Development and Validation of a Digital Pain-Reduction Kit for Musculoskeletal Injuries
Phase: NA
Conditions: Pain, Acute, Pain, Chronic
Sponsor: Cedars-Sinai Medical Center

Development and validation of a digital pain-reduction 
kit for  
musculoskeletal injuries 
Protocol Number: Pro00049015 
National Clinical Trial (NCT) Identified Number:  NCT03187132 
Principal Investigator: Brennan Spiegel, MD 
Sponsors: Travelers Insurance, Samsung, appliedVR 
Funded by: Travelers Insurance 
Version Number:  v.6.4 
30 August 2019 
Original: 22 February 2018 
Most recent changes highlighted in yellow 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
5.2, 5.5, 8.1 
EMA added, new Aleve unit contraindications, 
summary of LBP patient sampling 
 
1.3,2.2, 4.1, 
8.1, 6.1.1, 7.2, 
5.1, 2.3.1, 
2.3.3, 5.5, 
10.1.5 
Clarified number of visits, clarified focus on 
orthopedic injuries, updated sample size for 
consistency, added language on phone and 
equipment, modified inclusion criteria for 
smartphones, added data risks/mitigation, 
recruitment update, removed Bayer 
HealthCare from study funding/sponsorship 
IRB Approval 
4.1, 5.1 
Clarified recruitment strategy for LBP 
 
1.1, 1.3, 4.1, 
5.2, 6.1.1, 8.1, 
9.1 
Change from CG-CAHPS to different patient 
satisfaction questionnaire, added TENS 
protocol for all patients, and redefined 
digitalist physician as clinical health coach 
 

NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
  
ii 
1.1,2.1, 
2.2,5.1,5.2,5.5, 
6.1.1,10.1.1.2, 
Change in eligibility with clarifications made 
in other sections to reflect this change.  
This will allow patients at new clinical sites 
to be involved in the study and allow 
recruitment of LBP patients.  
6.1.1 
Change in technology used to display 
audiovisual content for the patient.  
The new technology will be far easier for 
the patients to use at home.  
5.5, 8.1 
Specific letters provided to patients, addition 
of Redcap as a method to collect PROs 
For the patients comfort a letter tailored to 
the treating provider will be added, Redcap 
was added to increase the number of ways 
patients could provide PROs. 
6.1.1 
PICO G2 added as another VR headset that 
patients may receive. 
An update to the Oculus software rendered 
the intervention software inoperable.  The 
software vendor has started to use a 
different but comparable VR headset. The 
headset they are using is called the PICO 
G2. It will have the exact same software 
provided to the patient as what was 
provided via the Oculus Go.   
1.1, 5.5 
Medical College of Wisconsin (MCW) 
added as fourth screening and enrollment 
site. 
The study is now multi-site with the 
addition of Medical College of 
Wisconsin (MCW) to accelerate 
recruitment rates. 
9.2 
Increased total sample size to 145 
A greater number of patients are 
required to maintain statistical power 
due to an unanticipated number of 
withdrawals due to low survey 
compliance. 

  
  
ii 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 3 
1 
PROTOCOL SUMMARY ............................................................................................................................... 4 
1.1 
Synopsis ................................................................................................................................................ 4 
1.2 
Schema ................................................................................................................................................. 6 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 7 
2 
INTRODUCTION ............................................................................................................................................ 7 
2.1 
Study Rationale .................................................................................................................................... 7 
2.2 
Background........................................................................................................................................... 7 
2.3 
Risk/Benefit Assessment .................................................................................................................... 7 
2.3.1 
Known Potential Risks ..................................................................................................... 8 
2.3.2 
Known Potential Benefits ................................................................................................ 8 
2.3.3 
Assessment of Potential Risks and Benefits ................................................................ 8 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 8 
4 
STUDY DESIGN ........................................................................................................................................... 10 
4.1 
Overall Design .................................................................................................................................... 10 
4.2 
Scientific Rationale for Study Design.............................................................................................. 10 
4.3 
Justification for Dose ......................................................................................................................... 10 
4.4 
End of Study Definition ..................................................................................................................... 10 
5 
STUDY POPULATION ................................................................................................................................ 10 
5.1 
Inclusion Criteria ................................................................................................................................ 10 
5.2 
Exclusion Criteria ............................................................................................................................... 11 
5.3 
Lifestyle Considerations .................................................................................................................... 11 
5.4 
Screen Failures .................................................................................................................................. 11 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 11 
6 
STUDY INTERVENTION ............................................................................................................................ 12 
6.1 
Study Intervention(s) Administration ............................................................................................... 12 
6.1.1 
Study Intervention Description ..................................................................................... 12 
6.1.2 
Dosing and Administration ............................................................................................ 16 
6.2 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 16 
6.3 
Study Intervention Compliance ........................................................................................................ 16 
6.4 
Concomitant Therapy ........................................................................................................................ 16 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 17 
7.1 
Discontinuation of Study Intervention ............................................................................................. 17 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 17 
7.3 
Lost to Follow-Up ............................................................................................................................... 17 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 18 
8.1 
Efficacy Assessments ....................................................................................................................... 18 
8.2 
Safety and Other Assessments ......................................................................................................... 1 
9 
STATISTICAL CONSIDERATIONS ............................................................................................................ 1 
9.1 
Statistical Hypotheses ......................................................................................................................... 1 
9.2 
Sample Size Determination ................................................................................................................ 2 
9.3 
Populations for Analyses .................................................................................................................... 3 
9.4 
Statistical Analyses.............................................................................................................................. 3 
9.4.1 
General Approach ............................................................................................................ 3 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................... 3 

  
  
iii 
9.4.3 
Analysis of the Secondary Endpoint(s) ......................................................................... 3 
9.4.4 
ACCOMODATING ADDITION OF TENS UNIT TO THE CONTROL ARM ............ 4 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ................................ 4 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ............................................................. 4 
10.1.1 
Informed Consent Process ............................................................................................. 5 
10.1.2 
Study Discontinuation and Closure ............................................................................... 5 
10.1.3 
Confidentiality and Privacy ............................................................................................. 6 
10.1.4 
Future Use of Stored Specimens and Data ................................................................. 6 
10.1.5 
Protocol Deviations .......................................................................................................... 6 
10.1.6 
Publication and Data Sharing Policy ............................................................................. 7 
10.1.7 
Conflict of Interest Policy ................................................................................................ 7 
10.2 
Additional Considerations ................................................................................................................... 7 
10.3 
Protocol Amendment History ............................................................................................................. 9 
11 
REFERENCES ............................................................................................................................................. 11 
 
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. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted 
to the 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. 
 
