Transcending COVID-19 Barriers to Pain Care in Rural America: Pragmatic Comparative Effectiveness Trial of Evidence-based, On-demand, Digital Behavioral Treatments for Chronic Pain
Phase: NA
Conditions: Chronic Pain
Sponsor: Cedars-Sinai Medical Center

 
 
 
 
 
Transcending COVID-19 barriers to pain care in rural 
America: Pragmatic comparative effectiveness trial of 
evidence-based, on-demand, digital behavioral 
treatments for chronic pain 
Protocol Number: STUDY00001262 
National Clinical Trial (NCT) Identified Number:  04933474 
Principal Investigator: Brennan Spiegel, MD  
Sponsor: NINR 
Funded by: NIH  
Version Number:  v.6.2 
Revision: 17 October 2023 
Original: 23 December 2020 
 
Summary of Changes from Previous Version: 
Affected Section(s) 
Summary of Revisions Made 
Rationale 
Objectives, Sections 
2.3.1, 2.3.2, 2.3.3, 3, 4.1, 
4.2, 4.3, 5.1, 5.2 5.2, 5.5, 
6.3, 7.2, 7.3, 8.1, 8.3, 9.2, 
9.4.1, 9.4.3, 9.4.5, 
10.1.1.2, 10.4.4 
• 
Edits to verbiage in Objectives, SOA, and 
sections throughout  
• 
Added tablet under Criteria 5 for 
inclusion criteria  
• 
Revision to loss-to-follow-up definition  
• 
Added updates to potential risk/AEs 
sections  
• 
Edits to sample size, power estimation, 
and analysis  
• 
Edits to language regarding consent 
procedures and documentation  
• 
Updated contact info under key roles 
and study governances 
Necessary edits  

 
 
 
 
• 
Added Table 2 Validated codes and 
validation performance metrics for each 
COPC after references section 
1.1, 1.3, 10.1.4 
• 
(Incorrectly modified description of VR 
study intervention to “one of three 
software programs;” implied 
painTRAINER is loaded on the headset) 
• 
Clarified study documents may also be 
shipped and honorarium may be sent to 
participants who do not need to return 
device 
• 
PROMI Anxiety Scale added to SOA 
• 
 Additional instruments added to SOA 
• 
Reformatted Key roles and Governance 
table 
Clarifying language leftover 
from pure VR studies 
1.3, 6.1 
• 
Added various self-reported 
querstionnaires to SOA 
• 
Updated description of EaseVRx 
intervention to reflect recent FDA 
authorization  
 
Incorporated new 
questionnaires, FDA 
authorization of intervention 
1.1, 1.2, 1.3, 5.1, 5.5, 11 
• 
Updated amendment history for v3 and 
v4 
• 
Modified descriptions of intervention to 
clarify two different programs and 
methods of delivery 
• 
Updated schema to incorporate Week 
12 survey 
• 
SoA updated to incorporate treatment 
usage and coping strategy 
questionnaires; cohort builders 
generalized  
• 
Inclusion criteria #1 clarified to indicate 
that chronic pain conditions are not 
explicitly limited to those listed in tables 
• 
Fourth recruitment site added 
(Bendcare) 
General cleaning of protocol, 
incorporated new 
questionnaires, fourth 
recruiting site added 

 
 
 
 
• 
Supplentary ICD-10 code table created 
to capture additional qualifying 
conditions identified by study team 
 
1.3 
• 
SOA modified and clarified 
Additional surveys added, 
SSQ needed to be separated 
from Week 1 
5.5 
• 
Recruitment procedures modified to 
allow for recruitment of individuals with 
valid email that was not in the 
electronic medical record 
These individuals should be 
eligible for enrollment. 
5.6, 8.3 
• 
New CRFs added about primary pain  
• 
Neck pain added as known risk 
Primary complaint may differ 
from whichever one of many 
qualifying ICD-10 codes are 
found during chart review; 
neck pain added as risk 
5.5, 6.4 
• 
Recruitment procedures modified to 
allow for recruitment of individuals by 
phone or email with elimination of 7 day 
waiting period.  
• 
Compliance procedures modified to 
allow for student interns with restricted 
access to PHI to make calls relating to 
facilitate survey compliance and device 
returns. 
Recruitment efforts to date 
suggest letters and waiting 
period are ineffective for this 
study population; all study 
teams agree that removing 
email requirements for 
contact improves access, 
equity, and diversity of 
potential study population. 
Some basic tasks involving 
brief interactions with 
patients to be delegated to 
student interns when 
possible. 
2.3.1, 10.1.8.1 
• 
Microsoft OneDrive added as possible 
secure cloud data management system 
OneDrive has features 
favorable to study staff that 
Box cannot accommodate; 
several study processes  

 
 
 
 
5.5 
• 
Onboarding procedures modified to 
take into account new instructional 
videos 
• 
Compliance procedures clarified and 
modified to account for optional SMS 
text messaging via REDCap 
Onboarding procedures now 
incorporate clear video 
instructions, and compliance 
monitoring updated to reflect 
current streamlined practices  
6.0 
• 
Exclusion criteria expanded to include 
history of seizure and prior exposure to 
either study intervention  
• 
Screener week failure criteria modified 
to exclude if any of 7 pain journals 
incomplete, housekeeping to reflect 
contents of finalized screener week 
surveys and procedures 
• 
Monitoring procedures expanded to 
allow for optional onboarding phone 
call, as instructional materials have for 
many patients rendered technical 
support calls obsolete. Patients may 
now use email confirmation to begin 
study procedures (see new study 
document "Study Onboarding 
Communications") 
• 
Survey expirations (active and 
screening) clarified and follow-up 
procedures modified to provide 
flexibility to study staff and statisticians 
• 
Defined expectation of survey 
missingness 
Survey procedures modified 
following findings of 2022 
monitoring visit by CS-IRB. 
Onboarding procedures 
streamlined to ease patient 
burden and adjust for 
changes to call screening for 
unknown numbers, which 
may cause participants to be 
unfairly withdrawn. 
5.5, 7.2 
• 
Included protocol for study staff to 
contact individuals who have not signed 
the ICF  
• 
Modified definition of replaceable 
participant to exclude individuals who 
used VR intervention before 
withdrawing from study 
Contacting screened 
participants to possibly assist 
with eConsent can be used to 
improve sample diversity and 
enrollment.  
Study adequately powered 
based on withdrawals to 
date, and analyses should 
include individuals who 
found the intervention 

 
 
 
 
unsatisfactory and 
subsequently withdrew 
5.5 
• 
Compliance procedures modified to 
allow a participant's recruiting site study 
staff to contact via patient portal when 
allowed by their local IRB. 
Study team is having 
difficulty contacting 
participants at non-CSMC 
from a California phone. 
 
Abbreviations 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
cLBP 
Chronic Low Back Pain 
CONSORT Consolidated Standards of Reporting Trials 
CBT 
Cognitive Behavioral Therapy 
CRF 
Case Report Form 
eCRF 
Electronic Case Report Forms 
EHR 
Electronic Health Record 
GLP 
Good Laboratory Practices 
HIPAA 
Health Insurance Portability and Accountability Act  
IRB 
Institutional Review Board 
ITQ 
Immersive Tendency Questionnaire 
LBP 
Lower Back Pain 
MRN 
Medical Record Number 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOA 
Schedule of Activities 
UP 
Unanticipated Problem 
US 
United States 
VR 
Virtual Reality 

Transcending COVID-19 barriers to pain care in rural America: Pragmatic comparative effectiveness trial of evidence-based, on-
demand, digital behavioral treatments for chronic pain 
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Protocol  
February 24, 2025 
 
 
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1 
TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ............................................................................................................................. 3 
1 
PROTOCOL SUMMARY ............................................................................................................................... 3 
1.1 
Synopsis ................................................................................................................................................ 3 
1.2 
Schema ................................................................................................................................................. 5 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 6 
2 
INTRODUCTION ............................................................................................................................................ 7 
2.1 
Study Rationale .................................................................................................................................... 7 
2.2 
Background........................................................................................................................................... 7 
2.3 
Risk/Benefit Assessment .................................................................................................................... 9 
2.3.1 
Known Potential Risks ..................................................................................................... 9 
2.3.2 
Known Potential Benefits .............................................................................................. 10 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 11 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 12 
4 
STUDY DESIGN ........................................................................................................................................... 13 
4.1 
Overall Design .................................................................................................................................... 14 
4.2 
Scientific Rationale for Study Design.............................................................................................. 14 
4.3 
Justification for Dose ......................................................................................................................... 14 
4.4 
End of Study Definition ..................................................................................................................... 15 
5 
STUDY POPULATION ................................................................................................................................ 15 
5.1 
Inclusion Criteria ................................................................................................................................ 15 
5.2 
Exclusion Criteria ............................................................................................................................... 15 
5.3 
Lifestyle Considerations .................................................................................................................... 15 
5.4 
Screen Failures .................................................................................................................................. 16 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 16 
6 
STUDY INTERVENTION ............................................................................................................................ 19 
6.1 
Study Intervention(s) Administration ............................................................................................... 19 
6.1.1 
Study Intervention Description ..................................................................................... 19 
6.1.2 
Dosing and Administration ............................................................................................ 21 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 22 
6.2.1 
Acquisition and accountability ...................................................................................... 22 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 22 
6.2.3 
Product Storage and Stability ....................................................................................... 22 
6.2.4 
Preparation ...................................................................................................................... 22 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 22 
6.4 
Study Intervention Compliance ........................................................................................................ 22 
6.5 
Concomitant Therapy ........................................................................................................................ 23 
6.5.1 
Rescue Medicine ............................................................... Error! Bookmark not defined. 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 23 
7.1 
Discontinuation of Study Intervention ............................................................................................. 23 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 23 
7.3 
Lost to Follow-Up ............................................................................................................................... 23 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 24 
8.1 
Efficacy Assessments ....................................................................................................................... 24 
8.2 
Safety and Other Procedures .......................................................................................................... 25 

Transcending COVID-19 barriers to pain care in rural America: Pragmatic comparative effectiveness trial of evidence-based, on-
demand, digital behavioral treatments for chronic pain 
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Protocol  
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8.2.1 
Procedures ...................................................................................................................... 25 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 26 
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 26 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 26 
8.3.3 
Classification of an Adverse Event .............................................................................. 27 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 27 
8.3.5 
Adverse Event Reporting .............................................................................................. 28 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 28 
8.3.7 
Reporting Events to Participants ................................................................................. 28 
8.3.8 
Events of Special Interest ............................................................................................. 29 
8.3.9 
Reporting of Pregnancy ................................................................................................ 29 
8.4 
Unanticipated Problems .................................................................................................................... 29 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 29 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 29 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 30 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 30 
9.1 
Statistical Hypotheses ....................................................................................................................... 30 
9.2 
Sample Size Determination .............................................................................................................. 31 
9.3 
Populations for Analyses .................................................................................................................. 31 
9.4 
Statistical Analyses............................................................................................................................ 32 
9.4.1 
General Approach .......................................................................................................... 32 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 33 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 33 
9.4.4 
Safety Analyses .............................................................................................................. 33 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 34 
9.4.6 
Planned Interim Analyses ............................................................................................. 34 
9.4.7 
Sub-Group Analyses ........................................................ Error! Bookmark not defined. 
9.4.8 
Tabulation of Individual participant Data ....................... Error! Bookmark not defined. 
9.4.9 
Exploratory Outcomes ................................................................................................... 34 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 34 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 34 
10.1.1 
Informed Consent Process ........................................................................................... 34 
10.1.2 
Study Discontinuation and Closure ............................................................................. 36 
10.1.3 
Confidentiality and Privacy ........................................................................................... 36 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 37 
10.1.5 
Key Roles and Study Governance .............................................................................. 38 
10.1.6 
Safety Oversight ............................................................................................................. 39 
10.1.7 
Clinical Monitoring .......................................................................................................... 41 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 41 
10.1.9 
Data Handling and Record Keeping ............................................................................ 43 
10.1.10 
Protocol Deviations ........................................................................................................ 44 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 44 
10.1.12 
Conflict of Interest Policy .............................................................................................. 44 
10.2 
Additional Considerations .................................................................... Error! Bookmark not defined. 
10.3 
Protocol Amendment History ........................................................................................................... 45 
11 
REFERENCES ............................................................................................................................................. 49 

Transcending COVID-19 barriers to pain care in rural America: Pragmatic comparative effectiveness trial of evidence-based, on-
demand, digital behavioral treatments for chronic pain 
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Protocol  
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STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.  See Staff Training Log. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Cedars-Sinai Institutional Review Board (IRB) for review and approval.  
Approval of both the protocol and the consent form must be obtained before any participant is 
enrolled.  Any amendment to the protocol will require review and approval by the IRB before 
the changes are implemented to the study.  In addition, all changes to the consent form will be 
IRB-approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent, using a previously approved consent form. 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
 
 
 
 
Title: 
Transcending COVID-19 barriers to pain care in rural America: Pragmatic 
comparative effectiveness trial of evidence-based, on-demand, digital 
behavioral treatments for chronic pain 
Study Description: 
This study will compare two available, evidence-based, digital pain 
treatment programs that patients can use at home. The goal is to see if 
one approach is better than the other, and whether certain patients 
respond to one more than the other. Study participants will be 
randomized to receive one of two treatment programs: Skills-Based VR or 
PainTRAINER. Study devices will be delivered to the participant’s home 
with instructions for use via FedEx; participants will receive remote 
technical support. They will be followed for 8 weeks and complete Patient 
Reported Outcome (PRO) questionnaires to assess functional status, pain 
levels, and use of pain medications (including opioids).  Participants will 
also be asked to provide consent/authorization to access medical records 
from their treating facility.  
 
 
Objectives: 
 
 
Primary Objective:   
To compare the effectiveness of EaseVRx and PainTRAINER in improving 
perceived pain intensity from baseline to 8 weeks. 

Transcending COVID-19 barriers to pain care in rural America: Pragmatic comparative effectiveness trial of evidence-based, on-
demand, digital behavioral treatments for chronic pain 
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Protocol  
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Secondary Objectives:  
To compare the effectiveness of EaseVRx and PainTRAINER in improving 
perceived pain catastrophizing over 8 weeks.  
To compare the effectiveness of EaseVRx and PainTRAINER in improving 
PROMIS anxiety over 8 weeks. 
To compare the effectiveness of EaseVRx and PainTRAINER in improving 
PROMIS pain interference over 8 weeks. 
To compare the effectiveness of EaseVRx and PainTRAINER in improving 
pain self-efficacy over 8 weeks. 
To compare the effectiveness of EaseVRx and PainTRAINER in reducing use 
of opioids over 8 weeks. 
 
