blinding 
Due to the nature of the study, it is not possible to blind patients or clinicians to the method of 
analgesia once the patient’s group is revealed.  However, to prevent selection bias, the study 
clinicians and patients will be blinded to the randomization process and selection until the time of 
surgery.  
8.3 
Test and Control Products 
8.3.1 
Test Product 
AtriCure cryosurgical system (AtriCure, Inc., West Chester, Ohio)  
The cryoprobe will be applied to the intercostal nerve under thoracoscopic visualization at the 
level of the incision and 2 interspaces above and below, bilaterally.  The temperature and duration 
of cryoablation therapy is pre-set by the probe and cryosurgical system at 2 minutes to -60°C. 
Each nerve will receive one cycle of cryoablation. 
8.3.2 
Control Product 
Thoracic epidural catheter will be placed by the pediatric anesthesia team prior to Nuss procedure. 
Catheters will be placed using sterile technique at approximately T5-6 or T6-7 interspaces; 
procedure specifics are dependent on the attending anesthesiologist’s patient-dependent 
preference.  Whether the patient will be awake or asleep for epidural placement will be at the 
discretion of the attending anesthesiologist.  After placement, epidural infusion will begin with 
0.1% ropivicaine and 2mcg/cc fentanyl.  No bolus doses will be used.  
8.4 
Supply of Study Drugs and Equipment at the Site 
All study drugs and equipment are regularly stocked in the hospital.  Prior to each Nuss procedure, 
both the AtriCure Cryosurgical system and supplies for thoracic epidural will be made available in 
the operating room. 
8.4.1 
Post-operative Pain Regimen 
Please see separate post-operative pain regimen document 
8.4.2 
Storage 
Medication for epidural administration and post-operative pain regimen should be stored by the 
study site at controlled room temperature, 15 to 30ºC (59 to 86ºF). If the temperature of study drug 


15-18202 
 
 
Version 1 
Version Date: 12/7/15 
Page 14 of 25 
Protocol Template Effective: 07 JAN 2015  
storage in the clinic/pharmacy exceeds or falls below this range, this should be reported to the 
Sponsor or study coordinator and captured as a deviation. All medications will be stored in the 
hospital pharmacy and dispensed by the patient’s nurse. On discharge, subjects will be instructed 
to store the medication in original packaging at room temperature according to the instructions 
outlined on the Drug Administration Instructions. 
8.5 
Study Drug Accountability 
An accurate and current accounting of the dispensing and return of study drug for each subject will 
be maintained on an ongoing basis by a member of the study site staff.  The number of study drug 
dispensed and returned by the subject will be recorded on the Investigational Drug Accountability 
Record.  The study monitor will verify these documents throughout the course of the study. 
8.6 
Measures of Treatment Compliance 
Subjects will be asked to keep a patient diary noting the day and date they take their pain 
medications and any adverse events. They will be asked to bring their patient diary to each study 
visit along with all used and unused study drug containers. 
9 
STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the duration 
of the study is diagrammed in Appendix 1. 
Prior to conducting any study-related activities, written informed consent and the Health Insurance 
Portability and Accountability Act (HIPAA) authorization must be signed and dated by the subject 
(if legally able to consent) or subject’s parents or guardian(s).  If appropriate, assent must also be 
obtained prior to conducting any study-related activities. 
9.1 
Clinical Assessments 
9.1.1 
Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at initial clinic 
visit/screening, during hospitalization, and at follow-up visits.  Dose, route, unit frequency of 
administration, and indication for administration and dates of medication will be captured. 
9.1.2 
Demographics  
Demographic information (date of birth, gender, race) will be recorded at screening. 
9.1.3 
Medical History  
Past medical history and information regarding underlying diseases will be recorded at screening. 
9.1.4 
Physical Examination 
A complete physical examination will be performed by either the investigator or a subinvestigator 
who is a physician at the initial clinic visit.   Qualified staff (MD, NP, RN, and PA) may complete 
the abbreviated physical exam at all other visits.  New abnormal physical exam findings must be 
documented and will be followed by a physician or other qualified staff at the next scheduled visit. 
9.1.5 
Vital Signs 
Body temperature, blood pressure, pulse and respirations will be performed at all clinic visits and 
according to nursing unit protocol while patients are hospitalized.  


