A Post-Market, Multi-Center, Prospective, Double-Blind, Randomized, Controlled Study to Evaluate the Iovera° Device in Treating Pain Associated With Total Knee Arthroplasty
Phase: NA
Conditions: Arthritis of the Knee
Sponsor: Pacira Pharmaceuticals, Inc

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Protocol MYO-1070 REV 02 
Page 1 of 36 
A POST-MARKET, MULTI-CENTER, PROSPECTIVE, DOUBLE-BLIND, 
RANDOMIZED, CONTROLLED STUDY TO EVALUATE THE IOVERA° DEVICE IN 
TREATING PAIN ASSOCIATED WITH TOTAL KNEE ARTHROPLASTY 
 
 
PROTOCOL NUMBER: 
MYO-1070 REV 02 
VERSION:  
MAY 20, 2015 
SPONSOR: 
(Pre-June 08, 2015) 
 
 
 
 
Sponsor: 
(Effective June 08, 2015) 
myoscience, Inc. 
1600 Seaport Blvd.  Suite 450 
Redwood City, CA 94063 
650-474-2600 (office) 
650-474-2900 (fax) 
 
myoscience, Inc. 
46400 Fremont Blvd. 
Fremont, CA 94538 
510-933-1500 (office) 
510-933-1501 (fax) 
 
 
SPONSOR REPRESENTATIVE(S): 
Tracey Henry 
Vice President, RAQA, Clinical Affairs  
 
 
 
MEDICAL MONITOR: 
 
 
Luga Podesta, MD 
  
 
 
 
 
 
Medical Monitor 
 
 
The information contained in this document is confidential and proprietary property of 
myoscience, Inc. 
 
 

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Protocol MYO-1070 REV 02 
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Revision 
Description 
DCO#
Release Date 
01 
 Initial Release. 
2473 
10/17/2014 
02 
 Grammar and punctuation corrections 
 Add Medical Monitor 
 Add NRS for Pain of Contralateral 
Knee questions to Screening Visit 
 Add questions to assess the blind Post-
Treatment and Follow-Up Visits 
 Increase Duration of Study 
 Specified use of Lidocaine, no 
epinephrine 
 Clarification on timing of visit windows 
and schedule of events 
 Clarification to Exclusion Criteria #2 
and Exclusion Criteria #5 
 Updated to reflect staff changes 
2589 
2/27/2015 
02 
 Admin fixes to update address, see 
DCO 
2642 
5/20/2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Investigator Protocol Signature Page (REV 02) 
Read and initial below. 
 
____ 
I understand this protocol contains information that is confidential and proprietary to 
myoscience, Inc. 
____ 
Any additional information added to this protocol is also confidential and proprietary to 
myoscience, Inc. and must be treated in the same manner as the contents of this 
protocol. 
____ 
I have read the entire protocol. 
____ 
I understand what the protocol asks me to do as an Investigator. 
____ 
I will conduct this study following this protocol and will make a reasonable effort to 
complete the study in the time noted. 
____ 
I will provide this protocol to study staff under my direct supervision. My study staff 
will keep the protocol and associated documents confidential.  
____ 
I will discuss this information with the study staff to ensure they are fully informed 
about the study and the test articles.  
____ 
I will not start enrolling in this study until it is approved by a governing Institutional 
Review Board.  
____ 
I understand the study may be terminated or enrollment suspended at any time by 
myoscience, Inc., with or without cause, or by me if it becomes necessary to protect the 
interests of the study Subjects. 
 
 
____________________________________ 
Name of Investigator 
 
____________________________________ 
 
_____________________ 
Investigator Signature  
 
 
 
 
Date 
 
 

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Protocol Synopsis 
Title 
A Post-Market, Multi-Center, Prospective, Double-blind, Randomized, 
Controlled Study to Evaluate the iovera° Device in Treating Pain 
Associated with Total Knee Arthroplasty 
Study Device 
iovera° (myoscience Inc., Fremont, CA) 
Study Objective 
To evaluate the outcomes of patients undergoing iovera° treatment of the 
ISN and AFCN prior to total knee arthroplasty to provide temporary 
postoperative pain relief  
Study Design 
Multi-center, prospective, randomized 
Treatment Groups 
Pre-operative iovera° treatment vs. pre-operative sham iovera° treatment  
Duration of Participation 
Up to 16 weeks (12 weeks post-op) 
Study Population 
Male or female, ages 22 to 79 scheduled to undergo a total knee 
replacement as a result of osteoarthritis  
Total Number of Subjects 
150 subjects 
Number of Sites 
Up to 8 sites 
Study Procedures 
iovera° treatment introducing temporary nerve conduction block of the 
ISN and AFCN 
Data Collection Tools 
 
 
WOMAC 
 
SF-36 
 
PROMIS 
 
NRS for Pain 
Primary Endpoint  
Cumulative Opioid Consumption at 6 weeks post-TKA Surgery  
Secondary Endpoints  
 
Length of Hospital Stay 
 
WOMAC Pain  
 
WOMAC Function 
 
Physical Performance (Measured by: Range of Motion, 30 
Second Chair Test and 40 Meter Walk Test) 
 

 
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Table of Contents 
PROTOCOL SYNOPSIS......................................................................................................................................... 4 
ABBREVIATIONS ...................................................................................................................................................... 7 
1. 
BACKGROUND.................................................................................................................................................. 8 
2. 
REGULATORY STATUS .................................................................................................................................. 9 
3. 
STUDY OBJECTIVE .......................................................................................................................................... 9 
4. 
STUDY DESIGN ................................................................................................................................................. 9 
5. 
BLINDING .......................................................................................................................................................... 9 
6. 
DURATION ........................................................................................................................................................ 9 
7. 
INVESTIGATOR QUALIFICATIONS ............................................................................................................ 9 
8. 
STUDY POPULATION ..................................................................................................................................... 9 
8.1 
TARGET PATIENT POPULATION .............................................................................................................................. 9 
8.2 
SUBJECT ELIGIBILITY ................................................................................................................................................ 9 
9. 
STUDY DEVICE AND TREATMENT PROCEDURE ............................................................................... 11 
9.1 
DESCRIPTION ........................................................................................................................................................... 11 
9.2 
INSTRUCTIONS FOR USE AND ADMINISTRATION ............................................................................................... 12 
9.3 
CONTRAINDICATIONS ............................................................................................................................................. 13 
9.4 
RISKS ......................................................................................................................................................................... 13 
10. 
STUDY PROCEDURES ............................................................................................................................. 14 
10.1 
OVERVIEW ................................................................................................................................................................ 14 
10.2 
RECRUITMENT ......................................................................................................................................................... 14 
10.3 
SCREENING /VISIT 1 (‐30 TO ‐1 DAYS) .............................................................................................................. 14 
10.4 
RANDOMIZATION ..................................................................................................................................................... 15 
10.5 
IOVERA° TREATMENT/VISIT 2 (‐07 ‐ 0 DAYS PRIOR TO TKA)...................................................................... 15 
10.6 
VISIT 3 / TOTAL KNEE ARTHROPLASTY (DAY 0) ............................................................................................. 16 
10.7 
STUDY FOLLOW UP ................................................................................................................................................. 17 
STUDY‐RELATED FOLLOW‐UP VISITS OCCUR AT THE INVESTIGATIONAL SITE AT WEEK 2, WEEK 4, WEEK 6, AND 
WEEK 12.  THE STUDY’S SCHEDULE OF ASSESSMENTS IS SHOWN IN TABLE 3. ............................................................ 17 
10.7.1 
Visit 4 / 2 Weeks Post‐op (14 ±3 Days), Visit 5 / 4 Weeks Post‐op (28 ±5 Days), and Visit 
6 / 6 Weeks Post‐op (42 ±5 Days) ................................................................................................................................... 17 
10.7.2 
Visit 7 / 12 Weeks Post-op (84 ±7 days) .................................................................................................. 18 
10.8 
PHOTOGRAPHS ......................................................................................................................................................... 20 
10.9 
STUDY EXIT .............................................................................................................................................................. 20 
10.10 
SUBJECT DISCONTINUATION ............................................................................................................................ 20 
10.11 
STUDY TERMINATION ....................................................................................................................................... 20 
10.12 
STUDY‐RELATED ASSESSMENTS ..................................................................................................................... 21 
10.12.1 
Western Ontario and McMaster Osteoarthritis Index (WOMAC) .............................................. 21 
10.12.2 
Numeric Rating Scale for Pain (NRS for Pain) ................................................................................... 21 
10.12.3 
Patient Reported Outcomes Measurement Information System (PROMIS) .......................... 21 
10.12.4 
36‐Item Short Form Health Survey (SF‐36) ......................................................................................... 22 
10.12.5 
Subject Satisfaction Questions .................................................................................................................... 22 
10.12.6 
Self‐reported Work Status Questions ...................................................................................................... 22 
11. 
STATISTICAL METHODOLOGY AND ANALYSES ........................................................................... 22 
11.1 
INTRODUCTION ........................................................................................................................................................ 22 
11.2 
STUDY ENDPOINTS ............................................................................................................................................... 23 