 

  
  
4 
  
1 
 
PROTOCOL SUMMARY 
  
1.1 
SYNOPSIS  
Title: 
Development and validation of a digital pain-reduction kit for 
musculoskeletal injuries 
Study Description: 
This study will test the effectiveness of an evidence-based, multi-modal, 
"digital pain-reduction kit" as a non-pharmacological supplement to 
managing patients with pain due to musculoskeletal injuries. Outpatients 
will be randomized to receive either the pain reduction kit or an active 
control. The kit will contain a virtual reality (VR) headset, therapeutic VR 
visualization software, a low-cost wearable transcutaneous electrical 
nerve stimulation (TENS) unit. The control group will receive a TENS unit; 
they will not receive VR, or remote coaching. Study devices will be 
delivered to the patient's home with instructions for use; patients will 
receive remote clinical and technical support. Patients will be followed for 
60 days and monitored for functional status, pain levels, use of pain 
medications (including opioids), satisfaction with care, and time to 
returning to work.  Participants will also be asked to consent/authorization 
to access medical records from their treating facility (if a non-CSMC site). 
Objectives: 
 
Primary Objective: The primary objective of this study is to develop and 
validate a multi-modal digital pain reduction kit for improving physical 
function over time. 
 
Secondary Objective: The secondary objective of this study is to 
investigate the efficacy of a multi-modal digital pain reduction kit in 
reducing pain interference over time, work productivity, opioid use, and 
satisfaction with care.  
Endpoints: 
Primary Endpoint: The primary outcome measures in this study are weekly 
surveys (PROMIS® PF short-form) of self-reported physical function. 
Secondary Endpoints: The secondary outcome measures in this study are 
pain interference (PROMIS® Pain Interference), work absenteeism and 
presenteeism (WPAI:LB), number of 90 Morphine Milligram Equivalent 
opioid prescriptions, and satisfaction with healthcare (Pain Treatment 
Satisfaction Scale and SF Patient-Satisfaction Questionnaire). 
Study Population: 
The study consists of 174 English adults (75 intervention; 75 control with 
TENS; 24 control without TENS) in the Greater Los Angeles Area presenting 
with pain from musculoskeletal injuries. 
Phase: 
N/A 
Description of 
Sites/Facilities Enrolling 
Participants: 
Cedars-Sinai Medical Center Orthopedic Clinic 
Cedars-Sinai Medical Delivery Network (MDN) 
Medical College of Wisconsin (MCW) 
Description of Study 
Intervention: 
Participants assigned to the control arm will receive standard of care, TENS 
unit. Participants assigned to the intervention will receive standard of 
care, plus the following study components: 
- 
Virtual reality headset with integrated video experiences (3x daily) 

  
  
5 
- 
Transcutaneous electrical nerve stimulation unit for pain reduction 
(used as needed) 
- 
Remote clinical and technical support (opt-in, then health coach-
initiated) 
Study Duration: 
16 months 
Participant Duration: 
60 days 
 
 

  
  
6 
Control Arm: 
Usual Care + TENS and 
wrist-worn sensor 
Intervention Arm: 
Digital Pain Reduction Kit and 
wrist-worn sensor 
 
 
1.2 
SCHEMA 
Prior to  
Enrollment 
 
 
 
 
 
 
 
 
 
 
Visit 1 
Day 1 
 
 
 
 
 
 
 
 
 
Visit 2 
Day 60 
 
 
 
Obtain informed consent. Screen potential participants by inclusion and exclusion criteria; 
obtain history, document. 
Administer initial study intervention kits.  
See Section 1.3, Schedule of Activities 
Final Assessments 
See Section 1.3, Schedule of 
Activities 
Remote monitoring of participants 
See Section 1.3, Schedule of Activities 
Randomize 

  
  
7 
1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures 
Screening 
Day -7 to -1 
Visit 1, Day 1 
Day 7  +/-1 day 
Day 14 +/- 1 day 
Day 21 +/-1 day 
Day 28 +/-1 day 
Day  35 +/-1 day 
Day 42 +/-1 day 
Day 49 +/-1 day 
Day 56 +/-1 day 
Final Study Visit 2 
Day 60 +/-1 day  
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
EHR data (opioid use) 
 
X 
 
 
 
 
 
 
 
 
X 
Administer study intervention kits 
 
X 
 
 
 
 
 
 
 
 
 
Intervention (Virtual reality) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Intervention (TENS) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PROMIS® questionnaires 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess absenteeism and presenteeism (WPAI) 
 
X 
 
 
 
 
 
 
 
 
X 
Satisfaction with pain treatment and healthcare 
 
 
 
 
 
 
 
 
 
 
X 
Collect VR compliance data 
 
X 
------------------------------------------------------------------------ 
X 
Remote clinical and/or technical support 
 
X 
------------------------------------------------------------------------ 
X 
Collect study intervention kits 
 
 
 
 
 
 
 
 
 
 
X 
 
Note: Participants will only have two site visits, the SoA illustrates additional days for remote measurement. Site visit days are labeled as “Visit 1” and 
“Visit 2.” 
 
2 
 
INTRODUCTION 
 
 
2.1 
STUDY RATIONALE  
 
The aim of this randomized, controlled trial (RCT) is to assess the relative benefits of using 
a digital pain-reduction kit (including virtual reality unit, transcutaneous electrical nerve stimulation unit, and remote 
clinical support) for pain management outcomes – including functional status, pain interference, work productivity 
and activity impairment, usage of pain medication, and satisfaction scores in a cohort of patients with pain related to 
musculoskeletal injuries. 
 
2.2 
BACKGROUND  
 
Pain from musculoskeletal injuries is a prevalent and expensive condition that negatively impacts health 
related quality of life (HRQOL), diminishes functional status, and leads to a high rate of work absenteeism. Some 
patients with musculoskeletal injuries, including lower back pain, turn to opioids, a class of medications that may 
provide effective analgesia but can lead to opioid use disorder, opioid-related overdoses and serious adverse events, 
including death. The average time lost for workers using opioids can total as much as $117,000 per insurance claim – 
a value that is 900% higher than the cost of claims for workers who do not take opioids. From both a clinical and 
health economic perspective, it is vital to identify opioid-free treatments to assist in the management of pain caused 
by musculoskeletal injuries. 
 
 
 
2.3 
RISK/BENEFIT ASSESSMENT   

  
  
8 
 
 
2.3.1 KNOWN POTENTIAL RISKS  
 
Short-term risks associated with the study may include minor psychological distress from questionnaires regarding 
health and employment status, acute virtual reality discomfort (e.g., headache, vertigo, nausea), and minor side 
effects from transcutaneous electrical nerve stimulation (e.g., muscle twitching, muscle soreness, skin irritation). 
There are no anticipated long-term risks from participating in this study.  
Participants may elect to receive standard of care in lieu of participation in the study. 
There are some risks associated with the electronic collection and transmission of protected health information for 
the purpose of research. Unanticipated breaches of data may result in exposure of confidential information to 
individuals outside of study staff. 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
Potential immediate benefits include reduction of pain due to musculoskeletal injuries and global improvements in 
psychological health. Potential long-term benefits include improved functionality and work productivity, reduced 
opioid use, and improves in global physical health. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
The TENS unit is an FDA-approved over-the-counter consumer-grade device and is contraindicative in women who 
are pregnant. Pregnant women were excluded from the study to minimize risk from the TENS unit. Virtual reality 
hardware and software has advanced significantly this decade and sophisticated motion tracking eliminates helps to 
minimize discomfort among participants. Modern studies utilizing VR have found general satisfaction with devices 
among participants. Still, individuals with neurological disorders or hypersensitivity to lights were excluded to 
minimize risk from VR exposure. Participation in the study may alleviate pain among individuals who have previously 
relied on opioids, subsequently decreasing both opioid-induced side effects and providing pain relief. Sustained pain 
relief may allow individuals to return to work faster, improve physical mobility, and enhance biopsychosocial health. 
We believe the short- and long-term anticipated benefits outweigh minimal short-term risks. 
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. 
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
The primary objective of this study 
is to develop and validate a multi-
modal digital pain reduction kit for 
improving physical function over 
time. 
 