15-18202 
 
 
Version 1 
Version Date: 12/7/15 
Page 15 of 25 
Protocol Template Effective: 07 JAN 2015  
9.1.6 
Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates), severity, outcome, treatment and relation to study drug will be 
recorded on the case report form (CRF). 
10 EVALUATIONS BY VISIT 
10.1 Visit 1 – Pre-operative evaluation 
1. 
Review the study with the subject (subject’s legal representative) and obtain written 
informed consent and HIPAA authorization and assent, if appropriate. 
2. 
Record demographics data. 
3. 
Record medical history, including a history of pectus excavatum and any prior treatments or 
procedures. 
4. 
Record concomitant medications. 
5. 
Perform a complete physical examination. 
6. 
Perform and record vital signs. 
7. 
Perform and record oximetry. 
8. 
Perform and record results of blood pressure testing. 
9. 
Assign unique study number for randomization 
10.2 Visit 2- Surgery and Post-operative hospitalization  
Time of Surgery 
1. Urine pregnancy test (females) 
2. Open randomization allocation envelope 
3. Initial analgesic application (cryoanalgesia or epidural) and Nuss procedure 
 
According to inpatient unit protocol 
1. 
Perform and record vital signs. 
2. 
Perform and record oximetry. 
 
Once per day while inpatient 
1. Concomitant medications review. 
2. Perform abbreviated physical examination. 
 
 
Twice-per-day study visits while inpatient  
1. Record any Adverse Experiences  
2. Administer inpatient survey (see separate document) 


15-18202 
 
 
Version 1 
Version Date: 12/7/15 
Page 16 of 25 
Protocol Template Effective: 07 JAN 2015  
10.3 Visit 3- 2 weeks post-procedure  
1. 
Record any Adverse Experiences and Review subject diary for adverse experiences and 
dosing compliance. 
2. 
Record changes to concomitant medications. 
3. 
Perform abbreviated physical examination. 
4. 
Perform and record vital signs. 
5. 
Perform and record oximetry. 
6. 
Perform post-op survey (see separate document for study tool). 
7. 
Review pill bottles for medication usage. 
10.4 Visit 4 – 1 month post-procedure 
1. Record any Adverse Experiences and Review subject diary for adverse experiences and 
dosing compliance. 
2. Record changes to concomitant medications. 
3. Perform abbreviated physical examination. 
4. Perform and record vital signs. 
5. Perform and record oximetry. 
6. Perform post-op survey (see separate document for study tool). 
7. Review pill bottles for medication usage. 
10.5 Visit 5- 3 months post-procedure 
1. Record any Adverse Experiences and Review subject diary for adverse experiences and 
dosing compliance. 
2. Record changes to concomitant medications. 
3. Perform abbreviated physical examination. 
4. Perform and record vital signs. 
5. Perform and record oximetry. 
6. Perform post-op survey (see separate document for study tool). 
7. Review pill bottles for medication usage. 
10.6 Visit 6- 1 year post-procedure 
1. Record any Adverse Experiences and Review subject diary for adverse experiences and 
dosing compliance. 
2. Record changes to concomitant medications. 
3. Perform abbreviated physical examination. 
4. Perform and record vital signs. 
5. Perform and record oximetry. 
6. Perform post-op survey (see separate document for study tool). 


