Pain Rehabilitation Virtual Reality (PRVR): Innovations to Enhance Mobility in the Presence of Pain
Phase: NA
Conditions: Chronic Pain, Musculoskeletal Pain, Fibromyalgia, Virtual Reality
Sponsor: Stanford University

Simons Clinical Protocol 03 March 2023 
 
Pain Rehabilitation Virtual Reality (PRVR) 
Innovations to Enhance Mobility in the Presence of Pain @ HOME 
 
Pediatric Pain Rehabilitation with Virtual Reality (PR-VR) Feasibility Study 
 
 
Clinical Protocol 
 
 
 
Principal Investigator: 
Dr. Laura Simons, PhD 
 
Professor 
Department of Anesthesiology, Perioperative, and Pain Medicine 
Stanford University School of Medicine 
 
 
 
Funded by: 
The National Institute for Arthritis and Musculoskeletal and Skin Diseases 
 
National Clinical Trial Identifier: NCT04636177 
Award Number: 1R21AR079140-01  
Version Number: v.1.2 
March 03, 2023 
 
 
 

 
2
Summary of Changes from Previous Version:  
Affected Section(s) 
Summary of Revisions Made 
Rationale 
 
 
 

 
3
 
Table of Contents 
STUDY TEAM ROSTER ............................................................................................................................................... 5 
PARTICIPATING STUDY SITES .................................................................................................................................... 8 
PRÉCIS...................................................................................................................................................................... 8 
2. BACKGROUND AND RATIONALE .................................................................................................................. 8 
2.1 
Background and Significance ........................................................................................................................ 8 
Innovation .................................................................................................................................................... 10 
2.2 
Study Rationale ......................................................................................................................................... 10 
3. STUDY DESIGN ................................................................................................................................................... 11 
5. STUDY INTERVENTIONS ............................................................................................................................. 12 
5.1 
Interventions, Administration, and Duration .............................................................................................. 12 
5.1.2 
Compensation ........................................................................................................................................... 12 
5.2 
Handling of Study Interventions ................................................................................................................. 12 
5.4 
Adherence Assessment .............................................................................................................................. 13 
6. Description of Evaluations .................................................................................................................................. 13 
6.1 Screening Evaluation ................................................................................................................................................................ 13 
6.2 Enrollment, Baseline, and Randomization ............................................................................................................................... 13 
7. SAFETY ASSESSMENTS ............................................................................................................................... 14 
7.1 
Specification of Safety Parameters ............................................................................................................. 15 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters ....................................... 15 
7.3 
Adverse Events and Serious Adverse Events ............................................................................................... 15 
7.4 
Reporting Procedures ................................................................................................................................ 16 
7.5 
Follow-up for Adverse Events .................................................................................................................... 16 
7.6 
Safety Monitoring ...................................................................................................................................... 16 
8. INTERVENTION DISCONTINUATION ........................................................................................................... 17 
9. STATISTICAL CONSIDERATIONS ................................................................................................................. 18 
9.1 
General Design Issues ................................................................................................................................ 18 
10. DATA COLLECTION AND QUALITY ASSURANCE ........................................................................................ 18 
10.1 
Data Collection Forms ................................................................................................................................ 18 
10.2 
Data Management ..................................................................................................................................... 19 
10.3 
Quality Assurance ...................................................................................................................................... 19 
10.3.1 
Training ........................................................................................................................................................................ 19 
10.3.2 
Quality Control Committee ......................................................................................................................................... 19 
10.3.3 
Metrics ........................................................................................................................................................................ 19 
10.3.4 
Protocol Deviations ..................................................................................................................................................... 19 
10.3.5 
Monitoring................................................................................................................................................................... 20 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY ......................................................................................... 20 

 
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11.1 
Institutional Review Board (IRB) Review .................................................................................................... 20 
11.2 
Informed Consent Forms............................................................................................................................ 20 
11.3 
Participant Confidentiality ......................................................................................................................... 20 
11.4 
Study Discontinuation ................................................................................................................................ 20 
12. COMMITTEES .......................................................................................................................................... 20 
13. PUBLICATION OF RESEARCH FINDINGS .................................................................................................... 20 
14. REFERENCES ............................................................................................................................................ 21 
 