The primary endpoint in this study is 
a clinically significant change in self-
reported physical function over time 
among individuals in the intervention 
arm compared to those in the active 
control. The outcome measure used 
to quantify this endpoint is the 
PROMIS® PF short-form, a validated 
self-report of physical function. The 
The PROMIS® PF short-
form scale is a widely 
validated instrument 
with excellent content 
validity, construct 
validity, and reliability 
in patients with spinal 
disorders and other 
conditions marked by 

  
  
9 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
outcome measure is administered on 
a weekly basis via a smartphone 
survey to capture longitudinal change 
and variation among participants. 
diminished mobility. 
The outcome measure 
allows us to place 
patients on a 
continuum of physical 
function with respect 
to various physical 
actions. 
Secondary 
 
 
The secondary objective of this 
study is to investigate the efficacy 
of a multi-modal digital pain 
reduction kit in reducing pain 
interference over time, work 
productivity, opioid use, and 
satisfaction with care.  
The secondary endpoints of are 
clinically significant changes in pain 
interference, work productivity, use 
of opioids, and satisfaction with 
healthcare among those in the 
intervention arm compared to 
participants in the active control. 
Outcome measures include pain 
interference (PROMIS® Pain 
Interference, measured weekly via 
smartphone surveys), work 
absenteeism and presenteeism 
(WPAI:LB, measured at baseline and 
exit surveys), number of 90 Morphine 
Milligram Equivalent opioid 
prescriptions (obtained via 
cumulative EHR records), and 
satisfaction with healthcare (CG-
CAHPS, measured once at the 
conclusion of the study). 
 
Tertiary/Exploratory  
 
 
N/A 
N/A 
 
N/A 
 
 
 

  
  
10 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
This RCT will enroll 174 patients with pain due to musculoskeletal injuries to test the efficacy of a multi- model digital 
pain reduction kit on short term pain management as an adjunct to traditional medical therapy. We will attempt to 
enroll a minimum of 90 patients reporting lower back pain specifically, as patients without lower back pain are less 
likely to use the TENS unit. Prior to adding the TENS unit to the control arm, we recruited 24 control patients. 
However, we will not discard their data since we intend on performing a supplementary sensitivity analysis. In 
addition to these 24 controls, we will randomize 75 patients to receive the study intervention (multi-modal digital 
pain-reduction kit with optional remote coaching support), and the other 75 patients will receive an active control. 
We will allocate patients using a random number generator to ensure that there is an equal distribution of 
participants in the control vs. experimental group. The primary outcome will be changes in self-reported physical 
function measured by the Patient Reported Outcome Measurement Information System (PROMIS®) Physical 
Function Scale. Secondary outcomes will include PROMIS® Pain Interference Scale, PROMIS® Global Health Scale, 
work productivity and activity impairment questionnaire (WPAI) (for patients with lower back pain specifically), 
patient satisfaction measured by the Pain Treatment Satisfaction Scale and SF Patient-Satisfaction Questionnaire), 
and use of opioids (measure in morphine milligram equivalents). 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
The active control group in the randomized control trial minimizes biases related to reactivity administering standard 
care of care in addition to a passive measurement component. Therefore, the control group may show some effect 
and limit the effect size of the intervention, given that TENS units have been shown to reduce pain, at least in the 
short term.  
 
4.3 
JUSTIFICATION FOR DOSE 
 
The TENS unit and VR are to be used as needed during patient flares of pain. The three daily doses are a 
recommendation and patients may deviate as necessary contingent on their pain levels. 
 
 
4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed all components of the study 
including the last visit shown in the Schedule of Activities (SoA), Section 1.3. 
 
The end of the study is defined as completion of the last visit shown in the SoA in the trial globally. 
 
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: 
 

  
  
11 
1. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study procedures and availability for the duration of the study  
3. Male or female, aged 18 or older 
4. Seeking care for a musculoskeletal injury  
5. Experiencing pain greater than 3 out of 10 on a visual analog scale 
6. English speaking 
7. Owns a compatible Android or iOS smartphone device (excluding tablets) 
 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
1. Unable to understand the goals of the study due to cognitive difficulty 
 
2. Pregnant (contraindication for TENS unit) 
3. Use of a cardiac pacemaker, implanted defibrillator, or other implanted metallic or electronic device or high 
frequency surgical equipment. (contraindication for TENS units) 
4. Current diagnosis of epilepsy, dementia, or other neurological disease that may prevent use of VR hardware 
or software 
 
5. Hypersensitivity to flashing light or motion 
6. Injury to the eyes, face, neck, or arms that prevents comfortable use of VR hardware or software, or safe use 
of other study hardware (e.g., open sores, wounds, or skin rash on face) 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
N/A 
 
5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are not subsequently 
randomly assigned to the study intervention or entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any serious adverse event (SAE). 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a will not be 
rescreened.  
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Male and female participants above the age of 18 will be screened to reach target enrollment 174 patients over a 
period of 16 months. Participants presenting with pain due to a musculoskeletal injury will be screened and enrolled 
at four sites (Cedars Sinai Orthopedic Clinic, Medical Delivery Network, Cedars Sinai Pain Management Clinic, 
Medical College of Wisconsin). Patients will be identified and approached by their providers. The treating physicians 
will contact their patients during their clinic visits and assess the patient’s willingness to be contacted about the 
research and the treating physician will document the patient’s willingness to be contacted on the CSMS Research 
Interest letter. The Research Letter will be tailored to each clinical practice of the treating provider.  Additionally, 
participating providers will distribute recruitment pamphlets to patients in clinic and/or through mail. Should the 
patient be interested in being contacted about the study, the study team will then approach the patient for 

  
  
12 
participation in the research either in person or over-the-phone. The patient will have the option to complete their 
consent forms on paper or electronically using the 21 CFR 11-compliant online platform, DocuSign. Every subject will 
be informed of the approximate time to complete the consent process. Consenting will be done with a research staff 
member either in-person or remotely via DocuSign to ensure the identity of the person signing the informed consent 
form is indeed the subject participating in the research study. A copy of the informed consent documents will be 
given to the participants for their records via their email or a physical hard copy. Participants who consent remotely 
will receive their study equipment through a secure FedEx package requiring a signature.  Retention to the 60-day 
study for the intervention group will be managed using weekly reminders to complete survey protocols, as well as 
optional opt-in monitoring of compliance and health data via remote clinical and technical support staff. Participants 
will not receive monetary compensation for participating in this study. 
 