 
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11.2.1 
Primary Effectiveness Endpoint .................................................................................................................. 23 
11.2.2 
Secondary Effectiveness Endpoints ............................................................................................................ 23 
11.2.3 
Safety ...................................................................................................................................................................... 24 
11.3 
ANALYSIS COHORTS ............................................................................................................................................ 25 
11.3.1 
Screening Cohort ............................................................................................................................................... 25 
11.3.2 
Safety/ITT (Intent to Treat) Cohort ............................................................................................................ 25 
11.3.3 
Per-Protocol Cohort ........................................................................................................................................ 25 
11.3.4 
Cohort for Primary Endpoint ....................................................................................................................... 25 
11.3.5 
Cohort for Secondary Endpoint .................................................................................................................. 25 
11.4 
STATISTICAL METHODS ...................................................................................................................................... 25 
11.4.1 
General .................................................................................................................................................................. 25 
11.4.2 
Derived Data – Change from Baseline Parameters ........................................................................... 26 
11.5 
HANDLING OF DROPOUTS OR MISSING DATA ............................................................................................. 26 
11.6 
POOLABILITY ......................................................................................................................................................... 26 
11.7 
SUBGROUP ANALYSIS ......................................................................................................................................... 27 
11.8 
ANALYSIS WINDOWS AND DEFINITIONS ....................................................................................................... 27 
11.9 
SENSITIVITY ANALYSES ..................................................................................................................................... 27 
11.10 
SAMPLE SIZE JUSTIFICATION ............................................................................................................................ 27 
12. 
ADVERSE EVENTS ................................................................................................................................... 29 
12.1.1 
Adverse Device Effect (ADE) ........................................................................................................................ 30 
12.1.2 
Serious Adverse Event (SAE)/ Serious Adverse Device Effect (SADE)/Anticipated Serious 
Device Effect (ASADE)/ Unanticipated Serious Adverse Device Effect (USADE) ...................................... 30 
12.2 
AE SEVERITY AND RELATEDNESS ........................................................................................................................ 31 
13. 
DEVICE TRACKING ................................................................................................................................. 32 
14. 
DEVICE DEFICIENCIES AND MALFUNCTIONS ................................................................................ 32 
15. 
ETHICAL AND REGULATORY CONSIDERATIONS ......................................................................... 32 
15.1 
COMPLIANCE WITH GOOD CLINICAL RESEARCH PRACTICE ............................................................................. 32 
15.2 
INSTITUTIONAL REVIEW BOARD (IRB) AND INFORMED CONSENT ............................................................... 32 
15.3 
PROTOCOL COMPLIANCE ........................................................................................................................................ 33 
15.4 
PROTOCOL REVISIONS ............................................................................................................................................ 33 
15.5 
STUDY MONITORING ............................................................................................................................................... 33 
15.6 
SAFETY REPORTING ................................................................................................................................................ 33 
15.7 
ELECTRONIC CASE REPORT FORMS/ELECTRONIC DATA CAPTURE ............................................................... 34 
15.8 
QUALITY ASSURANCE AUDITS ............................................................................................................................... 34 
15.9 
CONFIDENTIALITY ................................................................................................................................................... 34 
15.10 
RECORDS RETENTION ....................................................................................................................................... 35 
15.11 
PUBLICATION AND REPORTING OF STUDY RESULTS.................................................................................... 35 
16. 
SELECTED REFERENCES ....................................................................................................................... 35 
 
 
 
 
 
 

 
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Abbreviations 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AFCN 
AO 
Anterior Femoral Cutaneous Nerve 
Anticipated Observation 
ASADE 
Anticipated Serious Device Effect 
CFR 
Code of Federal Regulations 
CNS 
Central Nervous System 
eCRF 
Electronic Case Report Form 
EDC 
FCTTM 
Electronic Data Capture 
Focused Cold TherapyTM 
ESE 
Expected Side Effect 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IRB 
ISN 
Institutional Review Board 
Infrapatellar branch of the Saphenous nerve 
ISO 
International Organization for Standardization 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS Pain 
NSAID 
Numeric Rating Scale for Pain 
Non-Steroidal Anti-Inflammatory Drug 
NSR 
Non-Significant Risk 
OTC 
PT 
Over-the-Counter 
Preferred Terms 
PGIC 
Patient Global Impression of Change 
PROMIS 
 
QA 
Patient Reported Outcomes Measurement Information 
System 
Quality Assurance 
SADE 
Serious Adverse Device Effect 
SAE 
SF-36 
 
SOC 
Serious Adverse Event 
Medical Outcomes Study 36-Item Short-Form Health 
Survey 
System Organ Classes 
TKA 
UG 
Total Knee Arthroplasty 
User Guide 
USADE 
Unanticipated Serious Adverse Device Effect 
WOMAC 
Western Ontario and McMaster Osteoarthritis Index 
 
 

 
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1. 
BACKGROUND 
 
Total Knee Arthroplasty (TKA) is a highly effective procedure to relieve symptoms in patients 
with severe arthritis. Improvements in pain, physical function, and enhanced quality of life in 
patients who have undergone TKA are well established in the literature1,2.  However, post-
operative pain associated with TKA is severe. Effective pain control following TKA allows for 
earlier ambulation and initiation of physical therapy, which speeds recovery, reduces hospital 
length of stay, and decreases the risk of postoperative complications3.  The VHA/DoD and the 
American Society of Anesthesiologists have both issued guidelines suggesting that wherever 
possible, practitioners should use multimodal pain management4.  Clinical management of post-
op TKA pain should include both pharmacologic and non-pharmacologic modalities and 
minimize preventable postoperative complications5. As demand for primary TKAs is projected to 
grow to 3.48 million procedures per year by 2030 in the United States alone6, the need for 
effective and economic multi-modal pain management has never been greater. 
 
Managing pain via multi-modal strategies, including peripheral nerve blocks, in the inpatient 
postoperative phase has been shown to decrease opioid consumption7, decrease opioid related side 
effects, decrease hospital stay, and increase time to ambulation8,9,10.  Nursing, hospital, and 
pharmacy utilization in managing PCA, continuous regional nerve blocks, and administration of 
oral opioid dosing are associated with higher costs of care and introduce sources for staff 
error11,12. Furthermore, the idea of multi-modal pain management extends beyond the in-patient 
phase of treatment.  Decreasing prescription opioid use during outpatient rehabilitation decreases 
NSAID and opioid related side effects, especially important among the aging population13,14.   
 
Due to the mechanism of action, iovera° introduces a new mode of pain management delivery in 
TKA.  The iovera° system uses liquid nitrous oxide contained within the device and closed-end 
needles to create a precise zone of cold at the target nerve sites.  This Focused Cold Therapy™ 
delivery platform causes a temporary peripheral nerve block based on a process called Wallerian 
degeneration (2nd degree axonotmesis) without disrupting connective nerve tissue. With nerve 
conduction blocked, pain is relieved in sensory nerves (nerves that pass impulses from receptors 
toward or to the central nervous system). Degeneration of the nerve axons is followed by a 
predictable restoration of nerve function involving axon regeneration from the point of treatment 
to the distal end of the nerve at a rate of 1.0–1.5 mm a day15,16.  Early clinical study results have 
demonstrated that the duration of effect of iovera°, when applied to the infrapatellar branch of the 
saphenous nerve for knee pain, is two to three months; longer than that of other clinically adopted 
modalities (PCA opioids, single shot regional nerve blocks, continuous regional nerve blocks, 
extended-release peri-operative local opioids, oral and IV NSAIDs, acetaminophen, and oral 
opioids).  Early clinical data further suggests that iovera°, when applied to the infrapatellar branch 
of the saphenous nerve (ISN) and anterior femoral cutaneous nerve (AFCN) prior to TKA, 
reduces the amount of opioids requested by subjects to maintain similar levels of pain relief17.  
 
This study is designed to investigate whether iovera° treatment prior to TKA decreases 
cumulative patient opioid use over the course of 6 weeks following TKA while maintaining 
similar levels of pain relief.  The study will also investigate whether there is a relationship 
between patients treated with iovera° and length of hospital stay; patient reported pain and 
function as measured by WOMAC; and improved physical rehabilitation as measured by 
functional performance measures and range of motion. 
 
 

 
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2. 
REGULATORY STATUS 
The iovera° device is 510(k)-cleared (K133453) for producing lesions in peripheral nervous tissue 
by application of cold to selected sites for blocking pain. Cleared indications include general 
tissue destruction during surgical procedures and cryotreatment of nerves to block pain.  
Additionally, myoscience and an independent review board have determined that the iovera° 
device is a non-significant risk device under 21 CFR §812.2(b) as described for use within this 
protocol. Therefore, an approved Investigational Device Exemption (IDE) from FDA is not 
required to legally perform the study described herein in the US. 
3. 
STUDY OBJECTIVE 
To evaluate the outcomes of patients undergoing iovera° treatment of the ISN and AFCN prior to 
total knee arthroplasty to provide temporary postoperative pain relief.  
4. 
STUDY DESIGN 
This is a multi-center, prospective, randomized, double-blind, sham controlled trial. 
5. 
BLINDING 
This is a double-blind study.  The treating Investigator and Subject are blinded to study treatment. 
Investigators and Subjects will be unblinded as medical need arises.  Every effort should be made 
to maintain Subject and Investigator blinding throughout the study.  The blind will be assessed 
immediately following treatment and at the follow-up visits by asking the Subject which 
treatment they believe he/she received and why. 
6. 
DURATION 
Each Subject participates for up to 16 weeks.  Enrollment is expected to take up to 10 months.  
Total study duration is expected to be up to 12 months. 
7. 
INVESTIGATOR QUALIFICATIONS 
To participate in this study, an Investigator must have an active medical license and board 
certification in Orthopedic Surgery, Anesthesia, Pain Management, or Physical Medicine and 
Rehabilitation.  The Investigator or designee must undergo training conducted by myoscience, 
Inc., on the study device prior to enrolling Subjects in the study.   
8. 
STUDY POPULATION 
8.1 
Target Patient Population 
The target patient population is adult men and women ages 22 to 79 in the United States 
scheduled to undergo primary unilateral TKA under spinal anesthesia for primary 
diagnosis of osteoarthritis. 
 
8.2 
Subject Eligibility 
To be included in the study, Subjects must meet all of the inclusion criteria and none of 
the exclusion criteria list in Table 1. 
 