 
 

 
5
STUDY TEAM ROSTER  
Name 
Address 
Phone 
Email 
Role 
Laura Simons, 
PhD 
Department of 
Anesthesiology, 
Perioperative and Pain 
Medicine 
Stanford University 
School of Medicine 
 
 
 
Palo Alto, CA 94304 
(650) 736-0838 
lesimons@stanford.edu 
Principle 
Investigator 
 
-Trains staff on 
study procedures 
 
-Serves as 
contact to, 
delivers files to 
IRB 
Thomas 
Caruso, MD, 
MEd 
Department of 
Anesthesiology, 
Perioperative and Pain 
Medicine 
Stanford University 
School of Medicine 
 
 
Stanford, CA 94305 
(650) 723-5728  
 
tjcaruso@stanford.edu 
Co-Investigator 
Anya Griffin, 
PhD 
Motion & Sports 
Performance Laboratory 
Stanford Children’s 
Health  
 
 
 
Menlo Park, CA 94025 
 
 
  
 
Co-Investigator 
 
 
PhD 
Department of Medicine 
and Quantitative 
Sciences Unit, Stanford 
University School of 
Medicine 
 
 
 
Palo Alto, CA, 94304 
 
 
Biostatistician 
 
ManageXR 
 
 
York, NY 10023 
 
 
  
Virtual Reality 
Consultant 
 
 RN, 
PhD 
Child Health Evaluative 
Sciences, Hospital for 
Sick Children Research 
Institute 
 
 
 
 
Toronto, Ontario 
Canada M5G 0A4 
 
 
 
Digital Health 
Consultant 
Clinical 
Research 
Coordinator 
Department of 
Anesthesiology, 
Perioperative and Pain 
Medicine 
Stanford University 
School of Medicine 
 
 
 
Palo Alto, CA 94304 
 
  
Study Coordinator 
 
-Participant 
identification, 
screening, 
enrollment, and 
retention 
 
-Data entry and 
management 
 

 
6
 
, MD 
Department of 
Anesthesiology, 
Perioperative and Pain 
Medicine 
Stanford University 
School of Medicine 
 
, 
Stanford, CA 94305 
 
 
 
 
Virtual Reality 
Technical Support 
, 
PT, DPT 
 
Center for Rehabilitation 
Services, Stanford 
Children’s Health, Lucile 
Packard Children’s 
Hospital  
 
 
 
Menlo Park, CA 94025 
 
 
 
Physical Therapy 
Delivery Oversight 
, 
PT 
Clinic Director, California 
Rehabilitation and Sports 
Therapy 
 
 
Palo Alto 94306 
 
 
 
Physical Therapist 
, PT, DPT 
Clinic Lead, Agile 
Physical Therapy 
 
 
edwood City, CA 
94063 
 
 
 
Physical Therapy 
Delivery Oversight 
 
 Ph.D.  
Institute of Creative 
Technologies, University 
of Southern California  
 
 
Los Angeles CA 90094 
 
 
 
 
Director of 
Medical Virtual 
Reality 
 
 
, 
Ph.D. 
College of Engineering, 
University of Washington 
 
 Seattle, 
WA 98195 
 
 
 
Study Monitoring 
Committee 
 
VR in Pain expert 
, PT 
MSc 
 
The Ottawa Hospital 
Rehabilitation Centre 
 
 Ottawa, 
ON K1H 8M2, Canada 
 
 
 