Participants experiencing lower back pain will be oversampled to a minimum of 45 per arm in order to obtain 
sufficient sample size for testing the success of the TENS unit. 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
Study Intervention: Digital Pain Reduction Kit 
The study intervention will include evidence-based digital devices that offer non- pharmacological solutions to 
managing pain. Patients in the intervention group will receive access to two devices: (1) Oculus Go headset or PICO 
G2 headset with preloaded therapeutic visualization software developed by appliedVR; (2) Aleve® Direct Therapy 
TENS Device. Study staff will monitor patient progress remotely and provide guided support and coaching. The 
sections, below, describe the components of the intervention. 
Smartphone, VR Headset, and Software 
To care for the whole patient, clinicians must consider not only the physical impact of illness, but also the 
psychosocial impact. However, the dynamic nature of clinical medicine, coupled with limited time to spend with 
individual patients, pose challenges to offering holistic care for patients with pain. 
Treatment of pain is often focused on pharmacological management which can yield inconsistent and sub-optimal 
pain control.[2] However, extensive data reveal that adjunctive non-pharmacological techniques, such as cognitive 
behavioral therapy and relaxation techniques, can modify cognitions and behaviors that influence the perception of 
pain.[3] VR technology provides an immersive, multisensory, and three-dimensional (3D) environment that enables 
users to have modified experiences of reality by creating a sense of “presence”.[4 5] To date, VR has been used in 
numerous clinical settings to help treat anxiety disorders, control pain, support physical rehabilitation, and distract 
patients during wound care.[4-12] For example, VR coupled with medication is effective in decreasing pain during 
bandage changes for severe burns.[6 10 13 14] Similarly, VR reduces pain and provides positive distraction during 
routine procedures, such as intravenous line placements[9] and dental procedures.[7 15] Other studies reveal that 
VR helps manage chronic pain conditions such as complex regional pain syndrome[16] and chronic neck pain.[17] 
Our own research shows that VR can reduce pain by an average of 24% among hospitalized patients with a wide 

  
  
13 
range of somatic and visceral pain. By stimulating the visual, auditory, and proprioception senses, VR acts as a 
distraction to limit the user’s processing of nociceptive stimuli.[5] 
However, despite the evidence and increasing media attention surrounding VR, there have been no controlled trials 
using VR at scale to manage outpatient musculoskeletal pain, particularly low back pain (the most common reason 
for worker compensation claims and lost productivity). 
This RCT will use a Oculus Go or PICO G2 all in one head mounted display that delivers VR images and sound. We 
selected the Oculus Go and PICO G2 because they are commercially available, widely used, inexpensive, have 
minimal visual latency, and are much easier for patients to use than devices used in our previous research. [18] 
Higher end tethered headsets, such as the Oculus Rift, are currently more expensive and onerous to use at scale in 
an inpatient setting.  
Users will wear the VR goggles. Detailed instructions will familiarize patients with hardware; and telephonic and 
email technical support from study staff will be available to advise patients having trouble using the equipment. 
Patients unable to use the device at home will be offered an in-person visit with study staff to troubleshoot and 
train. 
We will use the appliedVR app to offer >30 therapeutic VR experiences through the headsets. Our team has worked 
with appliedVR to curate experiences that are acceptable to a wide range of patients. The app includes a menu of 
visualizations, each mapped to a therapeutic benefit (e.g. pain reduction, anxiety reduction, mindful meditation).  
The app includes “Pain RelieVR”, a 15-minute VR experience specifically designed to treat pain in patients with 
limited mobility. Pain RelieVR is an immersive, 360-degree game experience that takes place in a fantasy world 
where the user attempts to shoot balls at a wide range of moving objects by maneuvering their head towards the 
targets. This engaging, medium-intensity activity is free of interruption, offering the user a distracting experience 
designed to reduce the perception of pain. Pain RelieVR is a non-violent and non-competitive game that 
incorporates motivational music and features positively reinforcing sounds, animation and direct messages to 
patients. Forward- facing action allows patients with limited mobility to engage without having to turn backwards or 
contort into potentially uncomfortable positions. 
The app also includes “Anxiety RelieVR,” an interactive, meditative landscape along a peaceful shoreline . In contrast 
to Pain RelieVR, which acts through distraction therapy, Anxiety RelieVR employs mindful meditation to help manage 
the affective component of pain. These cornerstone experiences are supported by a wide range of additional 
therapeutic journeys, including an Iceland flyover in a helicopter, an undersea experience, and a variety of nature-
related experiences, among many others. 
Patients can pick and choose which visualizations to watch based on their own preferences. In clinical testing, we 
asked patents to use the headset at least thrice daily, for 10 minutes per treatment period, and to also use as 
needed for breakthrough pain between treatments. The appliedVR software allows our team to monitor adherence 
with the therapy, including the visualizations selected by the user, the amount of exposure time, and the time of day 
the visualization was viewed.  
TENS Device 

  
  
14 
We will supplement therapeutic VR with TENS, another evidence-based, non-invasive, non-pharmacological pain 
reduction technique. TENS employs an electric current to stimulate nerves in a manner thought to release intrinsic 
endorphins and to block transmission of nociceptive signals. Data measuring brain function with evoked cortical 
potentials and functional magnetic resonance imaging (fMRI) suggests that TENS may suppress pain signals centrally, 
in addition to its direct peripheral benefits on the sensory nerves. Although clinical evidence is inconsistent among 
studies, types of pain (chronic vs. acute), and location of pain, TENS units have been FDA cleared as a class II device 
for many years, and consumer satisfaction with these devices is consistently high. 
Clinical data reveal benefits of TENS for lower back pain. In a recent meta-analysis of RCTs, cohort studies, and 
randomized crossover studies for TENS in lower back pain, Jauregui and colleagues determined the technique 
significantly reduces pain intensity, particularly for short term treatment (<5 weeks).[19] The authors concluded that 
TENS may lead to less pain medication usage and should be incorporated into the treatment armamentarium for low 
back pain. 
For this study, we will use an over-the-counter, consumer-facing product called the Aleve  Direct Relief TENS Device. 
This device is designed for use over the lower back for management of pain of lumbosacral origin. Treatment periods 
last 30 minutes and include three stages. In stage I, the device emits 5 minutes of high frequency stimulation (>50 
Hz) to initiate anti-nociceptive effects through diminished processing of pain signals. In stage II, the device emits 20 
minutes of low frequency stimulation (<20 Hz) to release endorphins as a second mechanism of pain reduction. The 
treatment period ends with stage III, in which another 5 minutes of high frequency stimulation is deployed with the 
aim of  maintaining  the initial pain relief established by phases I and II. Patients receive a handheld remote control 
to adjust the intensity of the electrical stimulation based on personal preference and tolerance. The device is used as 
needed for breakthrough pain, or as baseline prophylactic treatment. 