Endpoints: 
 
Primary Endpoint: Daily Pain Intensity  
Secondary Endpoints: PROMIS Pain Interference, PROMIS Anxiety, Pain 
Catastrophizing, Pain Self-efficacy, and MME usage. 
Study Population: 
Individuals over age 13 with an ongoing pain problem that have 
experienced average pain intensity of >3 out of 10 within the previous 7 
days. 
Phase: 
Phase 2 
Description of 
Sites/Facilities Enrolling 
Participants: 
Four outpatient clinic sites, including Cedars-Sinai Medical Center; Ochsner 
Medical Center; The University of Alabama at Birmingham; Bendcare 
Physician Network. In addition, participants may enroll remotely. 
 
Description of Study 
Intervention: 
All participants will randomly receive one of two interventions: a VR 
headset with a 3D Immersive VR therapy (EaseVRx) or a web-based  2D 
mHealth intervention therapy(PainTRAINER) 
- 
 
Study Duration: 
36 months 
Participant Duration: 
12 weeks 
 
 

Transcending COVID-19 barriers to pain care in rural America: Pragmatic comparative effectiveness trial of evidence-based, on-
demand, digital behavioral treatments for chronic pain 
Version 5 
Protocol  
February 24, 2025 
 
 
5 
1.2 
SCHEMA 
 
 
 

Transcending COVID-19 barriers to pain care in rural America: Pragmatic comparative effectiveness trial of evidence-based, on-
demand, digital behavioral treatments for chronic pain 
Version 5 
Protocol  
February 24, 2025 
 
 
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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
 
 
Procedures 
Baseline
/ 
Screenin
g 
Day 1 
of 
Week 
1 
8-Week Intervention 
 
Post 
Intervention 
Week 
 
0 
1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
12 
Prospective patients identified 
(Cohort Builderor Provider) 
X 
 
 
 
 
 
 
 
 
 
 
 
Informed consent in person or 
over phone 
X 
 
 
 
 
 
 
 
 
 
 
 
Verify eligibility in chart review 
or from Dr. Letter:  
• 
Medical history 
• 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization  
X 
 
 
 
 
 
 
 
 
 
 
 
Baseline Questionnaires 
(Listed below with) 
X 
 
 
 
 
 
 
 
 
 
 
 
Shipment of VR device and/or 
study documents 
X 
 
 
 
 
 
 
 
 
 
 
 
Technical onboarding call 
 
X 
 
 
 
 
 
 
 
 
 
 
Milligram Morphine Equivalent 
(MME) Daily Dose 
X 
 
 
 
 
 
 
 
 
X 
 
 
Return of VR Device 
 
 
 
 
 
 
 
 
 
 
X 
 
Deliver  honorarium 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
Self-Reported Questionnaires 
 
NIH developed baseline 
demographics, biological sex 
X (Day 1) 
 
 
 
 
 
 
 
 
 
 
 
Daily Pain Medications Used 
X 
 
 
 
 
 
 
 
 
X 
 
 
Daily Pain Intensity 
X 
 
 
 
 
 
 
 
 
X 
  
 
Pain Catastrophizing Scale 
X (Day 4) 
 
X 
X 
X 
X 
X 
X 
X 
X 
  
 
PROMIS Anxiety Scale 
X (Day 4) 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PROMIS Pain Interference 
Scale 
X (Day 4) 
 
X 
X 
X 
X 
X 
X 
X 
X 
  
 
The Pain Self-Efficacy 
Questionnaire (PSEQ) 2-item 
short form 
X (Day 4) 
 
X 
X 
X 
X 
X 
X 
X 
X 
  
 
Simulator Sickness 
Questionnaire (VR Only) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Treatment Usage 
Questionairre 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Events Assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Custom Questions 
 
X 
 
 
 
 
 
 
 
X 
 
 
Treatment Expectation  
X (Day 4) 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant  Procedures 
Questionnaire 
X (Day 4) 
 
 
 
 
 
 
 
 
X 
 
 
Primary Pain Questionairre 
 
 
 
 
 
 
 
 
 
X 
 
 
Coping with Weekly Pain 
Questionnaire 
X (Day 7) 
 
 
 
 
 
 
 
 
X 
 
X 
 
 

Transcending COVID-19 barriers to pain care in rural America: Pragmatic comparative effectiveness trial of evidence-based, on-
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2 
 
INTRODUCTION 
2.1 
STUDY RATIONALE  
The COVID-19 pandemic has affected everyone in different ways. For people from rural areas of America 
with chronic diseases, particularly those who experience pain, the pandemic not only can worsen pain, 
but also it can trigger anxiety, depression, trouble sleeping, and substance use. This psychological 
distress is exacerbated by physical and social isolation, fear of seeking in-person visits, and diminished 
ability to access clinical care during the pandemic. One way doctors and health systems are reaching out 
is with video visits, where patients and their providers communicate online; however, video visits have 
limits. Therefore, we can help support them with other techniques. Beyond video visits, there are home-
based programs that patients can self-administer to help manage their pain. These proven programs can 
overcome staffing shortfalls, be used across long distance to reach anyone in the world, and can be used 
at the time and place of the patients' choosing. 
 
In this study, we will compare two available, evidence-based, digital treatment programs that patients 
can use at home. The goal is to see if one approach is better than the other, and whether certain 
patients respond to one more than the other. The first program is an app that can run on any 
smartphone or computer. The program offers an 8-week, at-home curriculum to learn and practice new 
skills that can help manage pain. The program runs on a standard screen on your phone or computer. 
The second program is also a proven, 8-week program, but it uses a technology called virtual reality, or 
VR. VR involves wearing specialized goggles that create a sensation of being in a 3D world. Evidence 
shows that virtual worlds can help people learn and retain new skills that help reduce pain. 
 
The study will recruit 300 people from rural communities in California, Louisiana, Florida, and Alabama 
and randomize them into either the 2D or 3D programs. We will then follow patients for 8 weeks and 
measure their pain levels. We will also measure signs of distress, including anxiety, along with 
medications used for pain, such as opioids, and the impact of pain on overall quality of life. To conduct 
the study, we will ask patients to periodically complete short surveys online and give their permission 
for the research team to collect information from the electronic health record. We developed this study 
working with patient partners from the American Chronic Pain Association (ACPA), and they will be part 
of the research team throughout the conduct, analysis, and reporting of the study. The results will help 
patients, doctors, and health system decide which homebased, patient-administered, digital treatment 
programs for pain to choose, better enabling providers to select the right treatment for the right 
patient. 
2.2 
BACKGROUND  
The COVID-19 Pandemic Presents Unique Biopsychosocial Barriers to Patients with Chronic Pain 
More than 50 million Americans suffer from chronic pain,1 defined as pain that persists for six months or 
longer.2 In addition to experiencing the physical symptom of pain, patients with chronic pain endure a 
multi-dimensional illness affecting biopsychosocial health, including low energy, impaired cognitive 
functioning, disrupted sleep, and diminished physical health, mental health, and social functioning.3-9 As 
a result, patients with chronic pain interact with the healthcare system frequently; one in five visits to a 
primary care provider is related to pain.10  
 
The COVID-19 pandemic presents unique environmental, social, and physical barriers to patients with 
chronic pain. Data reveal that the global pandemic can worsen physical pain and trigger anxiety, 

Transcending COVID-19 barriers to pain care in rural America: Pragmatic comparative effectiveness trial of evidence-based, on-
demand, digital behavioral treatments for chronic pain 
Version 5 
Protocol  
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depression, insomnia, and substance use.11-13 This psychological distress is exacerbated by physical and 
social isolation, fear of seeking in-person visits, and diminished ability to access clinical care.11,13  
 
Although video telemedicine visits are vital to bridge physical gaps between patients and providers, 
they are insufficient to address the scale of pain-related medical needs and emotional distress created 
by the pandemic. Video visits and online support groups rely on the availability of a fixed and limited 
number of trained clinicians. This structural limitation cannot address the overwhelming impact of 
COVID-19 on mental health, including the 31% of Americans endorsing anxiety and depression during 
the pandemic, 13% who started or increased substance use, and 11% who seriously considered suicide 
during this period, according to U.S. Centers for Disease Control data.14 In addition, telemedicine video 
visits can only occur at certain times of day and require that patients are willing to participate, are 
physically available and mentally prepared at the scheduled time, and reside in a home that affords 
sufficient privacy from others. Thus, additional treatment options are needed to bridge the growing gap 
between supply and demand of pain care services in the era of COVID-19.11 This need is especially 
pressing for patients living in rural areas and the socially disadvantaged. 
 
Evidence-based behavioral treatments for chronic pain are largely inaccessible to most Americans, 
particularly those in rural communities, due to limited availability of services coupled with COVID-19 
restrictions on therapist-delivered treatments.12 Moreover, barriers to pain care access, combined with 
exacerbated psychosocial distress caused by the pandemic itself, dually serve to amplify pain in this 
vulnerable patient population.12 The CDC recognizes that the COVID-19 pandemic is triggering emotional 
distress in people with preexisting chronic diseases, a phenomenon labeled by some investigators as a 
“global storm of stress-related psychopathological symptoms.”15 The CDC established public-facing 
guidance to help citizens navigate troubling emotions,16 and the Substance Abuse and Mental Health 
Services Administration (SAMHSA) launched a National Distress Helpline for people struggling to cope 
with pandemic stress.17 Both the SAMHSA helpline and other mental health services around the country 
have experienced dramatic increases in calls for help.  
 
In short, the COVID-19 pandemic has spawned a mental health crisis with disproportionate impacts on 
patients with chronic pain.13,14,18 A national shortage in mental health clinicians existed before COVID-
19. Now, healthcare organizations must decide how to rapidly scale and deploy behavioral pain care 
to a geographically widespread and increasingly isolated populace; there is no time to wait for 
expansion of the mental health workforce. There is an immediate need to deploy self-administered, 
remote, evidence-based treatments that leverage the time-tested science of cognitive behavioral 
therapy (CBT), long considered the gold-standard behavioral medicine for reducing pain-specific distress, 
anxiety, and depression in chronic pain.19 Several meta-analyses demonstrate that fully-contained, self-
administered CBT computer programs are feasible and effective for home-based management of 
chronic pain.20-23 Moreover, these self-contained programs can overcome geographic, staffing, and 
timing barriers of traditional video and in-person visits, particularly in vulnerable rural communities. For 
these reasons, an international COVID-19 consensus panel recently concluded that whenever possible, 
online self-management programs should be considered to help care for patients with pain during the 
pandemic.24 However, because traditional CBT typically requires 8-12 sessions with a trained provider, 
even in the limited places where CBT is available, attrition rates exceed 30% in clinical practice.25 Poor 
access to CBT, particularly in underserved rural communities and now magnified by the COVID-19 
pandemic, amplifies psychological distress and promotes the use of less effective but readily accessible 
modalities such as opioid medications.12 
 
 

Transcending COVID-19 barriers to pain care in rural America: Pragmatic comparative effectiveness trial of evidence-based, on-
demand, digital behavioral treatments for chronic pain 
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Protocol  
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The COVID-19 Pandemic Differentially Impacts Pain Care in Rural Populations 
The nearly 50 million Americans living in rural areas incur disproportionate risks from the COVID-19 
pandemic.26 Because rural Americans have higher rates of hypertension, heart disease, and obesity, 
endorse higher rates of cigarette smoking, have more disabilities, and are both older yet have less 
access to health insurance than non-rural Americans, rural Americans are at greater risk not only for 
developing adverse outcomes from COVID-19, but also face larger challenges in managing psychosocial 
consequences of the pandemic.26 As a result, rural communities are uniquely susceptible to the 
negative health impacts of COVID-19 and are considered highly vulnerable according to the CDC’s 
Social Vulnerability Index (SVI).  
 
Telemedicine offers an important approach for delivering healthcare to remote and vulnerable 
populations with diminished access to healthcare, particularly for mental health services such as chronic 
pain management. Even before the pandemic emerged, data revealed rapid growth in mental health 
telemedicine use among rural Medicare beneficiaries27 enabled by substantially increased access to the 
Internet, with roughly two-thirds of rural Americans now having access to broadband networks.28 
Although telemedicine has increased dramatically in the era of COVID-19,27 there is still a marked 
shortfall in the availability of mental health and pain practitioners throughout the U.S, particularly in 
rural communities;29 this mismatch in supply and demand differentially impacts vulnerable rural 
communities with diminished access to care.27 This vulnerability is further amplified by the 
disproportionate impact of the opioid epidemic on rural America,30 now considered to be an 
“epidemic in the midst of a pandemic.”31 Non-opioid pain care was a priority before the pandemic, but 
now it is even more pressing to strengthen delivery of pain-related mental health services, particularly in 
rural communities, as a consequence of the pandemic’s unequal forces on rural vs. non-rural regions.  
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
This study poses minimal risk to participants. Immediate risks may include minor psychological distress 
from questionnaire items asking about health and employment status. There is also a small32 short-term 
risk of transient risk of VR-related “cybersickness” for those allocated to the VR arm of this study. 
Cybersickness is transient vertigo, nausea, or headache. It results from sensory mismatch between the 
visual and vestibular systems33-36 and usually resolves within minutes of removing the VR headset. The 
prevalence of cybersickness has fallen with improvements in hardware and software. Technical 
advances have reduced eye strain, minimized physical discomfort of wearing a VR headset, and reduced 
unnecessary visual motion.35 In the therapeutic setting, we also choose slow-moving scenes rather than 
highly kinetic visuals. As a result, cybersickness has become less prevalent and significant for people 
using VR.35 In this study, each VR session lasts less than 20 minutes. Participants will be instructed to 
complete just one session during each use to reduce the risk of cybersickness. In very rare instances, 
materials used in VR headsets have caused a mild rash which resolves when the VR headset is 
discontinuedWe do not expect any meaningful risk associated with the 2D PainTRAINER program. 
 
There are no anticipated long-term physical risks from participating in this study. There is a small risk of 
breach of confidentiality associated with the electronic collection and transmission of protected health 
information. This risk will be minimized by following proper procedures for assuring data integrity and 
confidentiality. 
 
The following is our list of study participant confidentiality safeguards:  

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 
Electronic files – data identifying participants will be stored in status tracking 
logs within password-protected excel files on Cedars-Sinai encrypted shared 
drives.  
 
Forms – survey forms and other pages containing personal identifying 
information will be saved within the REDCap system.  
 
Data listings - participant name, name code, hospital chart, record number, 
Social Security Number, or other unique identifiers will not be included in any 
published data listing.  
 
Data distribution - data listings containing PHI such as name, MRN, or other 
identifiers easily associated with a specific participant will not be distributed.  
 
Data disposal - computer listings that contain participant 
identifying information will be disposed of in accordance with institutional 
policies and procedures, after study completion.  
 