 
 
 

 
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Table 1. Study Eligibility Criteria. 
Inclusion Criteria 
 
1. 22 to 79 years of age 
2. Scheduled to undergo primary unilateral TKA under spinal anesthesia for primary 
diagnosis of osteoarthritis 
3. American Society of Anesthesiology (ASA) Physical Classification System classes I-III  
4. Anticipation of discharge to home after inpatient acute post-op phase (age, co-morbidities, 
home environment, and social support are in favor of discharge to home in the opinion of 
the Investigator)  
5. Subject is willing and able to give written informed consent. 
6. Subject is fluent in verbal and written English.  
7. Subject is willing and able to comply with study instructions and commit to all follow-up 
visits for the duration of the study. 
8. Subject is in good general health and free of any systemic disease state or physical 
condition that might impair evaluation or which in the Investigator’s opinion, exposes the 
Subject to an unacceptable risk by study participation. 
Exclusion Criteria 
 
1. Chronic opioid use (defined as daily or almost daily use of opioids for >3 months). 
2. Concurrent painful physical condition, surgery, or musculoskeletal disease that requires 
analgesic treatment during study follow-up that is not strictly related to the target knee 
being treated with iovera°, which have the potential to confound the postoperative 
assessments (e.g., significant pain from other joints, chronic neuropathic pain, concurrent 
or planned contralateral TKA, concurrent foot, neck, spine, hip, or other musculoskeletal 
disease, arthritis, or planned surgery, etc.). 
3. Greater than 15° malalignment (varus or valgus) on pre-operative radiograph. 
4. Previous myoscience FCT™ treatment.  
5. Previous Partial or Total Knee Arthroplasty. Partial or Total Knee Arthroplasty of the 
contralateral knee is permitted if [surgery was completed at least twelve (12) months prior 
to Screening.] 
6. Body Mass Index ≥ 40 
7. Prior surgery in the treatment areas that may alter the anatomy of the infrapatellar branch 
of the saphenous nerve (ISN) or the anterior femoral cutaneous nerve (AFCN) or result in 
scar tissue in the treatment area. 
8. Any clotting disorder and/or use of an anticoagulant (e.g. warfarin, clopidogrel, etc.) 
within seven (7) days prior to administration of the device. Low dose aspirin (81mg or less 
daily) for cardiac prophylaxis allowed. 
9. Any local skin condition at the treatment sites that in the Investigator’s opinion would 
adversely affect treatment or outcomes. 
10. Open and/or infected wound in the treatment areas. 
11. Allergy to lidocaine. 
12. History of cryoglobulinemia 
13. History of paroxysmal cold hemoglobinuria. 
14. History of cold urticaria. 
15. History of Raynaud’s disease. 
16. History of opioid or alcohol abuse. 
17. Subject is pregnant or planning to become pregnant while enrolled in the study. 

 
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18. Current enrollment in any investigational drug or device study or participation within 30 
days prior to screening. 
19. Currently being treated for related knee injury under worker’s compensation claim or 
equivalent (i.e. legal case). 
20. Any chronic medical condition that in the Investigator’s opinion would prevent adequate 
participation. 
21. Any chronic medication use (prescription, over-the-counter, etc.) that in the Investigator’s 
opinion would affect study participation or Subject safety.  
22. For any reason, in the opinion of the Investigator, the Subject may not be a suitable 
candidate for study participation (i.e., history of noncompliance, drug dependency, etc.). 
 
 
9. 
STUDY DEVICE AND TREATMENT PROCEDURE 
The study device and sham treatment are described briefly below.  
9.1 
Description 
The myoscience iovera° device is a next generation device designed to temporarily reduce 
pain.  The device consists of a reusable, portable Handpiece, along with single-patient use 
sterile Smart Tips (aka cryoprobes) and disposable nitrous oxide (N2O) cartridges.  The 
Smart Tip contains embedded software that manages procedure parameters and provides 
physician feedback throughout all states of device preparation, treatment and post-
treatment via communication with the Handpiece.  The Handpiece is battery powered and 
is stored and recharged via the Charging Dock. 
The iovera° device produces the desired effect through initiation of a cooling cycle.  Each 
cooling cycle is initiated by fully inserting the Smart Tip into the selected procedure site 
and activating the cryogen flow.  A freezing zone forms around the end of the Smart tip 
affecting the adjacent tissue. 
The cryogen is provided in a nitrous oxide cylinder attached to a custom filter, known as 
the Cartridge.  To remove contaminants that may be present in the cylinder, a custom filter 
is added to the cylinder to filter the liquid nitrous oxide before it enters the Handpiece.  
This ensures optimal performance of the device. 
A specially designed Smart Tip is included.  The Smart Tip needles are made of stainless 
steel and have a closed-tip, fully enclosing the cryogen.  As the cryogen gas travels 
through the length of the needle, an ice ball develops around the needle causing the 
surrounding tissue to be frozen.  Operation instructions and further details on the device 
are provided in the User Guide.     
The appearance of the Smart Tips used for the sham treatment is identical to the tips used 
for an active treatment. The sham Smart Tip does not allow a freezing zone to form 
therefore it does not provide a therapeutic treatment.  External operation of iovera° (status 
indicator lights and audible cues) is identical for both the active and sham treatment to 
preserve the double-blind.   
Device training will be provided to the Investigator and study staff prior to the initiation of 
study enrollment. 

 
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9.2 
Instructions for Use and Administration 
Use of the iovera° device is described briefly herein. For details see the User Guide as 
provided by myoscience, Inc. 
The iovera° device is used on awake Subjects who are prepared with local anesthesia only.  
The treatment targets are the infrapatellar branch of the saphenous nerve (ISN) and the 
anterior femoral cutaneous nerve (AFCN) shown in Figure 1.  Training for the treatment 
procedure will be provided to the Investigator and study staff prior to the initiation of 
study enrollment. 
Figure 1.  Infrapatellar branch of the Saphenous Nerve and Anterior Femoral Cutaneous Nerve 
 
 
 
Treatment will be performed unilaterally and will be guided by visualization and palpation 
of anatomical landmarks. Landmarks and treatment line will be marked on the skin as 
shown in Figure 2.   
Figure 2. Treatment Lines (Figure not to scale)
 
AFCN
ISN

 
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Note that the study Sponsor will provide the following supplies: 
 iovera° devices, Smart Tips and cryogen cartridges 
 Surgical pen or other marking tool  
 Measuring tape 
 Safety cones (2) 
 Goniometers (2) 
 Marking Tape 
 Stop watch 
 
The investigational site will provide the following: 
 Injectable lidocaine (no epinephrine) used for local anesthesia 
 Syringes for administration of local anesthesia 
 Needles for administration of local anesthesia 
 Gauze 
 Alcohol wipes 
 Wound dressing(s) 
 
9.3 
Contraindications 
Use of iovera° is contraindicated in the following situations: 
 Cryoglobulinemia  
 Paroxysmal cold hemoglobinuria 
 Cold urticaria 
 Raynaud’s disease 
 Open and/or infected wounds in the target treatment area 
Note: physician discretion should be exercised when patient presents with existing neuromuscular disease 
compromising the regeneration of peripheral nerves that may be involved in the treatment.  
 
9.4 
Risks 
The iovera° device involves percutaneous access to subcutaneous tissue using a needle and 
use of dermal anesthesia. Passage of a needle into the skin, cooling of subcutaneous soft 
tissue and delivery of local anesthesia are known to be associated with the following risks: 
 Bruising (ecchymosis)  
 Swelling (edema)  
 Inflammation and/or redness (erythema) 
 Pain and/or tenderness 
 Altered sensation (localized dysesthesia) 
 
Proper use of the device as described in the User Guide can help reduce or prevent the 
following complications:  
 Injury to the skin related to application of cold or heat 
 Hyper- or hypo-pigmentation at the treatment site 
 Skin dimpling at the treatment site  
 Loss of motor function outside the target area 
 
 

 
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10. 
STUDY PROCEDURES 
10.1 
Overview 
An Overview of the study visits is shown in Figure 3.  Eligible Subjects are randomized to 
iovera° treatment or to sham treatment with the iovera° device. The primary endpoint is 
cumulative opioid consumption at 6 Weeks Post-TKA. 
Figure 3.  Overview of Study Visits 
 
*Screening and Treatment can occur on the same day.   
**Data collected retrospectively, iovera° Treatment may be same day as TKA. 
10.2 
Recruitment 
Potential study participants will be recruited from clinics of participating Investigators, as 
well as local advertising.  Any study-related advertisements will be approved by the 
governing IRB prior to use. 
10.3 
Screening /Visit 1 (-30 to -1 days) 
A patient who signs the informed consent document will be considered a study Subject. A 
Subject who withdraws from the study prior to randomization will not count toward the 
study’s sample size.  Potential participants will be screened for eligibility against Table 1. 
Once the informed consent form is signed, the Subject is assigned a study number. The 
Subject number is comprised of the 2-digit site number followed by a consecutively 
assigned 3-digit Subject number that starts with 001.  For example, the first screened 
Subject for site 05 will be assigned study number 05-001.  The Subject number is the 
identification number used on eCRFs and other study documents throughout the study. In 
the event a Subject withdraws from the study, their Subject number cannot be reassigned 
to any other Subject. 
 
The Investigator, or designee, will document the Subject’s medical history, demographic 
information, obtain vital signs, complete an assessment of the intended treatment areas and 
concomitant medications/concurrent procedures.  
 
Once a Subject has been determined to meet all inclusion and none of the exclusion 
criteria, the Subject will complete the following: 
 
Assessments: 
 NRS for Pain when standing from a seated position in target knee 
 NRS for Pain when standing from a seated position in the contralateral knee 
 PROMIS-29 Profile v2.0 Participant Format  
 WOMAC Osteoarthritis Index NRS3.1 
 SF-36v2® Health Survey Standard, United States (English) 
 
Physical Performance Measures in the following order: 
 Active Range of Motion 

 
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 40 Meter Walk Test 
 30 Second Chair Test 
Detailed instructions for the conduct of these performance measures are included in the 
Study Operations Manual. Assistive/ambulatory device usage and work status will also 
be assessed.  
 
Subjects may be complete Screening / Visit 1 and iovera° Treatment / Visit 2 on the same 
day.  
 