15-18202 
 
 
Version 1 
Version Date: 12/7/15 
Page 17 of 25 
Protocol Template Effective: 07 JAN 2015  
7. Review pill bottles for medication usage. 
10.7 Early Withdrawal Visit 
1. Record any Adverse Experiences and Review subject diary for adverse experiences and 
dosing compliance. 
2. Record changes to concomitant medications. 
3. Perform abbreviated physical examination. 
4. Perform and record vital signs. 
5. Perform and record oximetry. 
6. Perform post-op survey (see separate document for study tool). 
7. Review pill bottles for medication usage. 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
11.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a patient 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with the treatment.  An AE is therefore any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the administration 
of an investigational product, whether or not related to that investigational product.  An 
unexpected AE is one of a type not identified in nature, severity, or frequency in the current 
Investigator’s Brochure or of greater severity or frequency than expected based on the information 
in the Investigator’s Brochure. 
The Investigator will probe, via discussion with the subject, for the occurrence of AEs during each 
subject visit and record the information in the site’s source documents.  Adverse events will be 
recorded in the patient CRF.  Adverse events will be described by duration (start and stop dates 
and times), severity, outcome, treatment and relation to study drug, or if unrelated, the cause. 
AE Severity 
The guidelines shown in Table 1 below should be used to grade severity.  It should be pointed out 
that the term “severe” is a measure of intensity and that a severe AE is not necessarily serious. 
Table 1.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe. 


15-18202 
 
 
Version 1 
Version Date: 12/7/15 
Page 18 of 25 
Protocol Template Effective: 07 JAN 2015  
 
AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following the guidelines 
in Table 2. 
Table 2.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but 
that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the study 
drug. 
11.2 Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following outcomes: 
• 
death 
• 
a life-threatening adverse experience 
• 
inpatient hospitalization or prolongation of existing hospitalization 
• 
a persistent or significant disability/incapacity 
• 
a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on appropriate 
medical judgment, they jeopardize the subject or require intervention to prevent one of the 
outcomes listed.  
 
11.2.1 Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to study drug) per UCSF 
CHR Guidelines.  The collection period for all SAEs will begin after informed consent is obtained 
and end after procedures for the final study visit have been completed. 
In accordance with the standard operating procedures and policies of the local Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report SAEs to the 
IRB/IEC.   


15-18202 
 
 
Version 1 
Version Date: 12/7/15 
Page 19 of 25 
Protocol Template Effective: 07 JAN 2015  
11.3 Medical Monitoring 
Contact the Pediatric Surgery team to report medical concerns or questions regarding safety - 
(415) 476-2538. While subjects are inpatient, nursing staff and pediatric surgery service doctors 
are in-house 24 hours per day, 7 days per week.  
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
12.1 Early Discontinuation of Study Drug  
A subject may be discontinued from study treatment at any time if the subject, the investigator, or 
the Sponsor feels that it is not in the subject’s best interest to continue.  The following is a list of 
possible reasons for study treatment discontinuation: 
• 
Subject withdrawal of consent (or assent) 
• 
Subject is not compliant with study procedures 
• 
Adverse event that in the opinion of the investigator would be in the best interest of the subject 
to discontinue study treatment 
• 
Protocol violation requiring discontinuation of study treatment 
• 
Lost to follow-up 
• 
Positive pregnancy test (females) 
If a subject is withdrawn from treatment due to an adverse event, the subject will be followed and 
treated by the Investigator until the abnormal parameter or symptom has resolved or stabilized.   
All subjects who discontinue study treatment should come in for an early discontinuation visit as 
soon as possible and then should be encouraged to complete all remaining scheduled visits and 
procedures. 
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject withdrawals.   
12.3 
Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject, the investigator, or the 
Sponsor feels that it is not in the subject’s best interest to continue.   
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject withdrawals.  
The reason for the subject’s withdrawal from the study will be specified in the subject’s source 
documents.  As noted above, subjects who discontinue study treatment early should have an early 
discontinuation visit.  
12.4 
Replacement of Subjects 
Subjects who withdraw from the study treatment will not be replaced.   
Subjects who withdraw from the study will not be replaced.   
 