Access - participant records will not be accessible to 
persons/institutions outside those listed on the HIPAA form signed 
by  the participant.  
 
Storage - study forms and related documents retained during and after study 
completion will be stored within a secure Box and/or OneDrive folder accessible 
only by approved study staff. Some documents, such as survey exports, may be 
locally stored on a Cedars-Sinai encrypted shared drive or computer desktop 
during data analysis.  
 
Passwords – Multi-factor password authentication will be required to access 
documents stored on the cloud and on local desktops at Cedars-Sinai.  
 
User Training - study staff with access to clinical computer systems are trained 
and certified to maintain confidentiality prior to authorization by the Cedars- 
Sinai IRB.  
 
System Testing – new computer systems used by clinical staff are processed by 
the Cedars-Sinai IT (EIS) to ensure the password-activated systems perform as 
intended 
 
Certificate of Confidentiality – NIH funded research that involves human 
subjects and collects information which may identify a person is automatically 
protected by a Certificate of Confidentiality to prevent forced disclosures (e.g., 
subpoenas). 
 
Privacy Breach Reporting – In the rare instance where an accidental 
release of identifiable PHI may occur, it will be reported to the Cedars-
Sinai IRB and the Cedars-Sinai Privacy Office for adjudication and 
corrective actions.  
 
 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
Potential immediate benefits include reduction of pain and general improvement in psychological 
health. Potential long-term benefits include improved functionality, reduced opioid use, and 
improvements in overall physical and psychological health.  This research will contribute to societal 
knowledge about the safety and efficacy of therapeutic VR and will provide information about the use of 
digital health pain reduction programs in rural popluations.  
 

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2.3.3 ASSESSMENT OF POTENTIAL RISKS AND 
BENEFITS  
Virtual reality hardware and software has advanced significantly in the last decade.  Modern studies 
utilizing VR have found general satisfaction with devices among participants. The incidence and severity 
of VR-related side effects are low, and symptoms generally subside within minutes of taking off the 
headset. There is little discernable risk for PainTRAINER, as it is a program that will be accessed online 
from a computer or mobile device that the participant is already using. Still, some individuals may 
experience emotional and/or mental discomfort associated with learning ways to modify one’s behavior 
and the decisions around whether and how to implement these strategies. 
 
Participation in the study may alleviate pain among individuals who have previously relied on opioids, 
potentially enabling them to reduce opioid use and related side effects. Sustained pain relief also may 
allow individuals to return to work faster, improve physical mobility, and enhance biopsychosocial 
health. As a result, the short- and long-term anticipated benefits of participation outweigh the minimal 
short-term risks.  
 

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3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
To compare the effectiveness 
of 3D immersive Skills-Based 
VR with 2D mobile health 
application in improving 
perceived pain intensity from 
baseline to week 8. The trial 
will be considered a success if 
there is statistical evidence of 
difference in improvement 
between EaseVRx group and 
PainTRAINER group. 
The change from study baseline to 
week 8 in daily pain intensity as 
measured by the standard 11-
point numeric rating scale (NRS) 
with a 24-hour recall is the 
primary endpoint. The minimally 
clinically important difference 
(MCID) on the pain NRS is 2 
points. 
The NRS response scale is most 
often recommended in 
guidance documents. The 
empirical basis slightly superior 
measurement properties (e.g., 
reliability, validity, 
responsiveness) across a wide 
variety of contexts compared 
to other response scales37. 
 
Secondary 
 
 
To compare the effectiveness 
of 3D immersive Skills-Based 
VR with 2D mobile health 
application in improving pain 
interference from baseline to 
Week 8. The trial will be 
considered a success if there is 
statistical evidence of 
difference in improvement 
between the EaseVRx group 
and PainTRAINER group. 
 
The change from study baseline to 
week 8 pain interference as 
measured by the 8-item PROMIS 
PI scale is a secondary endpoint. 
This scale measures the 
consequences of pain on relevant 
aspects of life, including the 
extent to which pain hinders 
engagement with social, cognitive, 
emotional, physical, and 
recreational activities. 
We will test for a statistically 
significant difference of 5 points in 
the PROMIS PI  score from 
baseline, and compare differences 
between either EaseVRx group 
and PainTRAINER group. 
The PROMIS scale is a validated 
instrument with excellent 
content validity, construct 
validity, and reliability in 
patients with chronic pain.38 
Past work indicates that 
changes of 3.5 to 5.5 points in 
PROMIS-PI scores of people 
with LBP can be considered 
meaningful.39  
To compare the effectiveness 
of 3D immersive Skills-Based 
VR with 2D mobile health 
application in improving pain 
self-efficacy from baseline to 
week 8. The trial will be 
considered a success if there is 
statistical evidence of 
The change from study baseline to 
week 8 in pain self-efficacy as 
measured by the Pain Self-Efficacy 
Questionnaire (PSEQ-2) is a 
secondary endpoint. It is a two-
item instrument designed to 
assess the extent to which people 
in pain believe they are presently 
The PSEQ-2's validity and 
internal consistency were 
found to be sound and suitable 
for use in clinical and research 
settings. 2 items are preferable 
to 10 to reduce participant 
burden. Further its use has 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
difference in improvement 
between EaseVRx group and 
PainTRAINER group. 
 
able to work and live a normal life 
despite pain (work includes 
housework and paid and unpaid 
work).  
been widely used in studies of 
low-back and chronic pain40.   
 
To compare the effectiveness 
of 3D immersive Skills-Based 
VR with 2D mobile health 
application in improving 
PROMIS anxiety from baseline 
to Week 8. The trial will be 
considered a success if there is 
statistical evidence of 
difference in improvement 
between the EaseVRx group 
and PainTRAINER group. 
The change from study baseline to 
Week 8 in anxiety as measured by 
PROMIS anxiety scale. We 
hypothesize residual pandemic-
related anxiety can be captured by 
including this measure; increased 
anxiety at the population level is 
well borne-out in the literature.  
Improvement in this domain could 
support one intervention over the 
other for use during a pandemic 
or other similar event. 
The PROMIS scale is a validated 
instrument with excellent 
content validity, construct 
validity, and reliability.38 Past 
work indicates PROMIS-Anxiety 
scores among people with LBP 
is considered a responsive 
measure sensitive to 
meaningful changes.  
To compare the effectiveness 
of 3D immersive Skills-Based 
VR with 2D mobile health 
application in improving 
perceived self-reported pain 
catastrophizing from baseline 
to Week 8. The trial will be 
considered a success if there is 
statistical evidence of 
difference in improvement 
between EaseVRx group and 
PainTRAINER group. 
The change from study baseline to 
Week 8 in pain catastrophizing as 
measured by PCS SF-6 is a 
secondary endpoint.  
We will test for a difference in 
rates of high catastrophizing as 
defined by a score of ≥7 on the 
PCS-SF6, and compare these 
differences between EaseVRx 
group and PainTRAINER group. 
 
The NIH Pain Consortium RTF 
draft standards for research on 
cLBP recommend a uniform 
minimal data set that includes 
self-report measures of pain 
catastrophizing.44 Further, 
changes in catastrophizing are 
associated with improvement 
in multidisciplinary pain 
treatment.45 
 
To compare the effectiveness 
of 3D immersive Skills-Based 
VR with 2D mobile health 
application in reducing use of 
opioids from baseline to Week 
8. The trial will be considered a 
success if there is statistical 
evidence of difference in 
improvement between 
EaseVRx group and 
PainTRAINER group. 
The change from study baseline to 
Week 8 in weekly average opioid 
dosage calculated as a 7-day 
average of daily maximum 
milligrams morphine equivalent 
(MME) is a secondary endpoint. 
We will test for a greater than .5 
SD in change from baseline, and 
compare differences between 
EaseVRx group and PainTRAINER 
group. 
Despite some evidence from 
randomized controlled trials 
(RCTs) on the efficacy of 
opioids in the short-term  
treatment of low back pain, 
little evidence is available on 
long term efficacy and safety. 
Lowering MME as prescribed 
while lowering pain is an 
important goal of cLBP 
treatments.46  
 
 
4 
STUDY DESIGN  
 

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4.1 
OVERALL DESIGN 
 
We will perform a two-arm RCT among a geographically diverse group of patients with mixed-etiology 
chronic pain. Using a random number generator, patients will be allocated in a 1:1 ratio at the site level 
between two self-administered, remotely deployed CBT delivery platforms: (1) a 2D mHealth app called 
PainTRAINER; and (2) 3D VR app called EaseVRx. The primary analysis will compare changes in pain 
intensity over 8 weeks upon completion of the standardized 8-week digital CBT protocols. Secondary 
outcomes will include pain catastrophizing, pain interference, self-efficacy, anxiety, and opioid use.  
Patient blinding is not possible in VR versus non-VR studies; we will explain the purpose of our study is 
to determine if one of two self-taught pain-management skills programs is more effective in helping 
manage pain, alongside current treatment.  If so, how much more effective is it and which patients does 
the program help the most? Both programs have been proven effective; in other words, both programs 
have been studied and results for both showed improvement in patients’ ability to manage 
their pain.  To do this, participants will be randomly assigned to test either a virtual reality (VR) program 
called EaseVRx or an online/mobile program called painTRAINER.  Because it is important for 
researchers to exhibit equipoise when describing the competing interventions, we will prepare a  
script that uses neutral language regarding the two interventions, as per previous VR research. In 
addition, data analysts will be blinded to patient allocation. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The two-arm study design will allow us to compare two available, evidence-based, digital treatment 
programs that patients can use at home. The goal is to see if one approach is better than the other, and 
whether certain patients respond to one more than the other. The 60-day study duration was chosen to 
because both EaseVRx and PainTRAINER programs are 8 weeks in duration.  
 
4.3 
JUSTIFICATION FOR DOSE 
Prior research has shown that daily use of VR for 10 to 15 minutes is effective in managing pain, plus use  
as needed for breakthrough flares of pain. The skills-based VR therapy program, EaseVRx, is a 
standardized 56-day program consisting of scheduled daily virtual experiences. Each VR treatment 
experience lasts between 2-16 minutes, with an average duration of 6 minutes. To minimize the risk of 
cybersickness, participants are instructed to complete one VR treatment experience at a time. Given the 
low-risk nature of VR, they also may repeat experiences such as relaxation, breathing exercises, and 
games at other times during the day, in response to their pain.  
 
PainTRAINER is among the most widely validated mHealth interventions for pain management.18-25  
Originally developed by members of our team at Duke and Northwestern University with NIH funding, 
the app teaches evidence-based pain coping skills using a self-administered, home-based software 
program. The system delivers eight sessions via any web-connected platform, including Android or iOS 
smartphones, tablets, or personal computers. The digital curriculum covers progressive muscle 
relaxation, activity/rest cycling, pleasant activity scheduling, recognizing negative automatic thoughts, 
pleasant imagery/distraction, problem solving, and monitoring for maintenance. Patients complete one 
session per week in a pre-determined order. The program can be completed in a somewhat flexible 
manner to accommodate life and medical events but the 56 day programs must be completed within 66 
days. 
 

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4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed the online survey 
questionnaire that is emailed on Week 8, as shown in the Schedule of Activities (SoA), Section 1.3. The 
end of the study is defined as 66 days after the last participant is enrolled or when that participant 
completes the Week 8 survey questionnaire, whichever is sooner.  
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
 
1. have chronic pain, from any underlying condition, using as examples but not limited to the 
administrative definition of ICD-10 code series G89.X or one or more of 134 chronic overlapping 
pain condition codes, as previously standardized and validated by an expert panel (see Tables 2 
and 3) 
2. have experienced average pain intensity of >3 out of 10 within the previous week;  
3. are >13 years of age;  
4. are able to read/write English;  
5. have either a personal computer, tablet, or smartphone; 
6. live in a designated rural zip code as defined by the Federal Office of Rural Health Policy (FORHP) 
data (RUCA Codes 4-10). 
5.2 
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. have a condition that interferes with use of the intervention (e.g., significant visual or auditory 
impairment, any history of seizure);  
2. are hospitalized;  
3. are receiving active cancer treatment;  
4. are receiving end-of-life care;  
5. have cognitive impairment that affects participation.  
6. have previously used the EaseVRx+ or painTRAINER programs 
 
We will we will collect data on key patient characteristics, including type of pain condition, sex, age, 
race, ethnicity, State and zip code, Rural-Urban Commuting Area (RUCA) codes (a composite measure of 
population density, urbanization, and daily commuting), pain severity, opioid use, comorbidities, social 
support, and COVID-19 impacts (unemployment, financial hardship, family or personal COVID-19 
diagnosis).  
5.3 
LIFESTYLE CONSIDERATIONS 
 
Women who are currently pregnant or planning to become pregnant will not be excluded from the 
study 

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5.4 
SCREEN FAILURES 
All aspects of this study are conducted remotely, including the participants’ use of the digital 
intervention at home and collection of all PROs via survey questionnaires administered electronically. In 
addition, the VR headset has independent value. To ascertain their willingness and ability to respond to 
survey questionnaires delivered by email, potential participants are required to respond to daily, 
electronic, one-item “Pain Journal” questions and complete other  baseline survey questionnaires over 
the course of a “Screening Week,” following informed consent but prior to randomization. A screen 
failure is defined as a participant who completes fewer than 7 daily “pain journal” surveys. 
Participants are required to complete each survey within 14 days of the original send date, as these  
surveys will expire after 14 days. Age, socioeconomic status, race, and ethnicity are some of the 
information that will be collected for all participants even if they fail to complete any Screening Week 
surveys. Individuals who inform investigators during the Screening Week that they are no longer able or 
willing to participate in the study for any reason or who are discovered to meet any of the exclusion 
criteria will be recorded and withdrawn from consideration. Individuals who satisfactorily complete all 7 
pain journals and baseline survey questionnaires contained therein will be enrolled and randomized.   
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION  
 
The target sample size is 300. The population impacted by this research broadly encompasses 
individuals with many different types of chronic pain conditions, including somatic, musculoskeletal, 
neuropathic, and visceral pain. Using data from the Federal Office of Rural Health Policy (FORHP), rural 
Louisiana has a high prevalence of nearly 32% non-Hispanic Black, rural California has 2.5%, and 
Alabama 22.7%. We will oversample with a target of 20% for non-Hispanic Blacks in this study. We will 
have a monitoring plan to ensure that we maintain our 20% goal throughout conduct of the study. Rural 
California is 30% Hispanic, while Alabama and Louisiana have fewer than 2% Hispanic rural populations. 
The mean across states is 11.2%. The national mean of rural Hispanic populations is 6.6%. Because we 
will likely receive more patients from Alabama and Louisiana than from California (because there are 
two sites in the Deep South vs. one in urban California), we anticipate a weighted mean of closer to 8% 
Hispanic and will therefore target this value for our study.  
All four clinical sites have patient cohort search engines that will be used to identify patients with 
chronic pain. The informatics department at each site will pull zip code data for each potential 
participant, which will be matched with year 2010 RUCA zip codes provided by the USDA. This will 
provide a list of all possible participants that meet our desired criteria. We will monitor enrollment 
monthly and use the list to enrich enrollment as needed throughout the study to maintain the 20% 
target for the overall sample (across all three States). 
Across the four recruitment sites (Cedars-Sinai, Ochsner, UAB, Bendcare) over 10,000 patients are 
designated as being in a rural area. Though all four sites are based in urban location. There is a significant 
amount of rural area surrounding each area. Note that Dr. Curtis from University of Alabama is associated 
with Bendcare and the UAB coordinator will serve the same role for patients identified from Bendcare. 
Recruitment for the proposed trial will be maximized using several strategies: 
• 
Patients will be screened over a period of 24 months. Due to the COVID-19 pandemic, remote 
recruitment, which we have implemented and proved to be effective in our previous VR trials, will 
supplement in-person recruitment to ensure that we can reach the target enrollment goal.   