Study Monitoring 
Committee 
 
Psychology 
Expertise 

 
7
Study Abbreviations 
 
Acronym 
Expanded Term 
AE 
Adverse Event  
ANOVA 
Analysis of Variance 
BAS 
Baseline study visit  
CITI 
Collaborative Institutional Training Initiative  
CRC 
Research Coordinator  
DSMP 
Data Safety Monitoring Plan  
eCRF 
Electronic Case Report Form 
END 
Discharge 
FDA 
Food and Drug Administration  
FU 
Follow Up 
GCP 
Good Clinical Practice  
ICH 
International Conference on Harmonisation  
IRB 
Institutional Review Board  
MCID 
Minimally Clinical Important Difference 
MSK 
Musculoskeletal Pain 
NIAMS 
National Institute of Arthritis and Musculoskeletal 
and Skin Diseases  
NIH 
National Institutes of Health  
OHRP 
Office for Human Research Protections  
OSF 
Online Screening Form 
PD 
Protocol Deviation 
PI 
Principal Investigator  
PID 
Participant Identification Number  
PRVR 
Pain Rehabilitation Virtual Reality   
PT 
Physical Therapy/Therapist  
REDCap 
Research Electronic Data Capture 
SAE 
Serious Adverse Event  
SCH 
Stanford Children's Health  
SMC 
Safety Monitoring Committee  
SR 
Self-Report  
UP 
Unanticipated Problem  
 
 
 
 

 
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PARTICIPATING STUDY SITES 
The study will be conducted at the Department of Rehabilitation at Stanford Children’s Health (SCH) at the 
Pediatric Pain Management Clinic (PPMC). 
PRÉCIS   
Study Title  
Pain Rehabilitation Virtual Reality (PRVR) Innovations to Enhance Mobility in the Presence of Pain // Pediatric 
Pain Rehabilitation with Virtual Reality (PRVR) Feasibility Study 
 
Objectives  
For many adolescents suffering with chronic pain, fear associated with movement and return to activities 
significantly interferes with clinical improvement. Prior research supports virtual reality (VR)’s ability to 
reduce fear of movement-related pain, provide distraction from pain symptoms, encourage increased range 
of motion, improve endurance, facilitate postural improvements, and enhance tolerance to sensory stimuli 
for desensitization. Thus, VR has vast potential to become an instrumental tool in pediatric pain 
rehabilitation programs. 
We conducted a pilot study of the pain rehabilitation virtual reality (PRVR) platform, which included the 
development and feasibility testing of a number of unique VR experiences for youth undergoing chronic pain 
treatment and rehabilitation. With iterated improvement based on patient feedback, these VR rehabilitation 
experiences feature mirror therapy, exaggerated movement capabilities, biofeedback, and a Clinical 
Research Tool that tracks movement of each extremity in real-time with advanced analytic capabilities. 
Results from patients and clinicians (psychology, physical therapy, occupational therapy) in this study 
supported the PRVR platform as an acceptable, feasible, and useful intervention in this patient setting.  
Design and Outcomes   
This is a single arm feasibility study. A “participant” in this study is defined as a child and at least one 
parent.  The primary outcomes are feasibility, acceptability, and utility of VR. The secondary outcomes are 
physical function (child only) and pain-related fear and avoidance (child).  
Interventions and Duration  
All participants will receive an Oculus Quest 2 virtual reality (VR) headset for use during their treatment at 
the PPMC. VR will supplement treatment and be used in session (either in-person or telehealth) and at 
home as part of their prescribed treatment homework. 
 
Sample Size and Population  
Patients who meet eligibility criteria will be referred to the study by their clinician at clinic appointments.  
2. BACKGROUND AND RATIONALE 
2.1 
Background and Significance 
Overall Scientific Premise. Chronic musculoskeletal (MSK) pain in adolescence is a significant public health 
concern with median prevalence rates of 11 to 38%1,2, with 3 to 5% of adolescents suffering from significant 
pain-related disability25,26, costing society $19.5 billion annually in the US alone3. Notwithstanding the 
personal suffering and persistent physical and economic consequences for families, chronic pain in 
adolescence can predispose the development of adult chronic pain27. Progressively increasing activity in the 
presence of pain is critical for effective functional restoration in chronic MSK pain in adolescents6 and 
adults7-13 with physiotherapy (PT) a critical ingredient14. Despite the widespread use of Standard 
Physiotherapy Rehabilitation (SPR)15, daring to increase movement while in pain can often feel physically 
and emotionally unattainable with fear of pain a particularly salient influence on pain outcomes16-19, 