10.4 
Randomization 
After meeting all of the inclusion and none of the exclusion criteria and prior to study 
treatment, Subjects will be randomized in a 1:1 manner to either: 
 iovera° Treatment: Subject undergoes treatment with the study device using a 
functioning Smart Tip. 
 Sham Treatment: Subject undergoes treatment with the study device using a sham 
Smart Tip. 
Randomization assignments will be stratified by study center with randomly chosen block 
sizes of 4 or 6. Small but randomly determined block sizes preserve treatment assignment 
balance within study center while maintaining assignment unpredictability. The 
Investigator or designee will record the randomization assignment in the source 
documentation and eCRF.  Any Investigator who is discovered to tamper with 
randomization will be immediately terminated from the study. 
10.5 
iovera° Treatment/Visit 2 (-07 - 0 Days prior to TKA) 
 
Medical history will be reviewed as well as concomitant medications and procedures.  
Blood pressure and heart rate will be assessed.  The Investigator, or designee, will 
reconfirm all eligibility criteria are met. 
The iovera° device will be prepared by the trained Investigator (or Sponsor designee) 
according to the User Guide. If at any time the device does not perform as expected the 
Investigator (or designee) will follow procedures as outlined in the User Guide.  
Prior to the initiation of the iovera° treatment, the Investigator, or designee, will mark the 
treatment lines on the knee to be treated as shown in Figure 2 located in section 9.2.  After 
marking the treatment lines, the study coordinator or designee will measure the knee 
circumference at the treatment lines per guidance in the Study Operations Manual.  
Then the skin along the treatment lines will be cleansed with alcohol.  Lidocaine, no 
epinephrine, will be injected along the treatment lines superficially in order to achieve 
cutaneous anesthesia and to the bottom of the subcutaneous layer, atop the fascia, to 
temporarily block conduction of the infrapatellar branch of the saphenous nerve and the 
anterior femoral cutaneous nerve. 
Once localized anesthesia of the treatment lines and the nerves is achieved, the 
Investigator, or designee, will complete the iovera° treatment along the treatment lines.  
Regardless of the length of treatment lines (width of patella or from lower pole of the 

 
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patella down to tibial tubercle), adjacent insertions are placed along the treatment lines 
until the entire line has been treated so all Subjects receive the same treatment.  Treatment 
is not to be modified or influenced by any Subject response to changes in knee pain. 
Representatives of myoscience, Inc. may be present during the treatment. Photos of the 
treatment area may be taken.  
Upon completion of treatment, the treatment areas will be cleansed and the skin will be 
left undressed. The Investigator or designee will assess the treatment areas for adverse 
events.  Subjects will be asked to assess their treatment assignment (the blind). 
The Subject will be instructed to report any adverse events to the Investigator between and 
at the follow-up visits. Photographs of the treatment area may be obtained post-treatment.  
Subjects will be asked to bring all prescription opioid bottles to all study follow-up visits. 
A pill count will be completed by the study coordinator, or designee.  
10.6 
Visit 3 / Total Knee Arthroplasty (Day 0) 
The Investigator or Designee will confirm their ability to safely perform TKA within the 
following protocol requirements.  All surgical and in-patient data, safety information 
including adverse event assessments, will be collected retrospectively from hospitalization 
records: 
 
 Pre-operative History & Physical Exam, including assessment of the target knee, 
must be documented in the medical record and included as study data. 
 Surgery and Implant - Medial parapatellar surgical approach; cruciate-retaining or 
posterior-stabilized TKA; all surfaces replaced. 
 Pre-emptive analgesia – medications administered prior to TKA, orally, 
intravenously, or otherwise, for the purpose of pain management before, during, or 
after surgery, are to be recorded in the medical record and included as study data. 
 Procedural anesthesia – during Arthroplasty this will be limited to spinal 
anesthesia, the formulation, or “cocktail,” of medications used are to be recorded 
in the medical record and included as study data.  
 Local Infiltration Analgesia – permitted per surgeon or anesthesia preference, the 
formulation, or “cocktail,” of medications used are to be recorded in the medical 
record and included as study data.  
 Regional nerve block for post-operative analgesia – single shot Adductor Canal 
Block required, the formulation, or “cocktail,” of medications used are to be 
recorded in the medical record and included as study data.  
 Post-operative analgesia – opioid or other pain medications used are to be recorded 
in the medical record and included as study data 
 Other data to be collected retrospectively from hospitalization medical records 
include: Time of admission to and discharge from the hospital, Length of surgery, 
Method of wound closure, Tourniquet use, Blood loss, Post-operative drain use, 
and Adverse Events, including Opioid-related adverse events - sedation, dizziness, 
nausea, vomiting, constipation, physical dependence, tolerance, and respiratory 
depression. 
 
Outpatient analgesia – The subject will be required to bring all of their unused prescription 
narcotic medications dispensed during study participation to all study follow-up visits for 

 
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pill count.  Any other over-the-counter analgesic medications or other pain relief therapies 
used (per patient report) will also be recorded by the study coordinator, or designee, at 
each follow-up visit.   
 
Subjects will be asked to bring all prescription opioid medications to all study follow-up 
visits. A pill count / accountability will be completed by the study coordinator, or 
designee.  
10.7 
Study Follow Up  
Study-related follow-up visits occur at the investigational site at Week 2, Week 4, 
Week 6, and Week 12.  The study’s schedule of assessments is shown in Table 3. 
10.7.1 Visit 4 / 2 Weeks Post-op (14 ±3 Days), Visit 5 / 4 Weeks Post-op (28 ±5 Days), and Visit 6 / 6 Weeks 
Post-op (42 ±5 Days)  
Subjects will be evaluated and data collected per the schedule of events. Any changes in 
concomitant medications/concurrent procedures will be documented. Any anticipated 
observations, adverse events, adverse device effects and/or SAE/UADE/USADE will be 
assessed and documented. Photographs may be taken of the treatment area.  
The Subject will complete a WOMAC questionnaire, NRS for Pain when standing from a 
seated position, PROMIS questionnaire, and SF-36 questionnaire.  Subjects will be asked 
to assess their treatment assignment (the blind). 
Subjects will answer Satisfaction questions at Visit 6. 
The subject will complete the Physical Performance Measures in the following order 
under supervision of the investigator or designee: 
 Active Range of Motion 
 40 Meter Walk Test 
 30 Second Chair Test 
 
Detailed instructions for the conduct of these performance measures are included in the 
Study Operations Manual.  Assistive/ambulatory device usage and work status will also 
be assessed.  
 
Utilization of healthcare services post-discharge, or since the previous follow-up visit, will 
be assessed.  Subjects will be asked to report any Secondary Surgical Interventions, 
Emergency/Urgent care visits, Unscheduled physician office visits, and other healthcare 
services used since their last study visit.  Investigators will also record any additional or 
unscheduled services performed at follow-up visits (examples include knee aspiration, 
unscheduled x-ray, other unscheduled diagnostic procedures, etc.). 
Subjects will be asked to bring all prescription opioid bottles to all study follow-up visits. 
A pill count will be completed by the study coordinator, or designee, and opioid 
medication will be redispensed to subjects.  

 
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10.7.2 
Visit 7 / 12 Weeks Post-op (84 ±7 days) 
Subjects will be evaluated and data collected per the schedule of events. Any changes in 
concomitant medications/concurrent procedures will be documented. Any anticipated 
observations, adverse events, adverse device effects and/or SAE/UADE/USADE will be 
assessed and documented. Photographs may be taken of the treatment area.  
The Subject will complete a WOMAC questionnaire, NRS for Pain when standing from a 
seated position, PROMIS questionnaire, and SF-36 questionnaire.  Subjects will answer 
Satisfaction questions. Subjects will be asked to assess their treatment assignment (the 
blind). 
The subject will complete the Physical Performance Measures in the following order 
under supervision of the investigator or designee: 
 Active Range of Motion 
 40 Meter Walk Test 
 30 Second Chair Test 
 
Detailed instructions for the conduct of these performance measures are included in the 
Study Operations Manual. Assistive/ambulatory device usage and work status will be 
assessed. The total number of outpatient Physical Therapy visits conducted between 
hospital discharge and 12 Weeks post-op will also be obtained. 
 
Utilization of healthcare services since the last follow-up visit will be assessed.  Subjects 
will be asked to report any Secondary Surgical Interventions, Emergency/Urgent care 
visits, Unscheduled physician office visits, and other healthcare services used since their 
last study visit.  Investigators will also record any additional or unscheduled services 
performed at follow-up visits (examples include knee aspiration, unscheduled x-ray, other 
unscheduled diagnostic procedures, etc.). 
Subjects will be asked to bring all prescription opioid bottles to all study follow-up visits. 
A pill count will be completed by the study coordinator, or designee, and opioid 
medication will be redispensed to subjects.  
At the completion of this visit, the Subject will be exited from the study unless the Subject 
has any ongoing device-related or iovera° treatment-related adverse events as described in 
section 10.8.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Table 3. Schedule of Assessments 
Assessment 
Visit 1 / Screening  
Visit 2 / iovera° 
Treatment 
Visit 3 / DAY OF 
TKA (Day 0) 
Visit 4 / 2 Weeks 
Post-op 
Visit 5 / 4 Weeks 
Post-op 
Visit 6 / 6 Weeks 
Post-op 
Visit 7 / 12 Weeks 
Post-op 
Informed Consent 
X 
 
 
 
 
 
 
Eligibility 
X 
X 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
Concomitant medication 
assessment 
X 
X 
X 
X 
X 
X 
X 
Prior/Concurrent Therapy 
X 
X 
 
X 
X 
X 
X 
Randomization* 
 
X 
 
 
 
 
 
Study Treatment 
 
X 
 
 
 
 
 
Physical Exam 
 
X 
 
 
 
 
 
Vital signs 
X 
X 
 
 
 
 
 
Knee Circumference 
 
X 
 
 
 
 
 