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• 
Identification: The prospective participants will be identified through existing registries, provider 
recommendation, and via automated EHR review using queries / clinical trial search programs / 
cohort builders (e.g. Deep6, Slicer Dicer, i2b2) at partner sites.  
• 
Recruitment: No in-person visits are required to be recruited for this trial.  
o Main Method: All eligible participants with a valid email in the medical record will be 
contacted by a research coordinator by email and patient-portal using an IRB 
approved recruitment letter to explain the study. An informational brochure will be 
attached to the email communication. 
o Alternative Method: If no valid email is available but a phone number is available, the 
study coordinator will contact the potential participant  by phone to explain the study. 
At that time, the coordinator will also collect the potential participant’s email (if 
available and the potential subject expresses interest in receiving additional 
information via email). An informational brochure will be attached to a future email 
communication. 
Justification for the alternate method: Our study was funded to address healthcare 
disparities for underserved and vulnerable populations (rural participants, in this 
case), and we are concerned that our study is excluding individuals who would 
otherwise qualify but have inadequate contact information on their chart, to the 
detriment of the study. For example, our inclusion criteria specifically target 
populations who are unlikely to be in close proximity to the participating academic 
health systems, and this condition naturally hinders opportunity to collect some/all 
personal information due to the infrequency of these (often all-day when travel time 
is included) visits. Especially with this specific study, the recruitment letter 
requirement may be biasing our study sample to reflect a population of higher tech 
literacy, closer proximity to the health center, etc. Further, we are underperforming 
the recruitment targets of Black and Hispanic individuals set by our NINR project 
officer, and all sites have patients from these cohorts without valid email addresses. 
o All patients will be able to opt-out of the study via email or by phone. We request 
removal of an official wait time between sending the email/letter and contacting 
subjects by phone. Our justification is that, to date, in the rural chronic pain study 
alone, 153 recruitment letters have been sent to Cedars-Sinai patients. However, 
none of them have contacted our study staff prior to the 7-day period, and of the 33 
individuals who were sent a recruitment letter and later declined, only two declined 
by email. 98.7% of recruitment letters have not obviated the need for a follow-up 
recruitment call, and this response rate compares to our other trials. Most individuals 
do not recall seeing or reading the letter when finally reached by phone.  
o 
If contacting a patient by phone, study coordinators will ensure the identity of the 
person on the phone call is indeed the prospective participant that was intended to 
be called. 
• 
Consent: An IRB-approved script will explain the purposes, procedures, and potential risks of the 
study and rights as research participants. REDCap will be used to email the IRB approved 
electronic consent form to the patient. Participants will have the opportunity to carefully review 
the electronic consent form and ask questions prior to signing. Study staff may reach out to 
participants who have been sent a consent form but have not yet signed to assist with the 

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eConsent process or record a reason for withdrawn interest, a slong as the participant has not 
indicated a reason for not signing the form. Participants will complete their consent forms 
electronically using the 21 CFR 11-compliant online REDCap platform. The informed consent will 
be signed by the patient and the designated investigator before the participant undergoes any 
study-specific procedures. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study.  
• 
Post-Consent: A copy of the informed consent documents will be provided to the participants for 
their records via email, and via postal service if no email is available. Participants will consent 
remotely and those randomized to the VR arm will receive their study equipment through a secure 
FedEx package. Study participants will receive their study equipment or documentation through 
secure FedEx package delivery. Retention to the 12-week study will be managed using 
protocolized reminder calls, emails, and/or SMS text messages to complete the study surveys. . 
Study coordinators will contact the participant following non-completion of a survey if >1 week 
has elapsed since the initial survey send date. The study coordinator will employ a Tableau 
dashboard that provides protocol adherence data to guide contact decisions.  
• 
Participants who complete the consent form will be required to finish the baseline questionnaires 
in order to be randomized and have the study equipment shipped to them as described above. 
Participants will be emailed tracking information and, if randomized into the VR arm, videos 
describing use of the intervention. 
• 
Participantswill be called for study onboarding once the VR device or painTRAINER workbook is 
delivered to their home. During this call, patients will be asked if they reviewed the startup 
instructions that were provided in the intervention tracking information email, and coordinators 
will answer any remaining questions and guide participants through the device or program if 
necessary. If participants are unreachable by phone, study staff will seek to schedule a phone call 
or confirm the participant’s understanding of study procedure by email, or by patient prior to 
initiation of study surveys. Contact information will be provided for technical support throughout 
the participant’s study enrollment.  
This protocol is not high risk for subject attrition; the intervention itself is considered low risk by our IRB.  
Strategies for retention include the following: 
• 
During the recruitment process, subjects will be educated about the importance of their role in 
contributing to research, to increase the likelihood that they will complete the patient reported 
outcome measures even if they stop using the intervention.  
• 
Participants will be educated on how to use PainTRAINER or VR via educational videos, talking 
with study staff, and referring to any applicable documentation.  
• 
The subject burden is low. Several data will be acquired passively, through patients using the 
PainTRAINER (2D mHealth intervention) or EaseVRx (3D VR intervention). There are no visits to 
their medical provider required by the research protocol. 
• 
Subjects will be compensated for participation in this study (see budget). 
• 
Retention to the 12-week study will be managed using three 24hr reminder emails, phone calls, 
or SMS text messages, as preferred by the patient, to complete PRO measures. Study coordinators 
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initial survey send date. The study coordinator will have a dashboard that provides compliance 
information to the individual patient using a program called tableau (Mountain View, California).  
• 
Participants may be contacted to facilitate study onboarding and survey compliance by their 
recruiting site study team via patient-portal when allowed by local IRB policy.  
• 
Participants in the VR arm will be required to return the device after completing the surveys on 
the 8th week to be eligible for the honorarium.  
As health services researchers working in highly diverse populations, we recognize that racial and ethnic 
minorities are underrepresented in clinical research for a wide range of important historical and cultural 
reasons. We also recognize that there are many strategies that can help overcome barriers and obstacles 
to participation in clinical trials. Considering the large target populations of Black and Hispanic populations 
in our rural populations, we will engage in several recruitment strategies designed to increase targeted 
recruitment, as follows: 
• 
Clarify the agenda behind the research in all written and oral communications. 
• 
Provide clear information about the clinical trial that avoids medical jargon. 
• 
Make recruitment/retention a top priority for research staff. 
• 
Provide regular feedback to referral sources about the status of trial recruitment. 
• 
Speak informally to colleagues to promote protocol awareness and interest. 
• 
Speak at professional and community meetings about trial protocols, and request referrals.  
• 
Highlight our team members who are Black and Hispanic researchers. 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
The two active interventions evaluated in this study are EasVRx and PainTRAINER. EaseVRx is delivered 
via a commercially available VR headset. PainTRAINER consists of 2-D visualizations delivered via 
smartphone or computer.  
Skills-Based VR: EaseVRx 
EaseVRx was developed by AppliedVR in partnership with pain psychologist Beth Darnall, PhD, Associate 
Professor of Anesthesiology, Perioperative and Pain Medicine at Stanford University and an NIH- and 
PCORI-funded investigator in the use of VR for pain management. EaseVRx incorporates the evidence-
based principles of CBT, mindful meditation, and physiologic biofeedback therapy using embedded 
biometric sensors. It combines psychoeducation, pain education, breathing training, relaxation 
exercises, and executive functioning games to provide a mind-body approach toward living better with 
chronic pain. The standardized, prescriptive, and reproducible 56-day program delivers a combination of 
skills training and CBT-related treatments through scheduled daily virtual experiences. The participants 
are allowed to complete as many sessions as they would like. In addition to the prescribed schedule of 
content the participant will have access to the full library of content. Each VR experience lasts between 
2-16 minutes, with an average duration of 6 minutes. The VR treatment modules are designed to 
minimize triggers of emotional distress or cybersickness. There are 5 types of modules:  
 

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● Interoceptive: These modules are designed to help the user understand and perceive what is 
happening inside the body. They provide a biofeedback-like platform in which the changes in the 
observed environment reflect a progressively enhanced state of relaxation. 
● Education: Help the user understand why the VR exercises are relevant to their pain, as well as 
teaching specific topics often used in pain psychology, including the neurobiology of pain, the 
role of mood and stress in pain, pain catastrophizing, activity pacing and setting goals. The goal 
is for the user to create self-management steps and a toolkit of strategies they can use to 
manage their response to pain. 
● 360-degree videos: High-quality 360 videos with voiceovers, music, and sound effects that are 
designed to maximize relaxation and engagement of users. 
● Game modules: Games are designed to maximize distraction and engagement, increasing the 
cognitive load on patients, and decreasing their perception of pain. 
● Dynamic breathing: These modules are based on evidence-based biofeedback training designed 
to enhance awareness of one’s physiological response to pain and to self-regulate that 
response. In a virtual world, the user experiences a gamified biofeedback session in which they 
are introduced to awareness of their breath via visualization in the form of air bubbles. In 
multiple sessions, the user receives increasingly challenging tasks to practice diaphragmatic 
breathing while interacting with the virtual environment. The user is also asked to pace their 
breath according to an expanding and contracting ring in the environment to slow the breath 
and create physiological changes associated with relaxation. The user’s exhale is measured by 
the microphone embedded in the headset, offering biodata-enabled immersive therapeutics. 
 
The EaseVRx program has been authorized by the FDA to help with pain reduction in patients 18 years and older 
diagnosed with chronic lower back pain.  
 
PainTRAINER (2D mHealth intervention) 
PainTRAINER is among the most widely-validated mHealth interventions for pain management.47-54 
Originally developed by members of our team at Duke and Northwestern University under NIH funding, 
the app teaches evidence-based pain coping skills using a self-administered, home-based software 
program. The system delivers eight sessions via any web-connected platform, including Android or iOS 
smartphones, tablets, or personal computers. The digital curriculum covers progressive muscle relaxation, 
activity/rest cycling, pleasant activity scheduling, recognizing negative automatic thoughts, pleasant 
imagery/distraction, problem solving, and monitoring for maintenance. Patients complete one session per 
week in a pre-determined order. The program can be completed in a flexible manner to accommodate 
life and medical events. For example, patients can close a session before completing it and later resume 
where they left off. Training is led by a computerized virtual coach and content is provided in audio to 
minimize reading and facilitate program completion for sick or low literacy patients. Important 
information is highlighted on screen with brief, large-font text, with photos, graphics, animations, and 
interactive exercises to reinforce learning.  
PainTRAINER includes eight 35-45 minute sessions; each teaches an evidence-based pain coping skill. 
Users complete one session per week in a predetermined order and can close a session before completing 
it and later resume where they left off. They can also review completed sessions (e.g., an audio recording 
of a skill practice, or instructions on how to use a skill). The program uses an adaptive, mobile responsive 
mHealth platform: Users can access it with any Internet-enabled tablet, personal computer, or 
smartphone. Smartphone access is important; these devices are increasingly the main platform used to 
access the Internet, including in underserved populations. During development of PainTRAINER, patients 
clearly advocated for access to program content and resources through smartphones. Training is led by a 

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computerized virtual coach who speaks to users. Content is provided in audio to minimize reading and 
facilitate program completion for sick or low literacy patients. Important information is highlighted on 
screen with brief, large-font text, with photos, graphics, animations, and interactive exercises to reinforce 
learning. We also added other features to enhance learning and mastery of skills, guided by social 
cognitive theory (e.g., social modeling), adult learning theory (e.g., tying skills to personal goals and 
experiences), principles of multimedia instruction (interactive exercises, graphics to reinforce 
explanations), and behavior change theory (e.g., behavior tracking, reminders). 
The program includes: (i) the Home Page 
(customized to users’ progress and status by the 
expert system); (ii) Training Sessions; and (iii) the 
Expert 
System 
(a 
knowledge 
database 
and 
programmed decision rules or “algorithms” that 
customize users’ experience based on their progress 
in the program). A login screen takes users to the 
home page where they access the current week’s 
session, which is highlighted. From there, users 
access program sessions and features that allow 
them to manage reminders and goals, log practices, 
and review progress in easy-to-read graphs. The 
interface applies accepted principles of user-
centered design to enhance usability in diverse 
populations (e.g., screen layout consistent with major websites; use of audio to minimize reading; simple 
menus placed predictably on-screen; clear and consistent navigation aids; direct access to important 
screens and help). Screen elements are designed for a diverse population (e.g., easy-to-read type, plain 
language and audio for low literacy users, images of people from diverse race/ethnic backgrounds). 
Written content follows federal guidelines for plain language to ensure it is easy to read, understand, and 
use. The program’s back-end database tracks program use meta-data, including sessions experienced, 
time spent on session, and time of day the session was reviewed. These meta-data allow for secondary 
“dose-response” analyses. Figure 1 shows the home page.  
PainTRAINER has been validated in clinical trials, including multiple RCTs. Bennell et al. studied the 
program in a participant-blinded trial of patients with chronic pain and found greater increases in function, 
pain coping, and global improvement than a control condition after eight weeks; benefits persisted at 52 
weeks and 91% of participants (older adults, largely from rural, low income areas, consistent with the 
current study population) completed all 8 sessions.47 Rini et al. found similar results in a controlled trial 
in patients with painful arthritis that demonstrated improved self-efficacy, reduced anxiety, and less pain-
related interference with functioning.48 Qualitative research reveals that patients find the program easy 
to use and are likely to recommend the app to others.50 Taken together, research indicates that 
PainTRAINER as an effective and acceptable mHealth app that can reduce pain and psychological disability 
and has proven acceptable to users in rural communities. These findings are consistent with a Cochrane 
meta-analysis of RCTs of web-based behavioral interventions for persistent pain that found improvements 
in pain, impairment, depression, and anxiety.55  
6.1.2 DOSING AND ADMINISTRATION 
All participants are instructed to use the VR program at least once a day and as needed throughout the 
the 8 week study period. Thereafter, the participant can use the program as needed.  Section 4.3 
provides the justification of dose. PainTRAINER delivers eight sessions via any web-connected platform, 
Figure 1: PainTRAINER home page 

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including Android or iOS smartphones, tablets, or personal computers. Patients will complete one 
session per week in a pre-determined order. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
The PICO VR headsets loaded with the EaseVRx software programs will be provided by AppliedVR. The 
devices will be managed by the research team at Cedars-Sinai Medical Center.  
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND 
LABELING 
N/A 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
The PICO VR headsets will remain in the boxes supplied by AppliedVR until they are shipped to 
participants.  
 