 
9
hindering clinical improvement20. Virtual reality (VR) has the potential to break the vicious cycle of fear of 
movement and avoidance during PT. VR provides access to a multisensory, three-dimensional (3D) 
immersive experience to overcome obstacles that seem insurmountable in the real world. Thus, the current 
study tests pain rehabilitation virtual reality (PRVR) for adolescents with chronic MSK pain. PRVR was 
created with input from a multidisciplinary collaborative team of pediatric rehabilitation providers and 
patient end users, alongside VR technology developers in response to the growing need for VR programming 
specific to pediatric chronic pain populations whose mobility has been limited due to pain, fear and activity 
avoidance. PRVR gamifies PT, helping patients increase their range of motion and become more comfortable 
moving their bodies to achieve game objectives. The games offer a combination of acute distraction from 
pain, reinforcement of movement, and progressive increases in range of motion. With evidence that VR 
holds promise for chronic pain rehabilitation in adults23,24,28 and compelling preliminary results from our 
feasibility-tested immersive PRVR intervention, this feasibility study will provide the necessary findings to 
support or refute the feasibility of  scale implementation of PRVR, a tailored treatment option for 
adolescents struggling with persistent MSK pain, fear, and disability.  
 
 
Scientific premise for Virtual Reality. The application of VR in healthcare has rapidly accelerated in recent 
years due to increased market availability and declining costs. VR enables the user to interact with a 
computer-generated environment that harnesses sensory inputs (e.g., visual, audio, tactile) to provide an 
immersive experience to facilitate reaching therapeutic goals. Most commonly applied in the context of 
acute pain relief, research is emerging for its application in the realm of chronic pain rehabilitation. VR has 
been suggested as an alternative to opioids with the therapeutic mechanisms centered on distraction29,30, 
neuromodulation of body perception31, and graded exposure to feared/avoided movements23,24,28,32. 
Moreover, VR can potentially enhance motivation and engagement during physical rehabilitation, facilitate 
repetitive motions, and incorporate real-time and longitudinal feedback for the patient and clinician33-36. 
Perhaps most exciting is the prospect of VR to engage several cortical and subcortical neuronal circuits that 
potentiate learning and recovery37,38 with the potential for enhanced cortical reorganization39,40. The extant 
literature includes proof of concept, feasibility, and pilot RCT studies. One recently published study of VR 
combined with exercise for adults with fibromyalgia demonstrated greater improvements in pain, fear of 
movement, fatigue, level of physical activity, and quality of life when compared to exercise alone28. Overall, 
many studies report promising outcomes yet lack the rigor and measurement over time critical to establish 
VR as an evidence-based treatment for chronic pain rehabilitation.   
 
Scientific premise for physical activity monitoring. A cycle of fear of movement and activity avoidance in 
adolescents with chronic pain can lead to decreased tolerance of physical activity that persists into 
adulthood41. Abnormal kinesics, such as asymmetry in range of motion, or timing of muscle activation or 
joint motions, commonly exist as a compensatory mechanism in chronic pain41-43, potentially amplified by 
pain-related fear44. This trial will include self-report, objective tests of physical function45,46 coupled with real 
world objective physical activity monitoring via a wrist-worn actigraph. Actigraphy is particularly useful as 
self-report measures can be prone to response shift and reporter bias47,48. Unlike laboratory-based objective 
measures of physical activity, such as timed walks and peak oxygen consumption during exercise, actigraphy 
provides high ecological validity with unobtrusive measurement of activity levels during daily life49 with 
adolescents with chronic pain having lower mean and peak activity levels compared to healthy peers48. 
 
Significance of the expected research contribution: (1) harnessing immersive technology to overcome fear of 
movement in the presence of pain, (2) providing real-time feedback in a gamified context to sustain 
motivation and adherence, and (3) purposefully capturing both objective (physical function assessment, 
actigraphy) and subjective (self-report) daily functioning to define clinical endpoints and assess treatment 
progress in the clinic and at home. 
 