PROMIS Questionnaire 
X 
 
 
X 
X 
X 
X 
WOMAC Questionnaire 
X 
 
 
X 
X 
X 
X 
SF-36 
X 
 
 
X 
X 
X 
X 
NRS for Pain 
X 
 
 
X 
X 
X 
X 
Work Status Questions 
X 
 
 
X 
X 
X 
X 
Subject Satisfaction Questions 
 
 
 
 
 
X 
X 
Assessment of Blind 
 
X 
 
X 
X 
X 
X 
Physical Performance 
Measures 
X 
 
 
X 
X 
X 
X 
Pain Medication 
Accountability 
 
 
 
X 
X 
X 
X 
AE/SAE Assessment 
 
 
X 
X 
X 
X 
X 
X 
Photographs  
(if applicable) 
 
X 
 
X 
X 
X 
X 
* Randomization occurs after the subject has met eligibility criteria and prior to or at Visit 2 
 
Follow-up visits generally consist of the following:  
 The Investigator or designee assesses the occurrence of health status changes and 
adverse events since last study visit; 
 The Investigator or designee determines whether any changes in daily medications 
have occurred; 
 The Investigator or designee performs drug accountability (pill counts) of post-
operative outpatient opioid medication and re-dispenses unused opioid medications to 
subjects after use.  The Investigator or designee records other over-the-counter 
concurrent pain medication use and pain relief therapies used per subject report; 
 The Subject completes a WOMAC questionnaire, an SF-36 questionnaire, PROMIS 
questionnaire, Work Status Questions, Satisfaction questions (Visits 6 and 7 only), 

 
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self-assessment of the blind, and reports NRS for Pain when standing from a seated 
position; 
 The Investigator or designee performs Physical Performance Measures (Range of 
Motion, 30 Second Chair Test and 40 Meter Walk Test). 
 
10.8 
Photographs  
Photographs may be taken of the treatment area at the treatment visit and at the follow-up 
visits.  Photographs will be labeled appropriately, stored electronically (e.g., JPEG, PNG 
or other relevant format) and sent to the Sponsor according to Sponsor instructions. 
10.9 
Study Exit 
When the final study visit is complete, the Subject’s participation in the study is complete 
and the Investigator, or designee, will complete the study exit eCRF.  
If a Subject is experiencing an unresolved device or iovera° treatment related adverse 
events at the final study visit, the Subject will be followed by the Investigator until 
resolution occurs. 
10.10  Subject Discontinuation 
A Subject may be withdrawn from the study prior to completion for any of the following 
reasons: 
 Voluntary withdrawal of consent 
 Adverse event preventing continued study participation 
 Investigator believes risk of further subject participation outweighs benefit 
 Medical need for prohibited medications or treatment 
 Persistent non-compliance or lost to follow-up (A Subject is considered lost to follow-
up after the site makes 3 attempts to contact the via email or phone call and a certified 
letter is sent to the Subject.) 
  
The Investigator/Coordinator will complete a study exit form in the eCRF for any subject 
who prematurely discontinues from the study.  If discontinuation was the result of an AE, 
the AE will also be recorded in the eCRF. 
 
10.11 Study Termination 
The Sponsor may terminate the study as a whole or at individual study sites under the 
following circumstances: 
 Suspicion of risk to subjects, including occurrence of high rate of known AEs or 
unexpectedly high rate of unexpected AEs 
 Poor site compliance with the study protocol 
 Inadequate site enrollment 
 Obtaining new scientific knowledge that shows that the study is no longer valid or 
necessary 
 Persistent non-compliance with IRB or regulatory requirements 
 Persistent failure to comply with obligations arising from the clinical trial agreement 

 
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 Other business reasons (e.g., insolvencies or business entity liquidation) 
 
The Sponsor will document reasons for study suspension and notify relevant site 
Investigators and governing IRBs.  If suspension occurred because of a safety issue, all 
Investigators will be notified. When terminating the study, the Sponsor and Investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.   
10.12 Study-Related Assessments 
10.12.1 
Western Ontario and McMaster Osteoarthritis Index (WOMAC) 
The WOMAC is a tri-dimensional, disease-specific, patient-reported outcome 
measure.  It consists of 24 questions with 5 questions regarding pain, 2 questions 
regarding stiffness and 17 questions regarding function.  A copy of the WOMAC is 
located in Attachment 1. 
Completion of the WOMAC questionnaire will take approximately 15 minutes to 
complete.  After completion by the Subject, the study coordinator or designee will 
enter into the eCRF. 
10.12.2 
Numeric Rating Scale for Pain (NRS for Pain) 
The Numeric Rating Scale for Pain (NRS for Pain) is a measure of pain intensity. 
The investigator or designee conducts the 11-point scale verbally with the research 
subject in reference to the target knee.  The investigator or designee will ask the 
following questions,  
 “On a scale of 0 to 10, with 0 being no pain at all and 10 being the worst 
pain imaginable, how would you rate your pain RIGHT NOW when 
standing from a seated position.”   
 “On a scale of 0 to 10, with 0 being no pain at all and 10 being the worst 
pain imaginable, how would you rate your pain IN THE PAST 7 DAYS 
when standing from a seated position.” 
The Subject responds verbally and the study coordinator or designee will record 
the response. 
 
The NRS for Pain will be completed by the Subject and will take approximately 2 
minutes to complete.  The study coordinator or designee will enter the data into the 
eCRF. 
 
10.12.3 
Patient Reported Outcomes Measurement Information System (PROMIS) 
PROMIS® instruments use modern measurement theory to assess patient–reported 
health status for physical, mental, and social well–being to reliably and validly 
measure patient–reported outcomes (PROs) for clinical research and practice. 
PROMIS instruments measure concepts such as pain, fatigue, physical function, 
depression, anxiety and social function. A copy of the PROMIS is located in 
Attachment 2. 

 
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The PROMIS questionnaire will take approximately 10 minutes to complete.  After 
completion by the Subject the study coordinator, or designee, will enter into the 
eCRF. 
10.12.4 
36-Item Short Form Health Survey (SF-36) 
The SF-36 contains 36 questions assessing the Subject’s health-related quality of 
life.  A copy of the SF-36 is located in Attachment 3. 
 
The SF-36 will take approximately 15 minutes to complete.  After completion by 
the Subject, the study coordinator, or designee, will enter into the eCRF 
10.12.5 
Subject Satisfaction Questions 
Subject satisfaction questions will be verbally administered by the study 
coordinator or designee.  Questions will take approximately 3 minutes to complete.  
The Subject satisfaction questions are located in Attachment 4. 
10.12.6 
Self-reported Work Status Questions 
The Self-reported Work Status Questions will be given to the subject for 
completion at Visit 1, Visit 4, Visit 5, Visit 6, and Visit 7.  At Visit 1 / Screening, 
the questions are designed to assess the employment status of each subject prior to 
surgery.  At each follow-up visit, the questions will reassess working status.  
Patients who return to work are asked whether they are doing the same type of 
work as prior to TKA. For applicable subjects, the self-reported date of Return to 
Work will be recorded. Subjects who have returned to work will also be asked if 
there are any limitations in the amount or type of work they are able to perform at 
their current job.  Those subjects who have not returned to work will be asked the 
reason they have not returned to work.   
 
The Self-reported Work Status Questions will take approximately 5 minutes to 
complete.  The Work Status Questions are located in Attachments 5 and 6. 
 
 
 
11. 
STATISTICAL METHODOLOGY AND ANALYSES 
11.1 
Introduction 
This is a prospective, randomized, sham-controlled, multi-center, post-market trial to evaluate the 
iovera° device in treating pain associated with total knee arthroplasty (TKA).  The study is 
designed to investigate whether iovera° treatment prior to TKA decreases cumulative patient 
opioid use over the course of 6 weeks following TKA while maintaining similar levels of pain 
relief.   
 
The study will also investigate whether there is a relationship between patients treated with 
iovera° and length of hospital stay; patient reported pain and function as measured by WOMAC; 
patient satisfaction; and improved physical rehabilitation as measured by functional performance 
measures and range of motion. 
 

 
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The primary safety endpoint is the onset of device-related adverse events through twelve-weeks 
after TKA surgery.  The primary measure of effectiveness is the Total Daily Morphine Equivalent 
(TME) of pain medications used from Day of Discharge to the 6-week follow-up visit.  In 
addition, Change from Baseline in WOMAC Pain at the 6-week follow-up visit will be evaluated 
as a secondary endpoint.  A variety of secondary effectiveness endpoints, including performance 
and pain assessments, will be measured.  
 
Up to 8 study sites within the United States will screen a sufficient number of subjects to ensure 
that 150 subjects (Randomized 1:1 to approximate 75 Active Treatment subjects plus 75 Sham 
Treatment subjects) will be randomized and treated.   
Subjects will be randomized either to receive therapeutic treatment with the iovera° treatment or 
to receive a sham treatment with the iovera° treatment, using a balanced 1:1 active-to-sham 
randomization stratified by Study Site. 
 
11.2 
Study Endpoints 
11.2.1  Primary Effectiveness Endpoint 
The primary effectiveness endpoint is the cumulative consumption of opioids from the time of 
hospital discharge to 6 weeks post-TKA Surgery.  Opioid consumption will be converted to 
morphine equivalents and subject consumption will be verified by pill count at follow-up visits.  
The cumulative morphine equivalent will be divided by the number of days to provide the Total 
Daily Morphine Equivalent (TME) for the subject. 
 