6.2.4 PREPARATION 
Prior to shipping a VR headset to a study participant, the headset battery will be checked to make sure it 
is fully charged. Any headsets that are handled by staff will be sanitized by cleaning the fabric surfaces 
using Virex, the plastic housing using Sani-Wipes, and the glass lenses using alcohol-based lens cleaner.  
The group that gets the PainTRAINER program will be mailed a user’s guide.  
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
We will allocate study participants using a random number generator to assign every-other patient to 
blocks of 2, 5, or 6 to ensure there is an equal distribution in the EaseVRx skills-based group and 
PainTRAINER group. Participants, their clinical providers, and study statisticians will be blinded to the 
study arm. The groups will be labeled as 1 or 0 at random. Datasets will be provided to the statistician 
using these group labels. A clinical research coordinator will ship VR headset containers to participants 
in the EaseVRx group and enter the label into the log of enrolled participants; the research coordinator 
who maintains the list of randomization assignments will not call participants on the telephone. Because 
the intervention is conducted in participants’ homes and the data are collected remotely, the 
participants will not encounter each other and thus will be less likely to guess their study arm 
assignment. We anticipate there will be no circumstances during the study that require unblinding of an 
individual participant or a whole group because we do not expect any related SAEs to occur with this 
low risk intervention.  
 
6.4 
STUDY INTERVENTION COMPLIANCE   
Data collection will be monitored daily by the study team. Participants will initially be sent automated 
reminder emails when they have not completed a survey questionnaire within a certain time frame after 
the original scheduled datetime. For the screener week and Week 8 daily pain journals, these reminders 
will occur 12 hours after and then 7 days after the original send datetime to best avoid overlapping 

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responses. For weekly surveys (SSQ+ to Week 8), automated reminder emails will be sent 48-hours after 
the original send datetime; if the participant does not respond to the first reminder, two additional 48-
hr reminders will be sent. Study team members will call the participant after the third reminder if no or 
incomplete data are received. The articipant will be asked why they missed all three reminders and be 
encouraged to continue to complete surveys as they are sent. If the participant continues to miss 
subsequent surveys, they will be sent emails containing link(s) to active and incomplete surveys or 
considered lost to follow-up at the discretion of the study team.  
Study participants are not expected to complete 100% of surveys sent to them during the course of the 
study; incomplete surveys are not considered non-compliance with the protocol. In addition, surveys 
may be completed out of temporal order and on the same day(s)—study statisticians will determine 
usability of these data. 
Participants who are unable to complete >=80% of surveys sent during any of the three months of 
follow-up will be ineligible for the corresponding Amazon e-gift codes ($50 for month 1, $225 for 
month 2, and $25 for month 3, respectively.  
Student interns with access only to the names and phone numbers of participants needing contact may 
place phone calls relating to survey compliance and return of equipment. Interns will not be performing 
activities related to recruitment or consent. If a subject has any questions outside of administrative 
issues, the call will be immediately transferred to a research coordinator or investigator. 
6.5 
CONCOMITANT THERAPY  
Participants in the study can receive any ongoing treatment for their chronic pain. 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
We do not anticipate any events that would cause the study intervention to be discontinued. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
Participants are free to withdraw from the study at any time upon request. Participants who request to 
withdraw will be given the option to continue completing the periodic survey questionnaires, if they 
choose to continue responding to surveys, they will not be withdrawn. An investigator may withdraw a 
participant who develops any of the exclusions criteria in section 5. the  
The reason for participant discontinuation or withdrawal from the study will be recorded.  Subjects who 
signed the informed consent form, were randomized and received the study intervention, and 
subsequently withdraw, or are withdrawn from the study without engaging with the study intervention 
(defined as any recorded VR or painTRAINER metadata by participant or self-reported usage of 
intervention in survey responses) will be replaced.  
7.3 
LOST TO FOLLOW-UP   

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A participant will be considered lost to follow-up if he or she fails to schedule an onboarding phone call 
within 30 days of device delivery or if he or she fails to complete the initial SSQ+ survey within 30 days of 
onboarding completion. For participants who complete the initial SSQ+ survey and fail to complete 
>80% of future surveys, and become unreachable by phone or email, the participant will be considered 
lost to follow-up 6 days following the email date of the participant’s Day 60 survey.   
 
If a participant fails to complete the weekly surveys within six days, the following actions will be taken: 
 
• 
The research coordinator will attempt to contact the participant and counsel them on the 
importance of completing surveys and returning the equipment to be eligible for the gift card.   
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
Contact attempts will be documented in the participant’s study record.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS    
We will capture all survey data via REDCap. REDCap is a secure web application for building and 
managing online surveys and databases. While REDCap can be used to collect virtually any type of data 
(including 21 CFR Part 11, FISMA, and HIPAA-compliant environments), it is specifically geared to 
support online or offline data capture for research studies and operations. If subjects do not complete 
the surveys, they will be sent a reminder prompt.  
Primary Outcome  
The change from study baseline to Week 8 in monthly pain intensity as measured by the standard 11-
point numeric rating scale (NRS) scale is the primary endpoint. Consistent with NIH Helping to End 
Addiction Long- Term (HEAL) guidance, we will measure daily pain with NRS for 7-days during baseline 
week 0, and again during the final week of the study (week 8). The minimally clinically importance 
difference (MCID) on the pain NRS is 2 points. 
Secondary Outcomes 
The change from study baseline to week 8 in pain interference as measured by the 8-item PROMIS PI 
scale is a secondary endpoint.  The scale is rendered using a T-statistic, where a score of 50 represents 
the population mean and 10 points is a standard deviation (SD). Scoring of the instrument will occur in a 
SAS/R/STATA environment in which study statisticians are blinded to the study arm. 
The change from baseline to Week 8 in pain catastrophizing as measured by the 4-item short pain 
catastrophizing scale is a secondary endpoint. The Pain Catastrophizing scale (PCS) short form measures 
rates of high catastrophizing as defined by a score of ≥7. Scoring of the instrument will occur in a 
SAS/R/STATA environment in which study statisticians are blinded to the study arm.  
The change from study baseline to Week 8 in anxiety as measured by the PROMIS Anxiety Scale is a 
secondary endpoint. The scale is rendered using a T-statistic, where a score of 50 represents the 

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population mean and 10 points is a standard deviation (SD). Scoring of the instrument will occur in a 
SAS/R/STATA environment in which study statisticians are blinded to the study arm. 
The change from study baseline to week 8 in pain interference as measured by the 8-item PROMIS Pain 
Interference scale is a secondary endpoint. The pain interference scale measures the consequences of 
pain on relevant aspects of one's life. This includes the extent to which pain hinders engagement with 
social, cognitive, emotional, physical, and recreational activities. The scale is rendered using a T-statistic, 
where a score of 50 represents the population mean, and 10 points is a standard deviation (SD). 
The change from study baseline to week 8 in pain self-efficacy as measured by the two-item Pain Self-
Efficacy Questionnaire (PSEQ-2) is a secondary endpoint. It is a two-item instrument designed to assess 
the extent to which people in pain believe they are presently able to work and live a normal life despite 
pain (work includes housework and paid and unpaid work). There is strong evidence for the validity and 
reliability of the PSEQ-2, its sensitivity to change, and suitability in clinical and research settings. 
The change from baseline to Week 8 in 7-day average of daily maximum milligrams morphine equivalent 
(MME). Prescription opioid medication use will be collected via self-report and calculation of the 7-day 
average will occur in a SAS/R/STATA environment in which study statisticians are blinded to the study 
arm. 
 
8.2 
SAFETY AND OTHER PROCEDURES    
Safety will be monitored by following up with participants for any adverse events (AE), assessment of 
adherence, monitoring of biometric information, and questionnaires by support staff. 
 
8.2.1 PROCEDURES  
Virtual Reality Headset data 
Data from the PICO G2 4K device will be aggregated by AppliedVR’s cloud-based software solution that 
implements robust industry standards to maintain secure databases and keep data private. The 
AppliedVR cloud server is a HIPAA compliant platform. The device account that corresponds with each 
device will be created using a clinical trial number that is only linked to the patient via our office list of 
patients enrolled in the study. AppliedVR does not collect personally identifiable information and does 
not collect IP addresses from synced participant devices in our database. Data will be stored and 
indexed in the AppliedVR server database whenever devices upload batches of analytic events, and the 
analytic events are timestamped. The data collected by the device will include time of use, date of use, 
and the module selected. Our database servers are IP firewalled and whitelisted such that they refuse 
any connection from IP addresses not preprogrammed by our team.  
 
PAINTRAINER 
 
PainTRAINER® metadata will be downloaded and provided monthly by the coordinator at Northwestern 
as CSV files containing timestamped records of content accessed at the individual device level. These 
records will feature a user-ID unique to each patient. A linking list containing study-IDs and user-IDs will 
be stored on a secure server behind the Cedars-Sinai firewall, and only associated with other study data 
following database lock. In order to monitor weekly adherence, study-staff will access a subset of the 
metadata limited to study-ID and timestamps of usage. These data will be subjected to QC procedures in 
a SAS/STATA/R environment. 

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Technical Support 
Patients in both arms will receive remote technical support from the research team. The idea is that 
issuing technology is usually insufficient to achieve behavior change. 
Patients will be provided with onboarding material as well as emails with a link to our lab’s website. The 
website was developed based on experience from previous remote VR therapy clinical trial and 
feedback from patients within it. On the website we have instructional videos as well an extensive FAQ 
page.  
REDCap survey data will also be monitored. We will assign two technical support staff members to 
monitor patients in both arms. Patients will receive a telephone number and email to contact support 
staff as needed.  
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
An adverse event (AE) is defined as any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)). Short-term 
AEs associated with the study include “cybersickness,”32 a transient form of motion sickness that affects 
up to one in four people upon entering a VR environment. Cybersickness most commonly presents with 
a short-term feeling of dizziness that typically subsides quickly.  There are no anticipated long-term AEs 
from participating in this study. A comprehensive list of all potential cybersickness symptoms can be 
found below:  
• 
Nausea 
• 
Fatigue  
• 
Eyestrain  
• 
Blurred vision  
• 
Difficulty focusing  
• 
Dizziness  
• 
Vertigo (a sensation of spinning dizziness, as though the room or surrounding environment is 
spinning)  
• 
Headache  
• 
Fullness of the head  
• 
Difficulty concentrating  
• 
Postural instability  
 In very rare instances, materials used in VR headsets have caused a mild rash which resolves when the 
VR headset is discontinued. Participants may also experience neck pain if using the device. No AEs 
are expected with PainTRAINER. 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
A serious adverse event (SAE) or suspected adverse reaction is considered "serious" if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: death, a life-threatening 
adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions. Important 
medical events that may not result in death, be life-threatening, or require hospitalization may be 

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considered serious when, based upon appropriate medical judgment, they may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. We do not expect any serious adverse events with the EaseVRx or PainTRAINER 
intervention.  
8.3.3 CLASSIFICATION OF AN ADVERSE EVEN 
8.3.3.1 SEVERITY OF EVENT 
For adverse events (AEs) the following guidelines will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
Research staff will call the patient if an event is noted in event assessment that is sent on a biweekly 
basis. Nothing more than mild to moderate side effects are expected.  
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  
 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
8.3.3.3 EXPECTEDNESS  
Research staff will be responsible for determining whether an adverse event (AE) is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the study intervention.  
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT 
ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
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Day 1. We will employ a general question to allow the patient to provide an event description without 
bias by presupposing the nature of the event, as follows: 
 
1) 
During the past 14 days, have you experienced anything uncomfortable, distressing or upsetting 
as a result of using the technology?  
a. 
Yes 
b. 
No 
2) 
If Yes please describe what happened. A research staff member will follow-up up with you as 
soon as possible to learn more.  
a. 
[open text] 
 
A designated CRC will review the REDCap dashboard for completed AE assessments on a daily basis 
throughout the work week. Once they find a completed event assessment form, they will follow-up with 
a phone call. The following information be obtained from the patient during the call: onset of potential 
adverse event, event description, when they last used the technology, how long they used the headset, 
when they stopped using the headset, severity of the potential AE, outcome of the potential AE (see 
categories, below), time until resolution/stabilization of event, the perceived relationship of the event to 
the study intervention, whether or not the event was expected (Y/N), whether it was serious.  
 
The outcome can be labeled using one of the following categories:  
• 
Recovered, without treatment  
• 
Recovered, with treatment  
• 
Still Present, no treatment  
• 
Still Present, being treated  
• 
Residual effect(s) present-no treatment  
• 
Residual effect(s) present-being treated  
 
Research staff will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation.   
 
8.3.5 ADVERSE EVENT REPORTING   
 
Cedars-Sinai IRB 
If a mild or moderate event occurs it does not need to be submitted to the Reportable New Information 
(RNI). If the event is an unexpected (not usually associated VR side effects) or severe event (requiring 
treatment), an AE will be submitted to the IRB as soon as possible but within at least 10 working days.  
 