  
  
15 
 
Clinical and Technical Support 
Patients in the intervention arm will not only receive the digital pain reduction kit, but also will receive remote 
technical and clinical support from the research team. The idea is that issuing devices is usually insufficient to 
achieve behavior change; supporting those device with high-touch yet scalable care is a vital component. 
Rationale for “Digitalist” Model of Remote Clinical Monitoring 
Integrating digital technologies into a harmonized health delivery model may improve process and outcomes 
of care. If used effectively, digital health monitoring may tailor care to individual patients, extend clinicians’ 
reach outside of the hospital and clinic, improve timeliness and specificity of care, deliver proactive (not 
reactive) care, and better engage patients in their health.[20] 
Still, there are important questions we need to answer: Who will be checking all the data? How can doctors, 
who are busy in the clinical trenches, be responsible for monitoring and acting upon the data streaming off 
wearable sensors, apps, and patient-provider portals? Who has time for this? The reality is that no doctor has 
enough bandwidth to check mobile health (mHealth) data on a regular basis. Clinicians are too busy for this 
work.[20] 
One answer for moving digital health forward is to develop a new type of specialist called the “Digitalist.”[20] 
The Digitalist does not yet exist at scale, just as “The Hospitalist” did not exist prior to 1996, when Robert 
Wachter and Lee Goldman coined the term to describe a much-needed clinician to fill an unmet need for 
inpatient care.[21] Now we have an unmet need for a new clinician (though not necessarily a physician), 
trained in digital health, who will  monitor, interpret, and act upon remote patient data – in this instance 
among patients recovering from a low back injury. In this study, a health coach, acting similar to a Digitalist, 
will remotely track data from biosensors, portals, and apps, then combine the data to provide guidance with 
adhering to the intervention. 
Patients transmit actively and passively collected data through apps and portals. The Digitalist monitors the 
data, and, if needed, contacts the patient via EHR portal, telephone, or videoconferencing. If appropriate, the 
Health Coach communicates directly with clinicians, informs them of updates, and coordinates the optimal 
timing of in-person visits. The clinician may also access digital health reports, review the results with the 
patient, and make further decisions based on the data coupled with the traditional history and physical 
examination. 
This model has potential to expand care beyond the traditional clinic visit, uses visits more effectively, reduces 
avoidable admissions, and improves outcomes of care. 

  
 
 
Implementation of Health Coach Model in Intervention Arm 
In the current study, we will simulate aspects of the Health Coach model by allowing patients in the 
intervention arm to remotely share their secure mHealth data with selected members of the research team. 
VR usage data will also be transmitted remotely through the appliedVR app, allowing our team to monitor 
adherence with the VR intervention. We will assign two staff to monitor patients in the control arm: (1) 
technical support staff member, and (2) Health Coach. Patients will receive a telephone number and email to 
contact support staff as needed. The technical support staff will also reach out if there is low adherence with 
the devices, prolonged missing wearable data, or low battery power detected on the remote monitoring 
dashboard. The Health Coach will reach out if there is evidence of worsening physiologic or activity 
parameters (e.g. walking less, sleeping less, heart rate increasing) using their clinical judgment. Patients will be 
informed to contact 911 and/or call their physician directly if they experience any urgent, semi-urgent, or 
concerning signs or symptoms. The Health Coach will check mHealth data logs twice weekly on weekdays, and 
contact the patient by phone according to the patient’s stated preferences. Patients who do not want Health 
Coach remote monitoring will not receive this component of the intervention but will still be included in the 
intention-to-treat population. 
6.1.2 DOSING AND ADMINISTRATION 
 
Participants are assigned TENS devices and VR to be used as needed. Participants are also instructed to use VR 
at least three times a day. The dosage for both devices will not change throughout the study. Individuals 
assigned to remote monitoring will be continuously monitored and any action will be physician-initiated. 
Participants in the control group will receive standard of care and TENS unit. 
 
6.2 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Per the new protocol, participants will be randomized intervention or control until intervention and control 
groups each have 75 enrollees. In addition to these 150 participants, the group of 24 controls that were 
originally recruited without the TENS unit will remain accounted for in the supplementary analysis. There will 
be no blinding, as participants in the control group will be aware that they are missing components of the 
intervention as detailed in the consent form. 
 
 
6.3 
STUDY INTERVENTION COMPLIANCE 
 
Compliance to the protocol will be monitored using software for the VR modules and remote data uploads of 
survey logs. 
 
6.4 
CONCOMITANT THERAPY 
 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be recorded are concomitant prescription medications, 
over-the-counter medications, and supplements. 
 
 

  
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
Discontinuation from the use of the digital pain reduction kit does not mean discontinuation from the study, 
and remaining study procedures should be completed as indicated by the study protocol.  If a clinically 
significant finding is identified (including, but not limited to changes from baseline) after enrollment, the 
investigator or qualified designee will determine if any change in participant management is needed. Any new 
clinically relevant finding will be reported as an adverse event (AE). 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
• 
Pregnancy 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not previously recognized) 
that precludes further study participation 
The reason for participant discontinuation or withdrawal from the study will be recorded.  Subjects who sign 
the informed consent form and receive the study intervention, and subsequently withdraw, or are withdrawn 
or discontinued from the study, will be replaced. 
Participants will not be financially responsible for damage to, or loss of, equipment loaned to participants by 
investigators during this study. 
 
7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to comply to weekly surveys, misses exit 
appointment, and is unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for the final study visit: 
• 
The site will attempt to contact the participant and reschedule the exit appointment and counsel the 
participant on the importance of maintaining the assigned visit to return equipment and debrief 
(whether or not the participant chooses to complete exit surveys). 
• 
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). These contact 
attempts should be documented in the participant’s study file.  
• 
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  
 
PROMIS® Questionnaires 
The primary outcome for this study will be self-reported physical function (PF) using the PROMIS® PF short 
form scale. For patients with acute pain, PF is often diminished and patients seek return to normal function. 
The PROMIS® PF short-form scale is a widely- validated instrument with excellent content validity, construct 
validity, and reliability in patients with spinal disorders and other conditions marked by diminished mobility. 
The instrument place patients on a continuum of function from extremely low to very high across activities 
that require physical actions, ranging from self-care to more complex activities that require a combination of 
skills. 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 minimally clinically important difference (MCID) on the PROMIS® PF 
short form is 2 points, or 0.2 SD. [22] 
Secondary outcomes will include the PROMIS® pain interference scale and the PROMIS® global health scale. 
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 PROMIS® global health scale is an overall evaluation of one’s physical and mental health. We 
will include this instrument to address outcomes that are not often addressed in pain interventions, including 
fatigue and mental health. All PROMIS® measures use a 7-day recall period reflecting the previous week’s 
health status. 
To collect the patient reported outcomes (PROs) for this study, we will use ecological momentary assessment 
(EMA) software (LifeData), a HIPAA-compliant, cloud-based survey administration platform capable of 
administering surveys in real-time. We will also allow patients use Redcap as an alternative program to collect 
PROs. With this program the patient doesn’t have to use an app on their phone and instead just respond to 
surveys sent to their email address. To administer PROs, we will upload a list of patient email addresses into 
their HIPAA-compliant website which in turn allows scheduled administration of PRO questionnaires at daily 
and weekly intervals. Each week, the EMA app will send patients a reminder to fill out the scheduled PROs. If 
they do not fill them out, they will be sent a reminder prompt. The data collected by LifeData or Redcap will 
then be downloaded into a secure analysis and visualization file accessible to the research team and the 
Digitalist.  
Work Productivity and Activity Impairment 
Work productivity can be measured in terms of absenteeism (missing work) and presenteeism (diminished 
productivity at work). The Work Productivity and Activity Impairment (WPAI) questionnaire is a validated, 
widely used, brief, 6-item questionnaire that measures absenteeism and presenteeism related to specific 
health conditions.  
Use of Opioids 