The difference in the average TME between the two treatment groups will be calculated as Active 
TME average – Sham TME average, such that a positive difference indicates that the Active 
Treatment Group had a larger average TME than the Sham Treatment group, while a negative 
value indicates the opposite.  A negative difference between treatment groups reflects a positive 
outcome for the study. 
A superiority hypothesis test using the two-independent sample t-test will be used to statistically 
evaluate the difference in the average TME between the two treatment groups. A confidence 
interval for the difference in the average TME between the two treatment groups will be provided 
to assist in the interpretation of the results. 
The Primary Effectiveness Study Objective is met when the average TME for the Active 
Treatment group is less than the average TME for the Sham Treatment group, and the resulting t-
test is statistically significant using a one-sided α = 0.025 level of statistical significance 
11.2.2 Secondary Effectiveness Endpoints 
One of the secondary objectives of the study is to show that 6-weeks after treatment the Active 
Treatment group has a similar amount of pain relief as the Sham Treatment group.  Change in 
WOMAC Pain from the Baseline visit to the six-week visit will be calculated for each subject as: 
Change in WOMAC Pain =  
6-Week Visit WOMAC Pain – Baseline Visit WOMAC Pain 

 
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such that a negative value indicates a decrease in the WOMAC Pain, while a positive value 
indicates the opposite. 
The difference in the average Change in WOMAC Pain between the two treatment groups will be 
calculated as Active Change in WOMAC Pain average – Sham Change in WOMAC Pain 
average, such that a positive difference indicates that the Active Treatment Group had a larger 
average Change in WOMAC Pain than the Sham Treatment group, while a negative value 
indicates the opposite.  Since a negative Change in WOMAC Pain is indicative of pain relief, then 
a negative difference between treatment groups reflects a positive outcome for the study. 
A non-inferiority hypothesis test using the two-independent sample t-test will be used to 
statistically evaluate the difference in the mean Change in WOMAC Pain between the two 
treatment groups.  A confidence interval for the difference in the average Change in WOMAC 
Pain between the two treatment groups will be provided to assist in the interpretation of the 
results. 
The objective of this secondary endpoint is to show that the average reduction in WOMAC Pain 
for the Active Treatment group is not worse than the average reduction for the Sham Treatment 
group by more than one-half of the common standard deviation for the Change in WOMAC Pain 
scores.  The objective is met when the resulting t-test is statistically significant using a one-sided 
α = 0.025 level of statistical significance. 
A variety of additional secondary effectiveness endpoints will be assessed to further characterize 
pain relief, functional performance, and range of motion.  These include: 
 
 Active Range of Motion 
 40 Meter Walk Test 
 30 Second Chair Test 
 Length of Hospital Stay 
 WOMAC Scores (Pain, Stiffness, and Function) 
 SF-36 Scales and Summary Measures 
 PROMIS–29 Profile Domains and Pain Intensity Score  
 NRS for Pain 
 
For each secondary effectiveness endpoint, the result, as well as the Change from Baseline value, 
will be summarized at each visit the endpoint is collected.  Two sets of hypotheses tests will be 
performed: the paired t-test will be used to evaluate if the Change from Baseline result is 
statistically different from no change, while the two-independent sample t-test will be used to 
statistically evaluate the difference between the two treatment groups for both the original result 
and for the Change from Baseline result. Confidence intervals will be provided to assist in the 
interpretation of the results. 
11.2.3 Safety 
The frequency of each adverse event will be summarized by seriousness, severity and by 
relationship to the device.  Since some subjects may report the same event several times (e.g., 
headache), the first occurrence of the worst reported case of the event will be used for the purpose 
of analysis. Refer to the User Guide for full list of expected adverse events. 
 

 
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11.3 
Analysis Cohorts 
Different groups of subjects, or Cohorts, will be identified depending on the type and extent of 
analysis being performed.  These may include but are not limited to the following: 
11.3.1 Screening Cohort 
All subjects who are screened for the study will be included in the Screening Cohort.  Only an 
accounting of the numbers of subjects screened in the study, plus the reasons given for 
subjects not enrolled in the study will be performed on this Cohort. 
11.3.2 Safety/ITT (Intent to Treat) Cohort 
All subjects who are randomized are included in the Safety/ITT Cohort.  Subjects are 
analyzed in the treatment group they are randomized to. 
11.3.3 Per-Protocol Cohort 
The Per-Protocol Cohort is defined as the group of subjects who are randomized in the 
study, who receive the treatment they are randomly assigned to receive, and who complete 
their 6-week visit without any major protocol deviations. 
11.3.4 Cohort for Primary Endpoint 
The objective for the primary Effectiveness endpoint needs to be met for the study to be a 
success.  The analysis of the primary Effectiveness endpoint, Total Daily Morphine 
Equivalent, will be made using the Per-Protocol Cohort.  
11.3.5 Cohort for Secondary Endpoint 
The Secondary Endpoint, Change in WOMAC Pain, will be made using the Per-Protocol 
Cohort.  Analyses for all other secondary endpoints will be repeated using the Safety/ITT 
Cohort and the Per-Protocol Cohort. 
 
11.4 
Statistical Methods 
11.4.1  General 
Categorical data will be summarized using frequency tables, presenting the subject counts and 
relative percentages. McNemar’s chi-square may be used to assess within-subject changes in a 
bivariate response variable. 
Continuous variables will be summarized by the mean, standard deviation, median, minimum and 
maximum.  Within-subject changes will be analyzed parametrically using the paired t-test if the 
differences are normally distributed, or non-parametrically using the sign-rank test if the 
differences are not normally distributed. 
The SAS system or equivalent statistical package will be used to perform all analyses. 

 
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Exact confidence intervals will be generated for estimates of proportions.  Asymptotic confidence 
intervals will be generated for estimates of means.  Except where otherwise noted, the p-values of 
all tests will be reported without any correction for the multiplicity of tests performed.   
11.4.2  Derived Data – Change from Baseline Parameters 
Within-subject change-from-baseline (pre-treatment baseline) values for a parameter are 
calculated as: 
Change-from-Baseline = Follow-Up value – Pre-Treatment value  
such that a positive value indicates an increase from the pre-treatment value to the follow-up 
value, whereas a negative result indicates the opposite. 
 
11.5 
Handling of Dropouts or Missing Data 
 
All endpoints will be analyzed “as-is” without any special data imputation methods used to 
replace missing data.  Consequently, subjects missing results for a specific analysis will be 
excluded from that analyses.    
11.6 
Poolability 
Data will be pooled from multiple study sites for this analysis.  The justification for pooling is 
made on a clinical basis1.  The basis for pooling comes from three critical factors: the study sites 
must implement one common protocol; the sponsor must provide monitoring of study site 
compliance; the study sites must use common data collection procedures. 
In addition, poolability across study sites will be assessed by presenting results across study 
centers and by analyzing treatment-by-site interaction using a two-way analysis of variance with 
Treatment, Site, and Treatment-by-Site interaction as terms in the model.  Assessment of 
treatment-by-site interaction will be assessed at a 0.15 level of significance.  A non-significant 
interaction effect will support poolability of study sites.  A significant treatment-by-site 
interaction, if deemed to be only quantitative in nature as opposed to qualitative (i.e., if only due 
to a difference in magnitude of treatment effect across sites as opposed to a difference in direction 
of treatment effect across sites) will not necessarily disqualify study sites from being pooled.  
Note that prior to assessing interaction sites with less than 5 subjects will be combined. To avoid 
the scenario that the data from the combined super-site dominate the trial conclusion, sites with 
less than 5 enrolled subjects be combined according to their geographical closeness, and once a 
super-site have five or more enrolled subjects, then the forming of this super-site will stop and the 
forming of a new super-site will start.  Site by treatment interactions of a quantitative nature, (i.e., 
all sites show the treatment to be beneficial, but perhaps to a different degree by study site) will 
not be considered to be an impediment to pooling.  Site by treatment interactions qualitative in 
nature (i.e., the vast majority of sites show the treatment to be beneficial, but one or more sites 
show the treatment to be detrimental) will require extensive evaluation of the sites with contrary 
results to attempt to determine what factors at those sites led to the result2. 
                                                 
1 Meinert, C. (1986). Clinical Trials: Design, Conduct, and Analysis.  Oxford University Press, New York. 
2 Medical Devices Dispute Resolution Panel Meeting of September 6, 2001 (Panel Transcript) 

 
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Lastly, poolability between subjects younger than 65 years old and subjects that are 65 years or 
older will be assessed using the same methodology described above by replacing Site with Age in 
the analyses performed.  Assessment of treatment-by-age interaction will be assessed at a 0.15 
level of significance.  A non-significant interaction effect will support poolability of subjects 
younger than 65 years old and subjects that are 65 years or older.   
 
11.7 
Subgroup Analysis 
Analyses for the Primary Effectiveness endpoint and the Secondary Effectiveness endpoint will 
be repeated for subjects younger than 65 years old and for subjects that are 65 years or older. 
11.8 
Analysis Windows and Definitions 
Follow-up visits through 6-weeks should adhere to a window of ±05 days when identifying the 
analysis visit. The reported-as visit will be used to identify the analysis visit for all follow-up 
visits after the 6-week visit. 
11.9 
Sensitivity Analyses  
No imputations for missing data will be made for the Primary and Secondary Effectiveness 
Endpoints.  All patients enrolled and randomized in the study will be included in all analyses. 
Sensitivity analyses may be considered and will be described in the final Statistical Analysis Plan 
for the study.  Nevertheless, the totality of the results will be used when evaluating overall Study 
Success. 
11.10 Sample Size Justification 
Ultimately, the objective of this study is two-fold: 
1. 
Primary Effectiveness Endpoint:  Show that, on average, the Active iovera° treated 
subjects used less opioids than the Sham iovera° subjects. 
2. 
Secondary Effectiveness Endpoint:  Show that, on average, the Active iovera° treated 
subjects had similar pain relief as the Sham iovera° subjects. 
A feasibility study was conducted to evaluate the safety and effectiveness of iovera°.  In that 
study, the average (standard deviation) Total Daily Morphine Equivalent was 1826 mg (870 mg) 
among the iovera° subjects, and 2800 mg (1092 mg) among the non-iovera° subjects.  All subjects 
were followed for 12 weeks.  Assuming the following for the Primary Effectiveness Endpoint: 
Statistical Hypothesis: 
H0: µActive > µSham vs H1: µActive < µSham, 
where µActive is the average Total Daily Morphine Equivalent for the 
Active Treatment group, and µSham is the average Total Daily 
Morphine Equivalent for the Sham Treatment group. 
Statistical Test: 
 
two independent sample t-test  
Statistical Significance: 
one-sided α = 0.025  
Statistical Power: 
 