 
8.3.6 SERIOUS ADVERSE EVENTS REPORTING  
SAE will be submitted to the Cedars-Sinai IRB via RNI as soon as possible by study coordinators, but no 
later than 10 business days from the Principal Investigator’s or study team’s awareness of the event, 
incident, information or outcome.  
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
N/A  
 

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8.3.8 EVENTS OF SPECIAL INTEREST  
N/A 
 
8.3.9 REPORTING OF PREGNANCY  
N/A 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
This definition could include an unanticipated adverse device effect, any serious adverse effect on 
health or safety or any life-threatening problem or death caused by, or associated with, a device, if that 
effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects (21 CFR 812.3(s)). 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
Study coordinators will report unanticipated problems (UPs) to the Cedars-Sinai IRB as a RNI submission 
as soon as possible by study coordinators, but no later than 10 business days from the Principal 
Investigator’s or study team’s awareness of the event, incident, information or outcome. UPs include 
SAEs and AEs, which are both unexpected and possibly related to the research as well as SAEs and AEs 
that meet the definition of a Research-Related Subject Injury (RRSI) – a medical condition that is caused 
by and/or directly related to the research study (i.e., the condition would not have existed “but for” the 
subject’s participation in the study), and requires diagnosis or treatment.    
The UP report will include the following information: 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  

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• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
The following are actions that could be taken by the study staff:  
1. 
No action 
2. 
Revise protocol to eliminate apparent immediate hazards to subjects 
3. 
Modification of inclusion or exclusion criteria to mitigate newly identified risks 
4. 
Implementation of additional procedures for monitoring subjects 5 - Suspension of enrollment 
of new subjects 
5. 
Notify currently enrolled subjects 
6. 
Suspension of research procedures in currently enrolled subjects 
7. 
Modification of consent documents to include a description of newly recognized risks (site 
and/or study wide) 
8. 
Provision of additional information about newly recognized risks to previously enrolled subjects 
9. 
Other, specify 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
N/A 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
Primary Endpoint(s):   
Primary Outcome: Pain interference over time as measured by Daily pain intensity 
Hypothesis: EaseVRx will lead to a greater improvement in 7-day average daily pain intensity than 
PainTRAINER between baseline and week 8.  
Comparisons: EaseVRx vs. PainTRAINER .  
 
Secondary Endpoint(s): 
Secondary Outcome: Pain interference over time as measured by PROMIS-Pain Interference 8a (T-
Scored, Continuous). 
 
Hypothesis: EaseVRx will lead to a greater improvement in pain interference than PainTRAINER between 
baseline and Week 8.  
 
Comparisons: EaseVRx vs. PainTRAINER .  
Secondary Outcome: Pain catastrophizing over time as measured by Pain Catastrophizing scale (PCS) 
short form. 
Hypothesis: EaseVRx will lead to a greater improvement in Pain catastrophizing than PainTRAINER 
between baseline and Week 8.  
Comparisons: EaseVRx vs. PainTRAINER  

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Secondary Outcome:  Anxiety over time as measured by PROMIS anxiety scale.   
Hypothesis: EaseVRx will lead to a greater improvement in Coronavirus Anxiety Scale than PainTRAINER 
between baseline and Week 8.  
Comparisons: EaseVRx vs. PainTRAINER  
Secondary Outcome:  Pain Self-efficacy Questionaire  
Hypothesis: EaseVRx will lead to a greater improvement in Pain Self-Efficacy than PainTRAINER between 
baseline and Week 8.  
Comparisons: EaseVRx vs. PainTRAINER  
Secondary Outcome: Comparing the change from study baseline to Week 8 in weekly MME of 
prescribed medication between baseline and Week 8.  
Hypothesis: EaseVRx will have a statistically significant decrease in opioid use in comparison to 
PainTRAINER between baseline and Week 8. 
Comparisons: EaseVRx vs. PainTRAINER  
9.2 
SAMPLE SIZE DETERMINATION 
 
Sample Size calculations and Power Estimation 
Sample Size calculations and Power Estimation 
Sample Size Calculation: The primary goal of 
the study is to test the effectiveness of 
PainTRAINER vs. EaseVRx, in reducing pain 
intensity. The trial will be testing if there is 
statistical evidence that either PainTRAINER 
or EaseVRx is more effective in lowering 
average weekly pain intensity after 8 weeks 
from start of intervention. We estimate 
power 
to 
assess the 
effect of 
the 
interventions on the treatment response (achievement of a minimally clinically important difference 
[MCID] of 2.0 on the NRS 56,57 (y/n)) using logistic regression, accounting for possible confounding factors 
for the primary outcome described in Aim 1. The dependent variable is the treatment response and the 
main independent variable of interest is PainTRAINER vs. EaseVRx. Table 1 displays the minimum odds 
ratio that can be detected with 90% power with the two-sided 0.05 level of significance as a function of 
baseline probability of positive response when a patient is treated with EaseVRx and R2, the proportion of 
variability in the predictor of interest that is explained by all relevant baseline covariates in the model 
using data from 150 patients in the PainTRAINER arm and 150 in the EaseVRx. For example, data from 300 
patients achieve 90% power to detect an odds ratio of 2.25 if the probability of positive response when a 
patient is treated with PainTRAINER is 0.3 and 0.1 of the variability in intervention is explained by all other 
baseline covariates in the model. These odds ratios vary between 2.15 and 2.91 and are clinically 
meaningful. Therefore, we have enough power to test statistical significance of predictors in the 
multivariable logistic regression model. Regarding clinical significance, given an MCID of 2 points on the 
NRS and a SD of 2 on this scale from our own digital health trials, data from 150 patients in each group 
Baseline 
probability 
R2 
0.0 
0.1 
0.2 
0.4 
0.2 
2.32 
2.42 
2.55 
2.91 
0.3 
2.17 
2.25 
2.37 
2.69 
0.5 
2.15 
2.25 
2.37 
2.74 
Table 1. Minimum detectable odds ratio as a function of the proportion of 
variability in treatment type that is explained by all other relevant covariates in 
the model and the baseline probability of postitive treatment response. 

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will achieve 90% power to detect a mean pain intensity score difference of 0.75, corresponding to a 
clinically meaningful effect size of 0.38 SD.  
9.3 
POPULATIONS FOR ANALYSES   
All efficacy and safety data summaries and analyses will be performed by study arm using an Intent-to-
Treat (ITT) population defined as all randomized patients. The number of patients identified as 
candidates for the study will be reported, as will the number consented. The number and 
percentage of patients randomized, patient population (ITT), and treatment status (completed, 
discontinued/withdrew) will be summarized both by treatment group and overall. Reasons for 
discontinuation/withdrawal will be presented. An exploratory, per protocol (PP) analysis will focus on 
patients who used the assigned intervention on at least 50% of days during the first 30-day period. 
9.4 
STATISTICAL ANALYSES 
 
 
9.4.1 GENERAL APPROACH 
All statistical analyses will be performed jointly by the Cedars-Sinai Biostatistics Core and the Cedars-
Sinai Center for Outcomes Research and Education (CS-CORE) using SAS® software version 9.3 or higher 
(SAS Institute, Cary, NC, USA), R version 3.5.0 or higher (R Foundation for Statistical Computing, Vienna, 
Austria) or Stata software version 14 or higher (StataCorp LLC, College Station, TX, USA). Continuous 
variables will be summarized using descriptive statistics (N, mean, standard deviation, minimum, 
median, and maximum as appropriate). Categorical variables will be summarized using the number and 
percentage of patients in each category. Data will be summarized with respect to patient demographic 
and baseline characteristics both across the study and by study-arm. The efficacy endpoints, safety 
assessments, and other outcome results for each treatment group will be summarized descriptively 
unless otherwise indicated. In addition, statistical model estimates of least squares means, treatment 
differences, p-values and 95% confidence intervals will also be provided where relevant. The fit of 
general linear models will be assessed using residual plots and/or other diagnostic plots as appropriate. 
The fit of logistic models will be assessed using Hosmer-Lemeshow goodness-of-fit and/or receiver 
operating characteristic (ROC) curves as appropriate. All statistical tests will be 2-sided and performed at 
the 0.05 level of significance unless stated otherwise. 
 
Multiple Comparisons/Multiplicity: The family-wise type I error rate (FWER) for the statistical tests of 
the primary and secondary endpoints will be controlled at 0.05. To strongly control the FWER at this 
level, a gatekeeping approach will be utilized. A closed testing procedure will be employed to control the 
FWER. Any hypothesis tests conducted for model building purposes will be conducted outside of any 
gatekeeping. 
 
Missing Data: We anticipate two sources of missing data: the failure of patients to complete 
assessments and loss of patients to follow-up. Data patterns of baseline covariates with missing values 
will be examined using the method of Little and in case the data is not missing completely at random, 
missing values will be imputed using fully conditional specification with the multivariate imputation by 
chained equations (MICE) algorithm under the missing at random (MAR) assumption. Fifty or so datasets 
will be generated and analyzed separately, and the results combined using the formula in Carmichael et 
al. Similar considerations will be applied to missing data on the dependent variable in a repeated 
measure mixed model by investigating patterns of missingness. 
 
Sex as a Biological Variable: The effect of sex on each intervention will be assessed by fitting two 
separate multivariable mixed models for each of the study interventions. In each model, the dependent 

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variable is NRS pain intensity and the independent variable of interest is sex, after adjusting for all 
relevant baseline factors. The effect of sex will be tested at the 0.05 level of significance. To investigate 
the differential effect of sex on the study intervention, we will construct a multivariable mixed model for 
the PainTRAINER and EaseVRx interventions by including a treatment variable, sex, and the treatment x 
sex interaction term. The differential effect of sex is significant if the p-value of the test of interaction 
effect is less than 0.05. 
 
9.4.2 ANALYSIS OF THE PRIMARY ENDPOINT(S) 
 
Pain Intensity - The goal of this analysis is to test the effectiveness of PainTRAINER vs. EaseVRx in 
decreasing reported pain intensity. The trial will be a success if there is statistical evidence that either 
PainTRAINER or EaseVRx is more effective in reducing pain intensity. The primary outcome will be the 
baseline vs. week 8 difference-in-difference in 7-day average NRS pain intensity scores, dichotomized 
into if the MCID of 2 is achieved. The between arm difference of achieving the MCID of 2 will be tested 
using Chi-squared test. 
 
Additionally, we will use a logistic regression to determine whether the odds of achiving the 
MCID of 2 is different between the two groups after accounting for baseline-scores by including 
them as one of the predictors. 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Pain Interference, Pain Catastrophizing, Coronavirus-Related Anxiety, and Self-Efficacy 
The goal of these analyses is to test the difference in the effectiveness of PainTRAINER vs. EaseVRx in 
decreasing pain interference, pain catastrophizing, anxiety, and self-efficacy. While the concepts 
measured are different, and the tests of change distinct, the analysis approach will be similar for all 
PROs. Independently for each PRO, a two-sample t-test will be used to compare differences-in-
differences between the arms. Additionally, we will use an analysis of covariance (ANCOVA) to 
determine whether the average gain is different between the two groups after controlling for baseline-
scores by including them as covariates. If assumptions of ANCOVA are not met, we will consider 
generalized linear models, including ordered logistic regressions to determine whether the proportional 
odds of average gain in the scale are different between the two groups after controlling for baseline-
scores by including them as covariates. 
 
Opioid Usage - The goal of this analysis is to test the effectiveness of PainTRAINER vs. EaseVRx in 
decreasing weekly average milligrams morphine equivalent (MME) of prescribed medication between 
the baseline week and the week before week 8. Weekly average MME will be calculated as a 7-day 
average of daily maximum MME as prescribed. Analysis of this endpoint will proceed via ANCOVA, 
adjusting for subjects’ baseline MME. We will assess the assumptions underpinning the ANCOVA model 
graphically and will undertake appropriate transformation of the weekly average MME outcome as 
deemed appropriate. If no suitable transformations can be found, bootstrapped confidence intervals for 
the between-group differences in weekly MME will be produced. 
Both adjusted and unadjusted between-group comparisons will be presented with 95% confidence 
intervals. 
 
9.4.4 SAFETY ANALYSES 
All safety analyses will be descriptive. No statistical testing will be performed. 
 

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9.4.5 BASELINE DESCRIPTIVE STATISTICS 
We will summarize demographic and baseline characteristics both by treatment group and overall using 
mean and standard deviation or median and interquartile range for the continuous variables, and 
frequency and percentage for the categorical variables.  Any time-to-event counts will be measured 
from the day of randomization. Body Mass Index (BMI) will be calculated according to: BMI=weight 
(kg)/(height (m))2. Age will be calculated according to: Age=(date of event-birth date+1)/365.25. Weekly 
average opioid dosage will be calculated as a 7-day average of daily maximum milligrams morphine 
equivalent (MME) as prescribed. Zip code will be matched to median income using census data as an 
aggregate measure of socio-economic status.  
 
9.4.6 PLANNED INTERIM ANALYSES  
No formal interim analysis or interim statistical testing for treatment comparisons is planned.  
 
9.4.7 EXPLORATORY ANALYSIS 
 
The purpose of Aim 2, as described in the application, is to detect heterogeneity of treatment effect (i.e. 
differential response to the same treatment due to individual traits) on pain intensity by PainTRAINER or 
EaseVRx. The results will enable the research team to work with patient partners to make 
recommendations for optimizing deployment of home-based digital behavioral treatment across a 
diverse populace. We will investigate the predictive value of key patient characteristics, including type of 
pain condition, sex, age, race, ethnicity, State and zip code, Rural- Urban Commuting Area (RUCA) codes 
(a composite measure of population density, urbanization, and daily commuting), pain severity, opioid 
use, comorbidities, social support, and COVID-19 impacts (unemployment, financial hardship, family or 
personal COVID-19 diagnosis). The analysis for each covariate will consist of an unadjusted test of 
interaction with treatment group in a multivariate logistic regression model with responder status 
(subject achieved MCID difference or did not) as the dependent variable. These models will include fixed 
categorical effects for treatment, covariate, and treatment-by-covariate interaction. Interaction terms 
with a significance level of less than .10 will be included in full model testing. The p-values of interaction 
terms will be presented, as will the odds ratios and 95% confidence intervals by treatment and 
covariate. If multiple interaction terms demonstrate a significance level of less than .10, we will use a 
least absolute shrinkage and selection operator (LASSO) approach to variable selection. We will also use 
multivariable logit modeling with receiver operator characteristic (ROC) curve analysis to measure the 
accuracy of the resulting model in predicting achievement of an MCID response as measured by the area 
under the ROC curve by c-statistic. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 

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Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and electronic documentation of informed consent is required prior to starting screener 
week procedures.  
 