  
 
In order to capture medication use related to their injury, including the use of opioids, we will link patient 
electronic health record (EHR) data to the other data sources using Medical Record Numbers and date of 
birth. We will collect opioid prescription information using pharmaceutical claims data, and also collect 
information on medications commonly used by individuals with chronic pain conditions. Prescribed opioid 
medications include: codeine, dihydrocodeine, tramadol, morphine, hydromorphone, oxymorphone, 
tapentadol, buprenorphine, methadone, oxycodone, fentanyl, remifentanil. We will convert all opioid doses 
into a single metric using morphine milligram equivalents (MME). 
Satisfaction with Pain Treatment and Healthcare Surveys 
We will evaluate patient experience data as measured by the 39-item Pain Treatment Satisfaction Scale and 
the 18-item short-form version of the Patient-Satisfaction Questionnaire. Both questionnaires are validated 
for use in studies to compare patient satisfaction between different treatment assignments. 

Development and validation of a digital pain-reduction kit for acute musculoskeletal injuries 
Version 1.4 
Protocol Pro00049015 
31 July 2017 
 
  
 
1 
 
Use and satisfaction with the TENS device will be monitored via daily questionnaires administered by 
either LifeData or Redcap (as described above). 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
Safety will be monitored by following up with participants for any adverse events (AE), assessment of 
adherence by support staff, and monitoring of biometric information and questionnaires by the 
digitalist. 
   
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
• 
Primary Efficacy Endpoint(s):  
 
Primary Outcome: Physical function over time as measured by PROMIS PF score (T- Scored, Continuous) 
Question: Which intervention is more effective in improving physical function? 
Independent variable of interest: Comparator received, intervention vs. control (Dichotomous) 
Potential Covariates: Age, gender, race, ethnicity, mental health comorbidities, chronic pain diagnosis, 
use of other pain medications (neuropathic pain medications, NSAIDS, antidepressants), benzodiazepine 
use, number of office visits during study period, baseline PROMIS® scores, encounter month, physician 
years of practice, physician gender. 
 
• 
Secondary Efficacy Endpoint(s): 
 
Secondary Outcome: Pain over time as measured by PROMIS Pain Interference Score (T-Scored, 
Continuous) 
Question: Which intervention is more effective in improving patient’s pain interference? 
Independent variable of interest: Comparator received, intervention vs. control (Dichotomous). 
Potential Covariates: Same as Primary Aim. 
 

Development and validation of a digital pain-reduction kit for acute musculoskeletal injuries 
Version 1.4 
Protocol Pro00049015 
31 July 2017 
 
  
 
2 
 
Secondary Outcome: Effects of lower back pain symptom severity on work productivity and regular 
activities over time as measured by WPAI:LB (T-Scored, Continuous). 
Question: Which intervention is more effective in improving patient’s work productivity and 
participation in regular activities? 
Independent variable of interest: Comparator received, intervention vs. control (Dichotomous). 
Potential Covariates: Same as Primary Aim. 
 
Secondary Outcome: New Opioid Prescription over 90MME (Dichotomous) 
Question: Which intervention is more effective in reducing opioid prescriptions of 90 Morphine 
Milligram Equivalents (MME) or greater? 
Independent variable of interest: Comparator received, intervention vs. control (Dichotomous). 
Potential Covariates: Same as Primary Aim. 
Statistical Analyses: As in the primary aim analyses, we will employ mixed effects models featuring both 
fixed effects and random effects to account for within subject variation. 
Because this particular outcome is binary, we will use mixed logistic regressions in which the log odds of 
the outcomes are modeled as a linear combination of the predictors. 
 
Secondary Outcome: Satisfaction with Pain Treatment and Healthcare Scores 
Question: Which intervention is more effective in improving how satisfied patients feel with their care? 
Dependent variable: Pain Treatment and Patient Satisfaction Scores 
Independent variable of interest: Comparator received, intervention vs. control (Dichotomous) 
Potential Covariates: Same as Primary Aim. 
 
9.2 
SAMPLE SIZE DETERMINATION 
  
We will power this study to detected a 0.6 standard deviation (SD) effect size in 
PROMIS® PF scores between arms – a value that is three-times the established minimal 
clinical important difference of 0.2 SD and is considered a “moderate effect” using the 

Development and validation of a digital pain-reduction kit for acute musculoskeletal injuries 
Version 1.4 
Protocol Pro00049015 
31 July 2017 
 
  
 
3 
 
rules of Cohen. Assuming an 80% power,  a level of 0.05, and a 25% withdrawal rate, we calculate a 
minimal 
sample size requirement of approximately 120 per arm, for a total of 245  patients. 
 
9.3 
POPULATIONS FOR ANALYSES 
 
All randomized participants will be included in the dataset (ITT).  
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
Checks of assumptions underlying statistical procedures will be performed and all corrective procedures 
will be applied as necessary. 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
Statistical Analyses: Data for Aim 1 are repeated-measures data and will not support bivariate analysis 
by Pearson and/or Spearman correlations, as autocorrelation can cause transient or spurious 
relationships with high correlations for some periods and none for others. Similarly, for a linear 
regression model, this type of data may cause residuals for the same individual to be correlated. 
Therefore, we will employ linear mixed models featuring fixed effects and random effects (i.e. random 
intercepts) to account for within subject variation. We will also perform a differences-in-differences 
analysis comparing change between baseline and the end of the intervention to determine which 
strategy resulted in greater improvement in PF. 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Statistical Analyses: As in the primary aim analyses, we will employ linear mixed models featuring fixed 
effects and random effects to account for within subject variation. We will also perform a differences-in-
differences analysis comparing change between baseline and the end of the intervention to determine 
which strategy resulted in greater improvement in PF. 
Statistical Analyses: As in the primary aim analyses, we will employ linear mixed models featuring fixed 
effects and random effects to account for within subject variation. We will also perform a differences-in-
differences analysis comparing change between baseline and the end of the intervention to determine 
which strategy resulted in greater improvement in PF. 