15-18202 
 
 
Version 1 
Version Date: 12/7/15 
Page 20 of 25 
Protocol Template Effective: 07 JAN 2015  
13 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject or investigator fails to adhere to significant protocol 
requirements affecting the inclusion, exclusion, subject safety and primary endpoint criteria.  
Protocol violations for this study include, but are not limited to, the following: 
• 
Failure to meet inclusion/exclusion criteria 
• 
Interference with randomization 
• 
Non-compliance with study drug regimen 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol 
violation. The investigator will determine if a protocol violation will result in withdrawal of a 
subject. 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by a Sponsor 
representative and the Investigator. A copy of the form will be filed in the site’s regulatory binder 
and in the Sponsor’s files. 
14 STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will be 
written describing all analyses that will be performed.  The SAP will contain any modifications to 
the analysis plan described below.   
14.1 Data Sets Analyzed 
All eligible patients who are randomized into the study and receive at least the initial analgesic 
application (cryoanalgesia or epidural catheter placement) and undergo Nuss procedure will be 
included in the analysis. 
14.2 Demographic and Baseline Characteristics 
The following demographic variables at screening will be recorded: gender, age, race, height and 
weight, medical comorbidities, severity of pectus excavatum deformity.   
14.3 Analysis of Primary Endpoint 
Our primary outcome will be post-operative hospital length of stay, which will be analyzed using 
a two-tailed unpaired t test, with results considered statistically significant for p< 0.05. 
14.4 Analysis of Secondary Endpoints 
Secondary outcomes include post-operative pain scores, pain medication usage, and side effects.  
Pain scores will be analyzed with Mann-Whitney rank sum tests (to compare between groups at 
each time point) and Wilcoxson signed-rank test (to compare scores within groups over time), 
with results considered statistically significant for p< 0.05..  Pain medication usage between the 
two groups will be analyzed with two-tailed unpaired t test, again with results considered 
statistically significant for p< 0.05.   
Adverse events will be tabulated by treatment group and will include the number of patients for 
whom the event occurred, the rate of occurrence, and the severity and relationship to study drug.   


15-18202 
 
 
Version 1 
Version Date: 12/7/15 
Page 21 of 25 
Protocol Template Effective: 07 JAN 2015  
14.5 Sample Size and Randomization 
We used the UCSF Clinical & Translational Science Institute web-based sample size calculator 
(http://www.sample-size.net/sample-size-means/) to determine study size.  Based on previous 
Nuss procedures over the past 2 years at our institution, we determined the mean length of 
hospitalization was 7 days, with a standard deviation of 1.3 days.  From anecdotal data from our 
prior experience, as well as from speaking with other surgeons utilizing cryoablation, we expect 
patients in the cryoanalgesia group to have approximately 2 days shorter hospital stay.  With type 
1 error rate of 0.05 and type II error rate of 0.1 (yielding 90% power), our study would need 18 
patients total.  Allowing for some dropout, we will plan to enroll 20 patients to the study. 
15 DATA COLLECTION, RETENTION AND MONITORING 
15.1 Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents designed to 
record all observations and other pertinent data for each subject treated with the study drug.   
Study personnel at each site will enter data from source documents corresponding to a subject’s 
visit into the protocol-specific electronic Case Report Form (eCRF) OR paper CRF when the 
information corresponding to that visit is available.  Subjects will not be identified by name in the 
study database or on any study documents to be collected by the Sponsor (or designee), but will be 
identified by a subject number. 
For eCRFs: If a correction is required for an eCRF, the time and date stamps track the person 
entering or updating eCRF data and creates an electronic audit trail.  For paper CRFs:  If a 
correction is made on a CRF, the study staff member will line through the incorrect data, write in 
the correct data and initial and date the change. 
The Investigator is responsible for all information collected on subjects enrolled in this study.  All 
data collected during the course of this study must be reviewed and verified for completeness and 
accuracy by the Investigator.   
15.2 Data Management Procedures 
The data will be entered into a validated database.  The Data Management group will be 
responsible for data processing, in accordance with procedural documentation.  Database lock will 
occur once quality assurance procedures have been completed. 
All procedures for the handling and analysis of data will be conducted using good computing 
practices meeting FDA guidelines for the handling and analysis of data for clinical trials. 
15.3 Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database on a regular basis. The study database will 
be updated in accordance with the resolved queries.  All changes to the study database will be 
documented. 
15.4 Archival of Data 
The database is safeguarded against unauthorized access by established security procedures; 
appropriate backup copies of the database and related software files will be maintained.  
Databases are backed up by the database administrator in conjunction with any updates or changes 
to the database.   