 

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10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Eligible participants will be identified by patient cohort search engines and providers at each clinical site 
and an IRB approved email explaining the study will be sent by a research coordinator from the site at 
which the patient was identified. All study staff at all sites will use the same approved scripts, emails, 
and other communication materials. These documents will be customized by site to indicate where or by 
whom the patient was seen, as indicated by “[ ]” in the IRB approved materials. The patient will be able 
to reply, within 7 days, to the eligibility letter with a request to opt-out of further study-related 
communication. A research coordinator from the recruitment site where the patient was identified will 
telephone those who do not opt out within 7 days to discuss their interest in study participation. An IRB-
approved script will explain, in lay language, that this research study is being conducted jointly between 
Ochsner, UAB, and Cedars-Sinai and that Cedars-Sinai is the site that will be running the study.  The 
script will also explain the purpose, procedures, and potential risks of the study and research rights of 
study participants. Study Coordinators will ensure the identity of the person on the phone call is indeed 
the intended patient. If the patient indicates interest in participating, the study coordinator will explain 
that the next and further communications will be from Cedars-Sinai in Los Angeles, CA, and that they 
should expect an email containing the informed consent documentation in the near future. Study staff 
at Cedars-Sinai will use REDCap to email the IRB approved electronic consent form to the patient. 
Participants will have the opportunity to carefully review the electronic consent form and ask questions 
prior to signing. Participants will complete their consent forms electronically using the 21 CFR 11-
compliant online platform, REDCap. A child assent form will be included as part of the informed consent 
to allow for adolescent participants between the ages of 14 and 17 to be enrolled.  Every subject will be 
informed of the approximate time to complete the consent process. A copy of the informed consent 
documents will be provided to participants for their records via email. The informed consent will be 
signed by the patient and the designated investigator before the participant undergoes any study-
specific procedures. The rights and welfare of the participants will be protected, and it will be 
emphasized that their medical care will not be adversely affected in any way if they decline to 
participate in this study. 
A verbal explanation will be provided in terms suited to the participant’s comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants. 
Participants will have the opportunity to carefully review the electronic consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to starting the screening week surveys. Participants must be informed that 
participation is voluntary and that they may withdraw from the study at any time, without prejudice.  
The informed consent states that any changes in pain management should be made with the 
participants treating physician.  
10.1.1 STUDY DISCONTINUATION AND CLOSURE  
We do not anticipate any events that would warrant study discontinuation and closure. 
 
10.1.2 CONFIDENTIALITY AND PRIVACY   
Participant privacy is strictly held in trust by the participating investigators, their staff, and their 
interventions. Therefore, the study protocol, documentation, data, and all other information generated 

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will be held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor.  
Representatives of the IRB or regulatory agencies may inspect all documents and records required to be 
maintained by the investigator for the participants in this study. The clinical study site will permit access 
to such records as needed. 
Data in the study are collected in three ways: in real-time, at infrequent intervals throughout the study, 
and through medical record queries. Real-time data, including survey data delivered via mobile device, 
will be stored on secure servers hosted by CSMC secure servers and will contain only a unique identifier 
for each participant. Virtual reality adherence data will also be tracked in real-time and hosted on secure 
servers by AppliedVR; a separate unique ID will be assigned to each participant. Data collected at 
infrequent intervals throughout the study, such as entry, 14-day interval assessments, and exit 
questionnaires will be stored on secure CSMC servers with unique ID's for each participant. Data 
collected from medical record numbers will reside on secure CSMC servers and an ID will be assigned to 
each individual in order to abstract PHI/PII and the medical record number. Each dataset will utilize 
different unique ID's and a list linking each unique ID to each participant will be stored internally on the 
secured CSMC network. The linking list allows a researcher with access to the secured files to merge all 
data using statistical software, while maintaining data confidentiality. 
To minimize risk of breaches in confidentiality associated with the access and recording of protected 
health information, study staff will be assigned unique passwords and usernames to access secure 
servers. Additionally, identifiable information for participants will be obfuscated using unique ID 
numbers and a linking list will be held in a secure location. 
 
10.1.3 FUTURE USE OF STORED SPECIMENS AND DATA  
N/A 
 
 

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10.1.4 KEY ROLES AND STUDY GOVERNANCE    
Role 
Name 
Contact Information 
Principal Investigator 
Brennan Spiegel, MD, MSHS 
Director of Health Services 
Research 
Cedars-Sinai Medical Center 
116 N. Robertson Blvd, Suite 
800  
Los Angeles, CA 90048 
310.423.6784 
Brennan.Spiegel@cshs.org 
  
 
 
Co-Investigator 
Yashar Eshraghi 
Ochsner Clinic Foundation 
Napoleon Bldg., Suite 950 
2820 Napoleon Ave. 
New Orleans, Louisiana 
70115 
(504) 842-5300 
yashar.eshraghi@ochsner.org 
Co-Investigator 
Jeffrey Curtis, MD, MS, MPH 
Professor of Medicine 
University of Alabama at 
Birmingham 
510 20th Street South, FOT 
802 
Birmingham, AL 35294 
205-975-2176 
jrcurtis@uabmc.edu 
 
As shown in Figure 1, below, the PI oversees the grant and interacts with all the key stakeholders, including 
NINR, the Cedars-Sinai IRB, and members of the Clinical Research Team, Data Management Team, and 
the Study Statisticians.  
 
 

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10.1.5 SAFETY OVERSIGHT     
The study will be approved by the Institutional Review Board at the coordinating site (Cedars-Sinai) prior 
to starting any component of the trial.   
This project will use the SMART IRB Master Common Reciprocal Institutional Review Board 
Authorization Agreement (SMART IRB Agreement) to support single IRB review in compliance with NIH 
Policy on the Use of a Single Institutional Review Board for Multi-Site Research. SMART IRB streamlines 
and advances collaboration by establishing a common IRB authorization agreement and standardizing 
the roles and responsibilities of all parties involved in the review and conduct of multisite research.  
Further, the SMART IRB Agreement outlines the responsibilities of all Participating Institutions, the 
Reviewing IRB, and Relying Institutions, in addition to detailing the communication plan between the 
Reviewing IRB and Relying Institutions. 
Each engaged institution has joined SMART IRB by signing a Joinder Agreement to the master SMART IRB 
Agreement, thus avoiding the need for protracted negotiations about reliance details. Cedars-Sinai IRB 
has agreed to serve as Reviewing IRB, and the Relying Institutions (Ochsner and UAB), have agreed to 
cede review.  
The sites have agreed that IRB review, regulatory oversight, and roles and responsibilities of the parties 
will be governed by the SMART IRB Agreement and the SMART IRB Standard Operating Procedures 
throughout the life of the project.   

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In joining SMART IRB, each site has designated a Point of Contact (POC) to provide the Reviewing IRB 
with knowledge about local context and facilitate coordination among the sites.  
Given that this is a low risk study with centralized oversight by the reviewing IRB we do not believe that 
a separate Data Safety Monitoring Board (DSMB) will needed. 
Personnel: 
The Reviewing IRB at Cedars-Sinai will be composed of staff at Cedars-Sinai Medical Center with 
experience with randomized control trials in patients and expertise in pain management and patient 
reported outcomes. 
In accordance with the SMART IRB Agreement and SOPs: 
o 
Dr. Brennan Spiegel will serve as the Overall PI will serve as the primary contact on the Lead 
Study Team, and will distribute the results of IRB reviews and manage ongoing communications across 
site study teams. 
o 
The POC for the Reviewing IRB will ensure appropriate communication with Relying Institution 
POCs.  
o 
The POC at UAB will be Cassie Clinton. 
o 
The POC at Ochsner will be Tracy Jones. 
The Project Manager at Cedars-Sinai will be responsible for ensuring ongoing communication with all 
participating study teams via teleconferences and regular emails throughout the study. Key 
communication points will occur to: 
o 
Disseminate IRB determinations and IRB-approved documents 
o 
Educate study teams regarding the approved study and amendments to the study 
o 
Alert study teams to problems that may affect the conduct of the study or the rights and welfare 
of research participants, such as unanticipated problems and serious noncompliance 
o 
Inform study teams of any changes in study status (e.g., temporary suspensions of recruitment) 
or new information 
o 
Facilitate submissions to the Reviewing IRB, including:  
o 
Inclusion of site-specific requirements in consent documents 
o 
Identification of any variability in study implementation across sites that must be communicated 
to the Reviewing IRB 
o 
Collection of information from participating sites to include in continuing review reports to the 
Reviewing IRB 
o 
Site-specific amendments 
o 
Personnel updates (as required by the Reviewing IRB) 
o 
Reportable events (e.g., noncompliance, unanticipated problems) 
o 
Closure reports 
○ 
Ensure revisions to applicable conflict of interest management plans are provided to the 
Reviewing IRB 

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Purpose: 
The primary goals of the reviewing IRB are as follows: 
1. 
To monitor and advise on scientific and ethical issues related to the study implementation for 
the protection of human subjects 
2. 
To review and approve the protocol and subsequently conduct annual reviews to determine 
whether participant safety has been adequately safeguarded 
3. 
To review procedures and decisions regarding the adequate protection of specific participants 
when investigators break protocol because of adverse events or clinical deterioration 
4. 
To review progress to see that enrollment goals have been met 
5. 
To monitor and advise on ethical issues related to adverse events 
6. 
To oversee the confidentiality of data, and quality of data collection, management, and analysis 
7. 
To recommend, if necessary, discontinuation, modification, or termination of the study based 
upon emerging data (in the study and literature) and evaluation of risk/benefit ratio, 
 
 
10.1.6 CLINICAL MONITORING 
Schedule and Meetings: 
The Reviewing IRB will be called upon whenever possible to render judgments in the advent of serious 
adverse event or clinical deterioration. The Reviewing IRB will meet once per year, or as needed. For 
each meeting, the Reviewing IRB will first meet in an open session attended by the principal 
investigator. The IRB will first review the research protocol and plans for data and safety monitoring. 
The IRB will review any problems in implementing the safety plan and for suggesting any necessary 
modifications to the safety plan. The reviewing IRB will then meet in a closed session for the purpose of 
reviewing emerging trial data at subsequent meetings. 
1.4 Protection of Participants: 
Confidentiality will be maintained by providing data without any identifying information to the 
committee. 
2.1 Monitoring and Recommendations: 
After the meeting, the Reviewing IRB will make recommendations to the PI. The Reviewing IRB will make 
recommendations concerning the continuation or conclusion of the study. The Reviewing IRB will 
monitor both safety and outcome data as part of the yearly review. No interim analysis is planned. 
Safety evaluations sent before the annual meeting will include review of adverse events for each 
participant. The Reviewing IRB will further consider external factors such as scientific and therapeutic 
developments that may impact the safety or the ethics of the study. The investigators will ensure that 
the Data and Safety Monitoring Plan is reviewed and approved by the reviewing IRB before the initiation 
of the study protocol.  
 
10.1.7 QUALITY ASSURANCE AND QUALITY CONTROL 
Our quality assurance (QA) and control (QC) procedures are designed to support adherence to the 
protocol, obtain complete follow-up data for all participants enrolled, and establish and maintain high 

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standards for validity in collected data ahead of analysis. We approach QA as processes and safeguards 
for the prevention of data errors, and QC as mitigation efforts reducing impact from errors that have 
occurred during data capture and/or processing. While much of the QA effort occurs ahead of study 
launch, both efforts will require real-time and periodic tasks conducted through the duration of the 
study to ensure consistent checks of data integrity, completeness, and correctness. 
QA via error prevention will focus largely on the REDCap system. Before data is entered into REDCap, 
study personnel will:  
• 
Indicate units in question stems and use field validation whenever possible; 
• 
Define and enforce range minimum/maximum where applicable; 
• 
Ensure uniformity in date formatting across all REDCap date fields; 
• 
Program pre-defined multiple-choice fields whenever possible (as opposed to free text); 
• 
Indicate specific, standardized choices to identify data as intentionally missing (e.g “Not 
Applicable,” “Don’t Know”) as opposed to blank fields; 
• 
Enforce skip/no-skip logic where appropriate; 
• 
Standardize assignment of raw values. (i.e. if “Yes” is coded as a ‘1’ in one field, it should be 
coded as ‘1’ in all other project fields); and 
• 
Use case and punctuation consistently across all field labels. 
Each aspect of the REDCap data collection system will be tested before actual study data is collected. 
Study personnel will enter mock data into REDCap forms, serving as the “User” for acceptance testing. 
We will document the success or failure of a) the user interface for data entry, b) the on-line univariate 
and range data validation checks, and c) custom functions and coding. This mock data will be exported 
as SAS/R/STATA datasets by the research coordinator and subjected to QC procedures.  
Our fundamental QC approach prioritizes error detection. Automated QC will occur in a SAS/R/STATA 
programming environment and will be tested/iterated on mock data before being employed monthly to 
exported datasets from both REDCap and the EHR. These QC programs will target potential data 
anomalies including: 
• 
Missing data or forms; 
• 
Out-of-range or erroneous data; 
• 
Inconsistent, improperly formatted, or out-of-range dates; and 
• 
Fields on a "completed form" not completed.  
Once the study begins, routine QC reports will be prepared monthly by the study statisticians. These 
reports will describe target and actual enrollment, eligible participants screened with reasons for screen 
failure, and participant disposition (enrolled; active, completed, discontinued treatment, and lost to 
follow-up). These reports will also provide proportions of forms completed/missing, as well as 
summaries of problems identified by QC processes. Changes to QC programming will be documented 
and re-tested for accuracy. 
Finally, daily monitoring for data completeness will be undertaken by the study team as a QA effort. 
Patients will initially be sent a reminder email when they have not submitted data after 2 days. If no 
response is given two additional 48-hr reminders will be sent. Research staff will attempt to contact the 
patient up to 3 times in one week.  

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10.1.8 DATA HANDLING AND RECORD KEEPING  
 
10.1.8.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Study staff will develop, test, and maintain the data capture system using a web-based data collection 
system, REDCap, as the primary source of data entry and storage. Developed by Vanderbilt University, 
REDCap is a software toolset and workflow methodology for electronic collection and management of 
research and clinical trial data. The REDCap system provides a secure, web-based application that is 
flexible and provides: 1) an intuitive interface for users to enter data and have real time validation rules 
(with automated data type and range checks) at the time of entry; 2) HIPAA compliant audit trails for 
tracking page views, data manipulation and export procedures; 3) record locking and electronic 
signature functions; 4) control over user rights to view and manipulate data; 5) a report builder capable 
of querying patient records; and 6) automated export procedures for SAS/R/STATA datasets.  
The REDCap system complies with all applicable guidelines to ensure patient confidentiality, data 
integrity, and reliability. Quality assurance and control procedures will be applied to ensure the 
completeness, validity, and accuracy of the study database. The MOOP describes data collection 
processes, database development procedures, quality control processes, and reporting in greater detail. 
EHR data will be retrieved by the Research Informatics and Scientific Computing Core (RISCC) at Cedars-
Sinai, which facilitates interaction between the research community and the Epic data warehouse and 
production environment. We will collaborate with RISCC to design queries for portions of participants’ 
records as defined in the data dictionary. The data extracts issuing from these queries will be delivered 
monthly as CSV files via Box and/or OneDrive, HIPAA-compliant cloud content management systems. 
These will then be converted to SAS/R/STATA data sets and subjected to QC procedures in a 
SAS/R/STATA environment. 
VR device metadata will be provided monthly by AppliedVR as CSV files containing timestamped records 
of content accessed at the individual device level. These records will feature a device-ID unique to each 
patient. A linking list containing study-IDs and device-IDs will be stored on a secure server behind the 
Cedars-Sinai firewall, and only associated with other study data following database lock. In order to 
monitor weekly adherence, study-staff will access a subset of the metadata limited to study-ID and 
timestamps of usage. These data will be subjected to QC procedures in a SAS/R/STATA environment. 
PainTRAINER metadata will be provided monthly by coordinator at Northwestern as CSV files containing 
timestamped records of content accessed at the individual device level. These records will feature a 
user-ID unique to each patient. A linking list containing study-IDs and user-IDs will be stored on a secure 
server behind the Cedars-Sinai firewall, and only associated with other study data following database 
lock. In order to monitor weekly adherence, study-staff will access a subset of the metadata limited to 
study-ID and timestamps of usage. These data will be subjected to QC procedures in a SAS/R/STATA 
environment. 
 