Development and validation of a digital pain-reduction kit for acute musculoskeletal injuries 
Version 1.4 
Protocol Pro00049015 
31 July 2017 
 
  
 
4 
 
Statistical Analyses: In addition to unadjusted comparisons, we will employ multiple linear regression 
models. 
9.4.4 ACCOMODATING ADDITION OF TENS UNIT TO THE CONTROL ARM  
 
An ITT analysis “Includes all randomized patients in the groups to which they were randomly assigned, 
regardless of their adherence with the entry criteria, regardless of the treatment they actually received, 
and regardless of subsequent withdrawal from treatment or deviation from the protocol.”ref  
Accordingly, we will follow the original analysis plan described above with regard to analyzing results by 
study-arm. In addition to the ITT analysis, however, we will conduct a sensitivity analysis by repeating 
the statistical procedures in a per-protocol fashion wherein the members of the control arm who did not 
receive a TENS unit will be dropped from the sample. Directions, magnitudes, and significance of 
treatment effects will be presented for both analyses.  
 
Furthermore, because the TENS unit will appear in both study arms - and unevenly in the control arm – 
we recognize that an ITT analysis strictly by study-arm risks misidentifying the effect of treatment, while 
a per-protocol analysis risks introduction of bias. Therefore, we will conduct an additional linear mixed 
model regression analysis using a term for the TENS that captures the effect of the TENS separately from 
the effects of study-arm assignment. The model used to fit these data is as follows: 
 
 ŷ it= β0 + β1timeit + β2study_armit + β3TENSit  + eit 
 
where time represents change in time from baseline, study_arm indicates status as a control or 
experimental participant (0= control and 1=experimental), i is the individual participant, and TENS 
indicates TENS unit usage (0= no TENS unit and 1=TENS unit). We can therefore write a regression 
equation describing each type of patient differentiated by the addition of the TENS unit to control 
conditions: 
 
Treatment:  
ŷ it= β0 + β1timeit + β2study_armit + β3TENSit  + eit 
 
Control w/o TENS:  
ŷ it= β0 + β1timeit  + eit 
 
Control w/ TENS:  
ŷ it= β0 + β1timeit + β3TENSit  + eit 
In this manner we isolate the term of interest (study_arm). Given we are only adding one 
term but 20 subjects, we are comfortable relying on the original power calculation.  
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 

Development and validation of a digital pain-reduction kit for acute musculoskeletal injuries 
Version 1.4 
Protocol Pro00049015 
31 July 2017 
 
  
 
5 
 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
physician will explain the research study to the participant and answer any questions that may arise. 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 written 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 any delivery of study materials. Participants must be informed that participation is voluntary and that 
they may withdraw from the study at any time, without prejudice. A copy of the informed consent 
document will be given to the participants for their records. The informed consent process will be 
conducted and documented in the source document (including the date), and the form signed, 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. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigators, and sponsors.  If 
the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform 
study participants, the Institutional Review Board (IRB), and sponsor and will provide the reason(s) for 
the termination or suspension.  Study participants will be contacted, as applicable, and be informed of 
changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 

Development and validation of a digital pain-reduction kit for acute musculoskeletal injuries 
Version 1.4 
Protocol Pro00049015 
31 July 2017 
 
  
 
6 
 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor or IRB. 
 
 
10.1.3 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 
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.  
 
Individuals viewing private and identifiable information, such as physicians, are reasonably expected to 
be viewing such information whether participants were enrolled in the study. All research activities will 
be conducted in closed-door, private room during initial contact and subsequent follow-up. The setting 
for much of the study will be at the participant’s discretion, as only two visits (baseline and exit) are 
made during before and after the intervention period. 
 
Representatives of the Institutional Review Board (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 is collected in three ways: in real-time, at infrequent intervals throughout the study, 
and through medical record queries. Real-time data, including biometrics and survey data delivered via 
mobile device, will be stored on secure servers hosted by Amazon Web Services (AWS) 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, weekly, and exit 
questionnaires will be stored on secure CSMC servers with unique ID's for each participant. Data 
collected from medical record numbers, such as opioid prescriptions and physician history, 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. 
 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
N/A 
 
10.1.5 PROTOCOL DEVIATIONS  
 

Development and validation of a digital pain-reduction kit for acute musculoskeletal injuries 
Version 1.4 
Protocol Pro00049015 
31 July 2017 
 
  
 
7 
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP). 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.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 5 working days of identification of the protocol deviation, or within 10 working days of 
the scheduled protocol-required activity.  All deviations must be addressed in study source documents 
and reported to Travelers Insurance.  Protocol deviations must be sent to the reviewing Institutional 
Review Board (IRB) per their policies. The site investigator is responsible for knowing and adhering to 
the reviewing IRB requirements.  
 
10.1.6 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.  
 
 
10.1.7 CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership in conjunction with Cedars-Sinai IRB has established policies and procedures for all study 
group members to disclose all conflicts of interest and will establish a mechanism for the management 
of all reported dualities of interest. 
 
10.2 ADDITIONAL CONSIDERATIONS 
N/A 
 

Development and validation of a digital pain-reduction kit for acute musculoskeletal injuries 
Version 1.4 
Protocol Pro00049015 
31 July 2017 
 
  
 
8 
 
 
 

Development and validation of a digital pain-reduction kit for acute musculoskeletal injuries 
Version 1.4 
Protocol Pro00049015 
31 July 2017 
 
  
 
9 
 
10.3 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
1.0 
06/08/2017 
Initial Protocol 
N/A 
1.1 
06/19/2017 
Minor changes 
N/A 
1.2 
06/25/2017 
Changed criteria 
Clarification 
1.3 
07/05/2017 
Major changes throughout 
IRB review 
1.4 
07/31/2017 
Minor IRB changes 
IRB review (round 2) 
1.5 
02/22/2018 
Minor changes to questionnaires , 
TENS protocol, and health coach 
definition 
Clarification 
5.4 
10/22/2018 
Minor changes to eligibility criteria 
and other sections reflecting the 
change 
Addition of new clinical site and 
open recruitment for LBP.  
6.1.1 
11/12/2018 
Change in device used to display the 
audiovisual content.  
The new VR headsets will be far 
easier for patients to use at 
home.  
6.2 
8/7/19 
Specific letters provided to patients, 
addition of Redcap as a method to 
collect PROs 
For the patients comfort a letter 
tailored to the treating provider 
will be added, Redcap was added 
to increase the number of ways 
patients could provide PROs. 
6.3 
8/30/19 
PICO G2 added as another VR 
headset that patients may receive. 
An update to the Oculus software 
rendered the intervention 
software inoperable.  The 
software vendor has started to 
use a different but comparable 
VR headset. The headset they are 
using is called the PICO G2. It 
will have the exact same software 
provided to the patient as what 
was provided via the Oculus Go.   
6.4 
10/4/19 
Medical College of Wisconsin (MCW) 
added as an external study site, and 
Amit Singh added as an external 
study team member. 
The study is now multi-site with 
the addition of Medical College 
of Wisconsin (MCW) to 
accelerate recruitment rates. 
 