15-18202 
 
 
Version 1 
Version Date: 12/7/15 
Page 22 of 25 
Protocol Template Effective: 07 JAN 2015  
At critical junctures of the protocol (e.g., production of interim reports and final reports), data for 
analysis is locked and cleaned per established procedures. 
15.5 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized representatives 
of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., FDA) inspectors upon 
request.  A file for each subject must be maintained that includes the signed Informed Consent, 
HIPAA Authorization and Assent Form and copies of all source documentation related to that 
subject.  The Investigator must ensure the reliability and availability of source documents from 
which the information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study File 
Notebook, etc.) must be kept secured for a period of two years following marketing of the 
investigational product or for two years after centers have been notified that the IND has been 
discontinued.  There may be other circumstances for which the Sponsor is required to maintain 
study records and, therefore, the Sponsor should be contacted prior to removing study records for 
any reason. 
15.6 Monitoring 
Monitoring visits will be conducted by representatives of the Sponsor according to the U.S. CFR 
Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6).    By signing this protocol, the 
Investigator grants permission to the Sponsor (or designee), and appropriate regulatory authorities 
to conduct on-site monitoring and/or auditing of all appropriate study documentation. 
15.7 Subject Confidentiality 
In order to maintain subject confidentiality, only subject number will identify all study subjects on 
CRFs and other documentation submitted to the Sponsor.  Additional subject confidentiality issues 
(if applicable) are covered in the Clinical Study Agreement. 
16 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical 
Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other records 
will be identified by a coded number and initials only.  All study records will be kept in a locked 
file cabinet and code sheets linking a patient’s name to a patient identification number will be 
stored separately in another locked file cabinet.  Clinical information will not be released without 
written permission of the subject, except as necessary for monitoring by the FDA.  The 
Investigator must also comply with all applicable privacy regulations (e.g., Health Insurance 
Portability and Accountability Act of 1996, EU Data Protection Directive 95/46/EC). 
16.1 Protocol Amendments 
Any amendment to the protocol will be written by the investigator.  Protocol amendments cannot 
be implemented without prior written IRB/IEC approval except as necessary to eliminate 
immediate safety hazards to patients.  A protocol amendment intended to eliminate an apparent 
immediate hazard to patients may be implemented immediately, provided the IRBs are notified 
within five working days. 


15-18202 
 
 
Version 1 
Version Date: 12/7/15 
Page 23 of 25 
Protocol Template Effective: 07 JAN 2015  
16.2 Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC of each 
participating center prior to study initiation.  Serious adverse experiences regardless of causality 
will be reported to the IRB/IEC in accordance with the standard operating procedures and policies 
of the IRB/IEC, and the Investigator will keep the IRB/IEC informed as to the progress of the 
study.  The Investigator will obtain assurance of IRB/IEC compliance with regulations. 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, protocol 
amendments, Investigator’s Brochure, consent forms, information concerning patient recruitment, 
payment or compensation procedures, or other pertinent information) will be submitted to the 
IRB/IEC.  The IRB/IECs written unconditional approval of the study protocol and the informed 
consent form will be in the possession of the Investigator before the study is initiated.  This 
approval must refer to the study by exact protocol title and number and should identify the 
documents reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without prior 
written IRB/IEC approval except when necessary to eliminate immediate hazards to the patients or 
when the change(s) involves only logistical or administrative aspects of the study.  Such 
modifications will be submitted to the IRB/IEC and written verification that the modification was 
submitted and subsequently approved should be obtained.   
The IRB/IEC must be informed of revisions to other documents originally submitted for review; 
serious and/or unexpected adverse experiences occurring during the study in accordance with the 
standard operating procedures and policies of the IRB; new information that may affect adversely 
the safety of the patients of the conduct of the study; an annual update and/or request for re-
approval; and when the study has been completed. 
16.3 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US 
Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 50.27, 
and CFR Part 56, Subpart A), the Health Insurance Portability and Accountability Act (HIPAA, if 
applicable), and local regulations. 
The Investigator will prepare the informed consent form, assent and HIPAA authorization and 
provide the documents to the Sponsor or designee for approval prior to submission to the 
IRB/IEC.  The consent form generated by the Investigator must be acceptable to the Sponsor and 
be approved by the IRB/IEC.  The written consent document will embody the elements of 
informed consent as described in the International Conference on Harmonisation and will also 
comply with local regulations. The Investigator will send an IRB/IEC-approved copy of the 
Informed Consent Form to the Sponsor (or designee) for the study file. 
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written form and 
subjects (or their legal representatives) must be given ample opportunity to inquire about details of 
the study.  If appropriate and required by the local IRB/IEC, assent from the subject will also be 
obtained.  If a subject is unable to sign the informed consent form (ICF) and the HIPAA 
authorization, a legal representative may sign for the subject.   A copy of the signed consent form 
(and assent) will be given to the subject or legal representative of the subject and the original will 
be maintained with the subject’s records. 