1 – β = 0.80 
Minimum Treatment Effect: µActive - µSham = -7.14 mg 
Common SD:  
 
σ = 13.1 mg 

 
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Minimum Sample Size: 
n = 54 per treatment group 
It is expected that, on average, the Active treatment group will use 7.14 mg less opioids per day 
after 6-weeks of follow-up than the Sham treatment group.  Assuming a common standard 
deviation of 13.1 mg for the Total Daily Morphine Equivalent and 1 – β = 0.80 statistical power, 
the two independent sample t-test will be statistically significant at a one-sided α = 0.025 level of 
statistical significance when there are a minimum of 54 analyzable subjects in the Active 
treatment group and 54 analyzable subjects in the Sham treatment group. 
The study is also powered to show that, on average, the pain relief among Active subjects is not 
worse than the pain relief among the Sham subjects.   The non-inferiority margin, Δ, represents 
how much worse the pain relief among the Active subjects  can be than among the Sham subjects, 
and still be considered “not worse than” the Sham pain relief.  In Escobar, et al3.  the Minimum 
Detectable Change (MDC95) for WOMAC Pain was calculated as 22.39.  Standard deviations for 
the Change in WOMAC Pain in that paper ranged from 18 to 22, depending on the cohort.  In the 
feasibility study, pain was assessed using the Knee injury and Osteoarthritis Outcome Score 
(KOOS) instrument.  In that study, the average (standard deviation) Change in KOOS Pain at 6-
weeks was -24.0 (13.5) among the iovera° subjects, and -18.3 (27.7) among the non-iovera° 
subjects.  In this study, the non-inferiority margin is set at 11, a value roughly one-half the MDC95 
quoted in Escobar, and that is also equal to roughly one-half of the estimated standard deviation 
of 22 for the Change from Baseline WOMAC Pain results.  That is: 
Non-Inferiority Margin (Δ) 
= 11 
≃  Escobar MDC95 / 2 = 22.39 / 2 
≃  Change from Baseline WOMAC Pain SD / 2 = 22 / 2 
Assuming the following for the Major Secondary Effectiveness Endpoint: 
Statistical Hypothesis: 
H0: µActive > µSham + Δ vs H1: µActive < µSham + Δ, 
where µActive is the average Change from Baseline in WOMAC Pain 
for the Active Treatment group, µSham is the average Change from 
Baseline in WOMAC Pain for the Sham Treatment group, and Δ is 
the non-inferiority margin. 
Statistical Test: 
 
two independent sample t-test  
Statistical Significance: 
one-sided α = 0.025  
Statistical Power: 
 
1 – β = 0.80 
Expected Difference:  
µActive - µSham = 0 
Common SD:  
 
σ = 22 
Non-Inferiority Margin: 
Δ = 22 / 2 = 11 
Minimum Sample Size: 
n = 64 per treatment group 
                                                 
3 Escobar A, Quintana JM, Bilbao A, Aróstegui I, Lafuente I, Vidaurreta I. Responsiveness and clinically important 
differences for the WOMAC and SF-36 after total knee replacement.Osteoarthritis Cartilage. 2007 Mar;15(3):273-80. 

 
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It is expected that, on average, the Active treatment group will have the same pain relief after 6-
weeks of follow-up as the Sham treatment group.  Assuming a common standard deviation of 22 
for the Change from Baseline WOMAC Pain, a non-inferiority margin of 11, and 1 – β = 0.80 
statistical power, the two independent sample t-test will be statistically significant at a one-sided α 
= 0.025 level of statistical significance when there are a minimum of 64 analyzable subjects in the 
Active treatment group and 64 analyzable subjects in the Sham treatment group. 
Lastly, the study is powered to evaluate Length of Stay, the number of days from surgery to 
discharge.  Assuming a common standard deviation of 1 day for Length of Stay and 1 – β = 0.80 
statistical power, the Wilcoxon rank-sum test will be statistically significant at a one-sided α = 
0.025 level of statistical significance when there are a minimum of 69 analyzable subjects in the 
Active treatment group and 69 analyzable subjects in the Sham treatment group. 
To account for up to 10% of the subjects withdrawing early or not having data available for the 
analysis of the primary effectiveness endpoint, a total of 150 subjects (Randomized 1:1 to 
approximate 75 Active treatment subjects plus 75 Sham treatment subjects) will be randomized 
and treated.   
 
12. 
ADVERSE EVENTS 
The study Investigator and Coordinator will evaluate, characterize and record in the eCRF all 
adverse events (AEs) occurring in all subjects from the initiation of study treatment to study exit 
(or premature withdrawal).  Device or procedure related AEs will be followed until resolution.  
AEs may be reported spontaneously by the subject or detected by the Investigator or coordinator.  
AEs should be evaluated for diagnoses not just symptoms (i.e., “angina”, not “chest pain”). 
AEs may be either spontaneously reported or elicited during questioning and examination of a 
subject.  All AEs must be completely recorded within the Subject’s source documentation.  All 
AEs will be evaluated by the Investigator for relationship to the iovera° device and to the 
treatment. 
In addition to verbatim terms, the Sponsor will categorize all AEs using MedDRA preferred terms 
(PT) and system organ classes (SOC).  Analysis will report both verbatim and MedDRA terms. 
Adverse events4 (AEs) will be assessed continuously from the initiation of study treatment 
through study exit. Per ISO14155:2011, an AE is any untoward medical occurrence, 
unintended disease or injury, or untoward clinical signs in subjects, users or other persons, 
whether or not related to the investigational medical device.  An AE can arise from any 
use of the device (e.g., off-label use, use in combination with any drug) and from any 
route of administration. 
Timely and complete reporting of all AEs assists the Sponsor in identifying any untoward 
medical occurrence, thereby allowing:  
1) 
protection of the safety of study subjects;  
2) 
a greater understanding of the overall safety profile of the device;  
3) 
recognition of device-related ill effects; 
4) 
appropriate modification of study protocols;  
                                                 
4 Definition from ISO14155:2011 

 
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5) 
improvements in study design or procedures; and  
6) 
adherence to worldwide regulatory requirements.   
12.1.1  
Adverse Device Effect (ADE) 
Per ISO14155, an adverse device effect is an adverse event related to the use of an 
investigational medical device. Adverse events related to the use of iovera° include 
events resulting from insufficient or inadequate instructions for use, deployment, 
operation or any malfunction of the device.  User error or intentional misuse of the 
device is also defined as an ADE. 
 
ADEs may be either spontaneously reported or elicited during questioning and 
examination of a subject.  All ADEs must be completely recorded within the 
subject’s source documentation and reported to the Sponsor within 48 hours of 
Investigator becoming aware of the ADE. 
12.1.2 
Serious Adverse Event (SAE)/ Serious Adverse Device Effect (SADE)/Anticipated 
Serious Device Effect (ASADE)/ Unanticipated Serious Adverse Device Effect 
(USADE) 
Per ISO14155, an international clinical trial standard, an SAE is an AE that: 
1. Led to a death, 
2. Led to a serious deterioration in the health of the subject that 
a. Resulted in a life-threatening illness or injury, 
b. Resulted in a permanent impairment of a body structure or a body 
function, 
c. Required in-patient hospitalization or prolongation of existing 
hospitalization, 
d. Resulted in medical or surgical intervention to prevent permanent 
impairment to body structure or a body function. 
3. Led to fetal distress, fetal death or a congenital abnormality or birth defect 
An event that is serious must be recorded on the AE worksheet and requires 
expeditious handling to comply with regulatory requirements. 
Events NOT considered to be serious adverse events are: 
 Hospitalizations for the treatment, which was elective or pre-planned, of a pre-
existing condition that did not worsen, and 
 Treatment on an emergency, outpatient basis for an event not fulfilling any of 
the definitions of “serious” given above and not resulting in hospital 
admission. 
A serious adverse device effect (SADE) is an adverse device effect that has 
resulted in any of the consequences characteristic of an SAE per the ISO 
definition.  
An SADE which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report is defined by ISO as an 
unanticipated serious adverse device effect (USADE). Accordingly, an SADE 
which by its nature, incidence, or severity has been previously been identified in 

 
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the current version of the risk analysis report is considered an anticipated serious 
adverse device effect (ASADE). 
Any adverse events classified as “serious” by the Investigator or the Sponsor 
require expeditious handling and reporting to the Sponsor.  All SAEs, whether or 
not the event was related to the study device or anticipated, must be immediately 
(within 24 hours of becoming aware of the SAE) reported to the sponsor by 
telephone, email, or confirmed facsimile transmission: 
Tracey Henry, and/or Study Manager  
myoscience, Inc. 
510-933-1500 (office) 
510-933-1501 (fax) 
THenry@myoscience.com 
12.2 
AE Severity and Relatedness 
Each AE occurring in the study will be characterized by the study Investigator as to 
severity (Table 4) and relatedness (Table 5). 
Table 4.  AE Severity Grading System. 
Severity Grade 
AE Description 
Mild 
AE is transient and easily tolerated by the subject, even if it causes discomfort 
Moderate 
AE causes the discomfort and interrupts usual activities 
Severe 
AE causes considerable interference with usual activities and may be incapacitating or 
life-threatening 
 
Table 5. AE Relatedness Grading System.* 
Grade 
Relationship of AE to 
study device or 
procedure 
Description 
5 
Definite 
An event that follows a reasonable temporal sequence from administration 
of the study device; that follows a known or expected response pattern to 
the study device; and that is confirmed by improvement on stopping. 
4 
Probable 
An event that follows a reasonable temporal sequence from administration 
of the study device; that follows a known or expected response pattern to 
the study device; and that is unlikely to have been caused by 
concurrent/underlying illness or other drugs, procedures, or other causes. 
3 
Possible 
An event that follows a reasonable temporal sequence from administration 
of the study device; that follows a known or expected response pattern to 
the study device; but may have been caused by concurrent/underlying 
illness, drugs, procedure, or other causes. 
2 
Unlikely 
An event that does not follow a reasonable temporal sequence from 
administration of the study device; that does not follow a known or 
expected response pattern to the study device, or most likely was caused by 
concurrent/underlying illness, drugs, procedure, or other causes, because of 
their known effects. 
1 
Not related 
An event almost certainly caused by concurrent/underlying illness, drugs, 
procedure, or other causes. 
*Note that change in medical condition occurring between Screening and the initiation of Study Treatment will be reported as a 
change in Medical History. 
 