10.1.8.2 STUDY RECORDS RETENTION  
In compliance with Protection of Human Subjects regulations, records related to the conduct of this 
trial, including but not limited to source documentation, informed consent forms, essential study 
documentation, and documentation of IRB activities, will be retained by the Investigator for a period of 
3 years following the official close of the study.  
 
 

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10.1.9 PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol. The noncompliance may be 
either on the part of the participant, the investigator, or the study site staff. As a result of deviations, 
corrective actions are to be developed by the site and implemented promptly.  
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
A protocol deviation is any noncompliance with the clinical trial protocol. The noncompliance may be 
either on the part of the participant, the investigator, or the study site staff. As a result of deviations, 
corrective actions are to be developed by the site and implemented promptly. Protocol deviations must 
be sent to the reviewing IRB ASAP but within 5 business days of the Overall PI becoming aware of the 
deviation.  
  
10.1.10 
PUBLICATION AND DATA SHARING POLICY 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
This trial will be registered at ClinicalTrials.gov, and results information from this trial will be submitted 
to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed journals.  
Data from this study may be requested from other researchers 3 years after the completion of the 
primary endpoint by contacting the Cedars-Sinai Center for Outcomes Research and Education. 
We will also comply with the data sharing policy at NIH under NOT-OD-08-033. We will submit the final 
manuscripts to the NIH National Library of Medicine PubMed central for archiving upon acceptance for 
publication. 
 
10.1.11 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence is critical.  The Cedars-Sinai 
Identifying and Disclosing Researchers’ Financial Interests in Research Policy: Human Research 
Protection Program requires the Principal Investigator and all members of the study team to disclose 
their, their spouses’/domestic partners’, and dependent children’s financial interests in the research 
regardless of the source of funding. Additional disclosure requirements may apply to investigators 
involved in Federally-funded research as described in the Cedars-Sinai Management of Industry 
Relations and Conflicts of Interest Program Policy: Corporate Integrity Program. The Cedars-Sinai 
Institutional Review Board (IRB) retains authority to determine if the research is allowed to proceed 
under the terms of the management plan developed by IR/COI considering the potential impact on the 
process and documentation of informed consent and the equitable selection of subjects. Review of 
disclosed COIs associated with a human research protocol by 
 IR/COI is requested through submission 
of the CS-IRB COI Disclosure Form, which details IRB-supported guidelines on methods to manage, 
mitigate, or eliminate COIs.  
 
 

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10.2 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
2 
10/4/2021 
• 
Edits to verbiage in 
Objectives, SOA, and 
sections throughout  
• 
Added tablet under Criteria 5 
for inclusion criteria  
• 
Revision to loss-to-follow-
up definition  
• 
Added updates to potential 
risk/AEs sections  
• 
Edits to sample size, power 
estimation, and analysis  
• 
Edits to language regarding 
consent procedures and 
documentation  
• 
Updated contact info under 
key roles and study 
governances 
• 
Added Table 2 Validated 
codes and validation 
performance metrics for each 
COPC after references 
section 
Necessary edits 
3 
11/15/2021 
• 
(Incorrectly modified 
description of VR study 
intervention to “one of three 
software programs;” implied 
painTRAINER is loaded on 
the headset) 
• 
Clarified study documents 
may also be shipped and 
honorarium may be sent to 
participants who do not need 
to return device 
• 
PROMI Anxiety Scale added 
to SOA 
• 
 Additional instruments 
added to SOA 
• 
Reformatted Key roles and 
Governance table 
Clarifying language leftover 
from pure VR studies 
4 
1/10/2022 
• 
Added various self-reported 
querstionnaires to SOA 
• 
Updated description of 
EaseVRx intervention to 
reflect recent FDA 
authorization  
Incorporated new 
questionnaires and recruiting 
site 

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5 
2/17/2022 
• 
Updated amendment history 
for v3 and v4 
• 
Modified descriptions of 
intervention to clarify two 
different programs and 
methods of delivery 
• 
Updated schema to 
incorporate Week 12 survey 
• 
SoA updated to incorporate 
treatment usage and coping 
strategy questionnaires 
• 
Inclusion criteria #1 clarified 
to indicate that chronic pain 
conditions are not explicitly 
limited to those listed in 
tables 
• 
Fourth recruitment site 
added (Bendcare) 
• 
Supplemtary ICD-10 code 
table created to capture 
additional qualifying 
conditions identified by 
study team 
 
General cleaning of protocol, 
incorporated new 
questionnaires, fourth 
recruiting site added 
5.1 
3/4/2022 
• 
Minor edits to SOA 
Additional surveys added, 
SSQ needed to be separated 
from Week 1 
5.3 
4/5/2022 
• 
Recruitment procedures 
modified to allow for 
recruitment of individuals 
with valid email that was not 
in the electronic medical 
record 
• 
These individuals 
should be eligible for 
enrollment. 
5.4 
7/11/2022 
• 
New CRFs added about 
primary pain  
• 
Neck pain added as known 
risk 
• 
Primary complaint 
may differ from 
whichever one of 
many qualifying 
ICD-10 codes are 
found during chart 
review; neck pain 
added as risk 
5.5 
7/28/2022 
• 
Recruitment procedures 
modified to allow for 
recruitment of individuals by 
phone or email with 
elimination of 7 day waiting 
period.  
• 
Recruitment efforts 
to date suggest letters 
and waiting period 
are ineffective for 
this study population; 
all study teams agree 
that removing email 

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• 
Compliance procedures 
modified to allow for student 
interns with restricted access 
to PHI to make calls relating 
to facilitate survey 
compliance and device 
returns. 
requirements for 
contact improves 
access, equity, and 
diversity of potential 
study population. 
• 
Some basic tasks 
involving brief 
interactions with 
patients to be 
delegated to student 
interns when 
possible. 
5.6 
9/19/2022 
• 
Microsoft OneDrive added 
as possible secure cloud data 
management system 
• 
OneDrive has 
features favorable to 
study staff that Box 
cannot accommodate; 
several study 
processes  
5.7 
10/21/2022 
• 
Onboarding procedures 
modified to take into account 
new instructional videos 
• 
Compliance procedures 
clarified and modified to 
account for optional SMS text 
messaging via REDCap 
• 
Onboarding procedures 
now incorporate clear 
video instructions, and 
compliance monitoring 
updated to reflect 
current streamlined 
practices  
6.0 
3/28/2023 
• 
Exclusion criteria expanded 
to include history of seizure 
and prior exposure to either 
study intervention  
• 
Screener week failure criteria 
modified to exclude if any of 7 
pain journals incomplete, 
housekeeping to reflect 
contents of finalized screener 
week surveys and procedures 
• 
Monitoring procedures 
expanded to allow for 
optional onboarding phone 
call, as instructional materials 
have for many patients 
rendered technical support 
calls obsolete. Patients may 
now use email confirmation to 
begin study procedures (see 
new study document "Study 
Onboarding 
Communications") 
• 
Survey expirations (active 
and screening) clarified and 
follow-up procedures 
modified to provide flexibility 
to study staff and statisticians 
• 
Survey procedures 
modified following 
findings of 2022 
monitoring visit by 
CS-IRB.  
• 
Onboarding 
procedures 
streamlined to ease 
patient burden and 
adjust for changes to 
call screening for 
unknown numbers, 
which may cause 
participants to be 
unfairly withdrawn. 

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Defined expectation of survey 
missingness 
6.1 
8/21/23 
• 
Included protocol for study 
staff to contact individuals 
who have not signed the ICF  
• 
Modified definition of 
replaceable participant to 
exclude individuals who used 
VR intervention before 
withdrawing from study 
• 
Contacting screened 
participants to 
possibly assist with 
eConsent can be used 
to improve sample 
diversity and 
enrollment.  
• 
Study adequately 
powered based on 
withdrawals to date, 
and analyses should 
include individuals 
who found the 
intervention 
unsatisfactory and 
subsequently 
withdrew 
6.2 
10/17/23 
Compliance procedures modified to 
allow a participant's recruiting site 
study staff to contact via patient 
portal when allowed by their local 
IRB. 
Study team is having difficulty 
contacting participants at non-
CSMC from a California 
phone. 
 
 
 
 
 
 
 

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Table 2. 
Validated codes, and validation performance metrics 
for each COPC. 
COPC/Search terms 
ICD-10 Code 
N with 
code 
N captured by 
search terms, 
% 
True Positive, 
% 
False 
Negative, % 
Fibromyalgia 
M79.7 
8401 
8263, 98.4% 
19/20 95% 
0/200% 
• Fibromyalgia 
• fibrositis 
• fibromyalgia syndrome fibromyositis 
• FMS 
• diffuse myofascial pain syndrome 
  
  
  
  
  
  
Irritable Bowel Syndrome 
K58.0 
5551 
5551, 100% 
20/20 100% 
0/110% 
• irritable bowel syndrome 
• irritable bowel 
• irritable colon 
• IBS 
• mucous colitis 
• spastic colon 
• nervous colon 
K58.1 
1350 
1350, 100% 
K58.2 
1459 
1459, 100% 
K58.8 
239 
239, 100% 
K58.9 
9828 
9817, 99.9% 
  
  
  
  
  
  
Interstitial Cystitis/Bladder Pain Syndrome 
N30.10 
2111 
2110, 99.9% 
19/20 95% 
0/10% 
• interstitial cystitis 
• bladder pain syndrome 
• painful bladder syndrome 
• IC/BPS 
• IC/PBS 
• (“chronic pelvic pain” AND “urinary symptoms”) 
N30.30 
23 
23, 100% 
Chronic Prostatitis 
N41.1 
310 
308. 
19/20 
0/2 
• chronic prostatitis 
• inflammatory prostatitis 
• (“chronic” AND “prostatitis”) OR (“prostatitis” AND “unspecified”) 
  
  
99.3% 
95% 
0% 
  
  
  
  
  
  
Vulvodynia 
N94.810 
184 
184, 100% 
18/20, 90% 
0/1, 0% 
• Vulvodynia 
• Vestibulodynia 
• vulvar vestibulitis 
• vulvitis 
• vulvar discomfort 
N94.818 
1872 
1871, 99.9% 
N94.819 
76 
76, 100% 
  
  
  
  
  
  
Migraine 
G43.XXX 
(exclude G43.6- 
[cerebral infarct] 
and G43.A- / 
[cyclical 
vomiting] 
34604 
34,567, 
99.9% 
20/20, 
100% 
0/20, 0% 
• Migraine 
• Migraines 
• sick headache 
• chronic daily headache 
• status migrainosus 
  
  
  
  
  
  
Chronic tension-type headache 
G44.201 
168 
168, 100% 
20/20, 
100% 
1/20, 5% 
• tension headache 
• tension type headache 
• stress headache 
• tension-vascular headache 
G44.209 
2873 
2835, 98.6% 
G44.211 
42 
42, 100% 
G44.219 
809 
808, 99.9% 
G44.221 
447 
446, 99.8% 
G44.229 
1274 
1272, 99.8% 
  
  
  
  
  
  

Transcending COVID-19 barriers to pain care in rural America: Pragmatic comparative effectiveness trial of evidence-based, on-
demand, digital behavioral treatments for chronic pain 
Version 5 
Protocol  
February 24, 2025 
 
 
54 
COPC/Search terms 
ICD-10 Code 
N with 
code 
N captured by 
search terms, 
% 
True Positive, 
% 
False 
Negative, % 
Temporomandibular disorder 
M26.60 
1293 
1265, 97.8% 
18/20, 90% 
9/20, 45% 
• temporomandibular disorder 
• TMD 
• temporomandibular joint disorder 
• TMJD 
• temporomandibular joint disease 
• ((“temporomandibular” AND (“disease” OR “disorder”)) 
• TMJ syndrome 
• TMJ arthralgia 
• TMJ tenderness 
• TMJ pain 
• TMJ disease 
• TMJ dysfunction 
• temporomandibular joint syndrome 
M26.62 
1474 
1462, 99.9% 
M26.63 
616 
614, 99.7% 
S03.0XXA 
326 
293, 89.8% 
  
  
  
  
  
  
Chronic low back pain 
M54.5 
43,850 
33,169, 
75.6% 
19/20, 95% 
8/20, 40% 
• back pain chronic~6 
• back pain persistent~6 
• back pain recurrent~6 
• back pain unspecified~6 
• back pain nonspecific~6 
• back pain idiopathic~6 
• back pain functional~6 
M54.40, 41, 
42 
10649 
9470, 88.9% 
M54.89 
804 
644, 80.1% 
  
  
  
  
  
  
Chronic fatigue syndrome 
R53.82 
8917 
8916, 99.9% 
20/20, 
100% 
0/1, 0% 
• chronic fatigue 
• chronic fatigue syndrome 
• myalgic encephalomyelitis 
• CFS 
• ME/CFS 
• systemic exertion intolerance disease 
• SEID 
  
  
  
  
  
  
Endometriosis With pain 
N80.XXX AND 
1586 
1561, 98.4% 
18/20, 90% 
6/20, 30% 
• endometriosis pain~4 
• endometriosis painful~4 
• endometrioma pain~4 
• endometrioma painful~4 
• adenomyosis pain~4 
• adenomyosis painful~4 
• ((“endometriosis” OR “endometrioma” OR “adenomyosis”) AND 
(“pelvic pain” OR “dysmenorrhea” OR “dyspareunia” OR “intercourse 
pain”~4 OR “intercourse painful”~4)) 
(“R10.2” OR 
“N94.4” OR 
“N94.5” OR 
“N94.6” OR 
“N94.10 “ OR 
“N94.11 “ OR 
“N94.12 “ OR 
“N94.19 “) 
  
  
  
  
 
 
 

Transcending COVID-19 barriers to pain care in rural America: Pragmatic comparative effectiveness trial of evidence-based, on-
demand, digital behavioral treatments for chronic pain 
Version 5 
Protocol  
February 24, 2025 
 
 
55 
Table 3. 
Additional codes identified by study team which capture chronic pain conditions. 
ICD-10 
Code 
Description 
M05.* 
Rheumatology 
M06.* 
M45.* 
M46.* 
L40.5* 
M1A.* 
M15.* 
M16.* 
M17.*