15-18202 
 
 
Version 1 
Version Date: 12/7/15 
Page 24 of 25 
Protocol Template Effective: 07 JAN 2015  
16.4 Publications  
The preparation and submittal for publication of manuscripts containing the study results shall be 
in accordance with a process determined by mutual written agreement among the study Sponsor 
and participating institutions.  The publication or presentation of any study results shall comply 
with all applicable privacy laws, including, but not limited to, the Health Insurance Portability and 
Accountability Act of 1996.  
16.5 Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. 
Conduct the study in accordance with the protocol and only make changes after notifying the 
Sponsor (or designee), except when to protect the safety, rights or welfare of subjects. 
2. 
Personally conduct or supervise the study (or investigation). 
3. 
Ensure that the requirements relating to obtaining informed consent and IRB review and 
approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. 
Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64. 
5. 
Ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments. 
6. 
Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make 
those records available for inspection with the Sponsor (or designee). 
7. 
Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. 
Promptly report to the IRB and the Sponsor (or designee) all changes in the research activity 
and all unanticipated problems involving risks to subjects or others (to include amendments 
and IND safety reports). 
9. 
Seek IRB approval before any changes are made in the research study, except when necessary 
to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements listed in § 21 CFR part 312. 
 


Protocol Number 
Confidential 
 
Version #: 
Version Date: Date  
Page 25 of 25 
Protocol Template © CFFT TDN   Effective: 12 SEP 2007 
APPENDIX 1.  SCHEDULE OF STUDY VISITS 
 
VISIT 1 
pre-op 
VISIT 2 
procedure/hospit
alization 
VISIT 3 
2 weeks 
post-op 
VISIT 4  
1 MONTH 
POST-OP 
VISIT 5 
3 MONTHS 
POST-OP 
VISIT 6 
1 YEAR 
POST-OP 
Informed Consent 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Complete 
Physical Exam 
X 
 
 
 
 
 
Abbreviated 
Physical Exam 
 
X 
X 
X 
X 
X 
Height  
X 
X 
 
 
 
 
Weight  
X 
X 
 
 
 
 
Vital Signs  
X 
X 
X 
X 
X 
X 
Oximetry 
X 
X 
X 
X 
X 
X 
Randomization 
X 
 
 
 
 
 
Urine Pregnancy 
Test (females) 
 
X 
 
 
 
 
Administration of  
Initial Analgesia 
(cryo vs. epidural)  
 
X 
 
 
 
 
Survey 
Administration 
 
X 
X 
X 
X 
X 
Documentation of 
Pain Medication 
Usage 
 
X 
X 
X 
X 
X 
Counting of 
Returned Post-op 
Pain Medication 
 
 
X 
X 
X 
X 
Initiate Subject 
Diary 
 
X 
 
 
 
 
Subject Diary 
Review 
 
 
X 
X 
X 
X 
Concomitant 
Medication 
Review 
X 
X 
X 
X 
X 
X 
Adverse 
Experiences 
 
X 
X 
X 
X 
X