 
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13. 
DEVICE TRACKING 
The Sponsor will send the investigational devices to study sites. The Investigator must house 
study devices in a secure location.  The Investigator must carefully and completely track receipt, 
use and disposition of all investigational devices. The Sponsor will track sending and receiving of 
devices.  The Sponsor will monitor site device accountability periodically. 
If a Sponsor representative or designee is present at the time of use, he/she may directly take 
possession of used device(s). All devices will be returned to the Sponsor after the study is 
complete.  
14. 
DEVICE DEFICIENCIES AND MALFUNCTIONS 
Throughout the study, the Investigator and study staff will report and document all device 
deficiencies and malfunctions related to the identity, quality, durability, reliability, safety or 
performance of the device.  This includes reporting of device deficiencies/malfunctions that did 
not lead to an AE but could have if: 1) suitable action had not been taken, 2) intervention had not 
been made, or 3) circumstances had been less fortunate.  If possible, the Investigator should return 
devices suspected of deficiency or malfunction to the Sponsor for analysis. 
15. 
ETHICAL AND REGULATORY CONSIDERATIONS 
15.1 
Compliance with Good Clinical Research Practice 
This study will be conducted in compliance with the principles of the Declaration of 
Helsinki, with the current Good Clinical Practice (GCP) guidelines and with other 
applicable regulations. The Investigator and all study staff will conduct the study in 
compliance with this protocol. Voluntary informed consent will be given by every subject 
prior to the initiation of any study-related procedures. The rights, safety and well-being of 
the study subjects are the most important considerations and prevail over the interests of 
science and society. All personnel involved in the conduct of this study must be qualified 
by education, training and experience to perform their assigned responsibilities. 
15.2 
Institutional Review Board (IRB) and Informed Consent 
Before study initiation, the Investigator must have written and dated approval from the 
IRB for the protocol, consent form, subject recruitment materials/process (e.g., 
advertisements), and any other written information to be provided to subjects. The 
Investigator should also provide the IRB with a copy of the product labeling, information 
to be provided to subjects and any updates. The Investigator will submit documentation of 
the IRB approval to the Sponsor. Copies of all correspondence with the IRB regarding this 
study must be sent to the Sponsor. 
The IRB-approved consent form must include all elements required by FDA, state, and 
local regulations, and may include appropriate additional elements. 
The Investigator/designee will explain the study to each potential subject and the subject 
must indicate voluntary consent by signing and dating the approved informed consent 
form. The Investigator must provide the subject with a copy of the consent form in a 
language the subject understands. The Investigator will maintain documentation that 
informed consent was obtained prior to the initiation of any study-specific procedures. 
Withdrawal of IRB approval of the Investigator’s part in the investigation must be 
reported to the Sponsor within 5 working days. 

 
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15.3 
Protocol Compliance 
The Investigator will comply to the extent possible with the IRB-approved protocol.  All 
deviations from the protocol must be documented.  The Investigator will notify the 
Sponsor immediately if a deviation from the protocol was required to protect patient 
safety.  
15.4 
Protocol Revisions 
Revisions to the study protocol can be made only by the study Sponsor. A revised protocol 
can be put into place only after governing IRB approval.  All administrative letters must 
be submitted to the IRB for their information.  
New or altered consent forms required by the IRB due to a protocol change must be signed 
by all subjects currently enrolled in the study and must be used for any subsequent subject 
enrollment. 
15.5 
Study Monitoring 
Representatives of the Sponsor will visit all study sites intermittently to review study 
records and to directly compare them with source documents (including, but not limited to 
patient and hospital records), to discuss the study conduct with the Investigator and study 
staff and to verify that the Investigator, study staff and facilities remain acceptable for the 
conduct of the study. 
Representatives of government regulatory authorities may also evaluate the study records, 
source documents, Investigator, study staff and facilities. 
The Investigator should immediately notify the Sponsor of any audits of this study by any 
regulatory agency, and must promptly provide copies of any audit reports. 
15.6 
Safety Reporting 
The Sponsor is responsible for performing ongoing safety evaluation in this study 
protocol.  Sponsor activities regarding safety include: 
 classification of all AEs, 
 review of all AEs reported in the study, 
 confirm site’s classification of AEs in terms of severity and relatedness to the study 
device and/or study procedure, 
 review of severity and relatedness with the study Investigator, especially when there is 
disagreement between the Investigator and the Sponsor, 
 review of device deficiencies and malfunctions, including determination and 
documentation of whether deficiencies/malfunctions could have led to an AE or SAE, 
 ensuring the reporting of all SAEs and device deficiencies/malfunctions that could 
have led to an AE or SAE to the IRB and, if required, regulatory authorities in a timely 
fashion, 
 informing all site Investigators in writing of all SAEs at all sites in a timely fashion 
and 
 updating the risk analysis and assessment of corrective or preventive actions 
potentially required as a result of new information obtained in the investigation 
 

 
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The Sponsor will evaluate all serious adverse events against US reporting requirements 
(Medical Device Reporting, 21 CFR 812) and Medical Device Directive (vigilance 
incident reporting) as per its standard operating procedures.  The Sponsor will investigate 
each SAE to determine whether the event represents an unanticipated serious adverse 
device effect (USADE, see Section 12.1.2).  The Sponsor will report any event to 
regulatory authorities, Investigators and reviewing IRBs/ECs as necessary. If an 
investigation shows that a USADE presents an unreasonable risk to subjects, the Sponsor 
will terminate all investigations or parts of investigations presenting that risk as soon as 
possible. The Sponsor will only resume a terminated investigation after corrective actions 
have taken place, site Investigators are informed and IRBs/ECs have been notified and 
given approval to resume the study. 
15.7 
Electronic Case Report Forms/Electronic Data Capture 
The study will use an electronic data capture (EDC) system to implement electronic case 
report forms (eCRF).  The system will allow compliance with 21 CFR 11 Electronic 
Signatures.  All CRFs are housed in the EDC system.  The Investigator and Coordinator 
will be trained in use of the eCRF prior to study initiation. Retraining in use of EDC can 
occur at any time. The EDC system will be validated prior to use. 
An eCRF is required and should be completed for each randomized Subject. The 
Investigator has ultimate responsibility for the collection and reporting of all data entered 
on the eCRFs and any other data collection forms (source documents) and ensuring that 
they are accurate, authentic/original, attributable, complete, consistent, legible, timely 
(contemporaneous), enduring and available when required. The eCRFs must be signed by 
the Investigator to attest that the data contained therein are true.  
The site will be provided with eCRF Completion Guidelines which will assist in data entry 
and data issues/questions. All persons allowed to enter or change eCRF data must appear 
on the Delegation of Responsibilities Log.  
The Sponsor will remotely monitor eCRFs to identify possible data errors. The system will 
have query mechanism whereby the site Coordinator can respond to Sponsor queries.  All 
data discrepancies will be resolved prior to database lock.  
15.8 
Quality Assurance Audits 
Sponsor representatives or designees may conduct site quality assurance (QA) audits 
during the study.  The Investigator must agree to provide the auditor with direct access to 
all relevant documents and discuss any findings with the auditor. 
In the event of an inspection by the FDA or other regulatory authorities, the Investigator 
must give the inspector direct access to relevant documents and to discuss any findings 
with the inspector. The Investigator must notify myoscience, Inc. in the event of a FDA 
site audit. 
15.9 
Confidentiality 
The Investigator is responsible for ensuring the confidentiality of subjects throughout the 
trial.  A unique identification code will be assigned to each Subject participating in this 
trial.  Any data that may be published in abstracts, scientific journals, or presented at 
medical meetings will reference a unique subject code and will not reveal the subject’s 
identity.  

 
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15.10 Records Retention 
The Investigator must maintain all study records (including device disposition, informed 
consents, source documents, correspondence, regulatory documents, contracts etc.) for at 
least 2 years after study completion.  At the Investigator’s discretion, all records may be 
sent to the Sponsor for permanent storage. 
The Investigator must contact the Sponsor or designee prior to destroying any records 
associated with this study.  If the Investigator withdraws from the study, all study-
associated records must be transferred to a mutually agreed upon designee. Written 
notification of such a transfer must be given to the Sponsor or designee. 
15.11 Publication and Reporting of Study Results 
The study will be registered with clinicaltrials.gov before the first patient is treated.  Study 
results will be documented in a study report that will be signed by myoscience 
representatives and by the Principal Investigator of the entire Study. Individual site 
Principal Investigators will not be required to sign this report. 
The results of this myoscience sponsored study will be published in accordance with 
standard editorial and ethical practices. Results from multi-center studies must be 
published or presented at congresses only in their entirety with data pooled from all 
centers. Individual Investigators may not publish data from individual centers, unless 
granted specific written permission by myoscience to do so. 
The list of authors of any formal publication or presentation of study results may include, 
as appropriate, representatives of myoscience. 
16. 
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Patients: Treatment Options. Drugs & aging,31(2), 83-91.  
14 White, P. F. 2002. The role of non-opioid analgesic techniques in the management of pain after ambulatory 
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17 Data on File, Vinod Dasa, MD, 2014. Retrospective chart review of patients treated with iovera° prior to TKA. 
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