 
 
 
 
 
 
 

Development and validation of a digital pain-reduction kit for acute musculoskeletal injuries 
Version 1.4 
Protocol Pro00049015 
31 July 2017 
 
  
 
10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Development and validation of a digital pain-reduction kit for acute musculoskeletal injuries 
Version 1.4 
Protocol Pro00049015 
31 July 2017 
 
  
 
11 
 
11 REFERENCES  
1. Barry Meier BM. The Soaring Cost of the Opioid Economy. Secondary The Soaring Cost of the 
Opioid Economy  June 22 2013 2013.  http://www.nytimes.com/interactive/2013/06/23/sunday-
review/the-soaring-cost-of-the-  opioid-economy.html?_r=2&. 
2. Turk DC, Wilson HD, Cahana A. Treatment of chronic non-cancer pain. Lancet 
2011;377(9784):2226-35 doi: 10.1016/S0140-6736(11)60402-9[published Online First: Epub 
Date]|. 
3. Okifuji A, Ackerlind S. Behavioral medicine approaches to pain. Anesthesiol Clin 2007;25(4):709-
19, v doi: 10.1016/j.anclin.2007.07.009[published Online First: Epub Date]|. 
4. Malloy KM, Milling LS. The effectiveness of virtual reality distraction for pain reduction: a 
systematic review. Clin Psychol Rev 2010;30(8):1011-8 doi: 10.1016/j.cpr.2010.07.001[published 
Online First: Epub Date]|. 
5. Li A, Montano Z, Chen VJ, Gold JI. Virtual reality and pain management: current trends and 
future directions. Pain Manag 2011;1(2):147-57 doi: 10.2217/pmt.10.15[published Online First: 
Epub Date]|. 
6. Carrougher GJ, Hoffman HG, Nakamura D, et al. The effect of virtual reality on pain and range of 
motion in adults with burn injuries. J Burn Care Res 2009;30(5):785-91 doi: 
10.1097/BCR.0b013e3181b485d3[published Online First: Epub Date]|. 
7. Furman E, Jasinevicius TR, Bissada NF, Victoroff KZ, Skillicorn R, Buchner M. Virtual reality 
distraction for pain control during periodontal scaling and root planing procedures. J Am Dent 
Assoc 2009;140(12):1508-16 
8. Garrett B, Taverner T, Masinde W, Gromala D, Shaw C, Negraeff M. A rapid evidence assessment 
of immersive virtual reality as an adjunct therapy in acute pain management in clinical practice. 
Clin J Pain 2014;30(12):1089-98 doi: 10.1097/AJP.0000000000000064[published Online First: 
Epub Date]|. 
9. Gold JI, Kim SH, Kant AJ, Joseph MH, Rizzo AS. Effectiveness of virtual reality for pediatric pain 
distraction during i.v. placement. Cyberpsychol Behav 2006;9(2):207-12 doi: 
10.1089/cpb.2006.9.207[published Online First: Epub Date]|. 
10. Hoffman HG, Doctor JN, Patterson DR, Carrougher GJ, Furness TA, 3rd. Virtual reality as an 
adjunctive pain control during burn wound care in adolescent patients. Pain 2000;85(1- 2):305-9 
11. Hoffman HG, Garcia-Palacios A, Patterson DR, Jensen M, Furness T, 3rd, Ammons WF, Jr. The 
effectiveness of virtual reality for dental pain control: a case study. Cyberpsychol Behav 
2001;4(4):527-35 doi: 10.1089/109493101750527088[published Online First: Epub Date]|. 
12. Morris LD, Louw QA, Crous LC. Feasibility and potential effect of a low-cost virtual reality system 
on reducing pain and anxiety in adult burn injury patients during physiotherapy in a developing 
country. Burns 2010;36(5):659-64 doi: 10.1016/j.burns.2009.09.005[published Online First: Epub 
Date]|. 

Development and validation of a digital pain-reduction kit for acute musculoskeletal injuries 
Version 1.4 
Protocol Pro00049015 
31 July 2017 
 
  
 
12 
 
13. Hoffman HG, Patterson DR, Carrougher GJ. Use of virtual reality for adjunctive treatment of 
adult burn pain during physical therapy: a controlled study. Clin J Pain 2000;16(3):244-50 
14. Hoffman HG, Patterson DR, Seibel E, Soltani M, Jewett-Leahy L, Sharar SR. Virtual reality pain 
control during burn wound debridement in the hydrotank. Clin J Pain 2008;24(4):299-304 doi: 
10.1097/AJP.0b013e318164d2cc[published Online First: Epub Date]|. 
15. Hoffman HG, Patterson DR, Carrougher GJ, Sharar SR. Effectiveness of virtual reality-based pain 
control with multiple treatments. Clin J Pain 2001;17(3):229-35 
16. Sato K, Fukumori S, Matsusaki T, et al. Nonimmersive virtual reality mirror visual feedback 
therapy and its application for the treatment of complex regional pain syndrome: an open- label 
pilot study. Pain Med 2010;11(4):622-9 doi: 10.1111/j.1526- 4637.2010.00819.x[published 
Online First: Epub Date]|. 
17. Sarig-Bahat H, Weiss PL, Laufer Y. Neck pain assessment in a virtual environment. Spine (Phila Pa 
1976) 2010;35(4):E105-12 doi: 10.1097/BRS.0b013e3181b79358[published Online First: Epub 
Date]|. 
18. Mosadeghi S, Reid MW, Martinez B, Rosen BT, Spiegel BM. Feasibility of an Immersive Virtual 
Reality Intervention for Hospitalized Patients: An Observational Cohort Study. JMIR Ment Health 
2016;3(2):e28 doi: 10.2196/mental.5801[published Online First: Epub Date]|. 
19. Jauregui JJ, Cherian JJ, Gwam CU, et al. A meta-analysis of transcutaneous electrical nerve 
stimulation for chronic low back pain. Surgical technology international 2016;28 
20. Spiegel B. 2015 American Journal of Gastroenterology Lecture: How Digital Health Will 
Transform Gastroenterology. The American journal of gastroenterology 2016;111(5):624-30 
21. Wachter RM, Goldman L. The emerging role of "hospitalists" in the American health care 
system. The New England journal of medicine 1996;335(7):514-7 doi: 
10.1056/NEJM199608153350713[published Online First: Epub Date]|. 
22. Hays RD, Spritzer KL, Fries JF, Krishnan E. Responsiveness and minimally important difference for 
the Patient-Reported Outcomes Measurement Information System (PROMIS) 20-item physical 
functioning short form in a prospective observational study of rheumatoid arthritis. Annals of 
the rheumatic diseases 2013:annrheumdis-2013-204053 
23. Agency for Healthcare Research and Quality. Principles Underlying CAHPS Surveys. Secondary 
Principles Underlying CAHPS Surveys  2016. http://www.ahrq.gov/cahps/about-  
cahps/principles/index.html. 
24. Rabe-Hesketch S, Everitt BS. A Handbook of Statistical Analysis Using Stata. Fourth Edition ed. 
Boca Raton, FL: Chapman & Hall/CRC: Taylor & Francis Group, 2016.