 
 
 
 

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Innovation 
Treatment of chronic pain remains a tremendous challenge51. Developing mechanistically informed and 
innovative treatment approaches results in optimal clinical care. This application shifts current research and 
clinical practice by: (1) Increasing physical functioning using a motivating and gamified context with 
concomitant decreases in fear of pain. PRVR targets functional improvement through harnessing the 
immersive and fun elements of VR gaming. Making gains in physical function and movement is not only 
highly reinforcing in itself, we have shown that it can lead to changes at the neural circuit level in 
somatosensory and motor processing while simultaneously decreasing 
fear of pain52. (2) Leveraging digital solutions. Emerging trends in 
healthcare call for a precision medicine approach53 with its success 
contingent on the collection of patient data across domains as well as the 
development of efficient and effective targeted treatments. Digital health 
has the potential to integrally contribute to both data collection and 
intervention and is at the core of the current proposal. Data collected 
from the child (electronic daily diary, actigraphy, wearable sensors in VR) 
can be communicated to providers to inform clinical decision-making and 
support tailored, point of care decisions that result in science-forward, 
targeted, and effective interventions. We envision this synergistic and 
dynamic model (Figure 1; Richardson et al., in submission) as the future of 
evidence-based treatment for pediatric chronic pain. (3) Nonpharmacological solution with the potential 
for brain circuit engagement. Identifying nonpharmacological interventions for adolescents is critical as few 
analgesics or psychotropics have documented long-term safety and efficacy in the developing brain and 
opioids are known to have adverse long-term effects on the brain54. Given we have demonstrated neural 
plasticity of adolescents with chronic pain after pain rehabilitation52,55,56 and the prospect of VR to engage 
cortical and subcortical neuronal circuits that potentiate learning and recovery37,38 and the potential for 
enhanced cortical reorganization39,40, testing the effectiveness of VR for adolescents with MSK pain is 
justified. Overall, the momentum is building in the field of VR for pain with over 100 active studies registered 
at ClinicalTrials.gov with this study representing the first targeting adolescents with MSK pain, thus, this 
proposal is timely.
2.2
Study Rationale
Preliminary Studies/Progress Report 
Preliminary Data to Support Aim 1. 
(a) Human-centered design and feasibility testing of PRVR. The 
pediatric pain rehabilitation team at Stanford Children’s Health 
(SCH) worked collaboratively with the Stanford CHARIOT Program 
and consultant Luke Wilson (Mighty Immersion, Inc.) to develop 
PRVR content, Fruity Feet (Griffin et al., in submission). Fruity Feet
was developed using a human-centered approach with patient and 
clinician end-user feedback across four phases: (1) Needs 
Assessment, (2) Prototyping, (3) Iteration and Refinement, and (4) 
Feasibility 
and 
Acceptability. 
It 
was 
designed 
to 
be 
developmentally appropriate for youth by focusing on fun, while 
leaning on stylized graphics and encouraging in-game 
feedback. Gameplay mechanics were built around PT 
movement goals, for example for lower extremity: 
multiplanar stepping (i.e., forward, side, back), stomping, 
marching, kicking, raising leg to different heights, and 
active ankle range of motion tasks. Importantly, it was also 
built to scale to a patient’s mobility, ensuring that patients 
Figure 4. Fruity Feet settings. Providers can
adjust the game to fit patient needs. Intensity
affects rate fruit appears. Left/Right Focus
encourages use of affected side. Fruit Size affects
foot lift to stomp fruit. Extremity Focus focuses on
lower or upper extremities. Foot/Hand Mirroring
mirrors the virtual extremity, like mirror-therapy.
Foot/Hand Exaggeration amplifies or decreases
translation of real-world movement. 
Figure 1. Transforming 
Healthcare with Digital Solutions

11
of all abilities could play the game and benefit from the VR intervention (Figure 4). Consistent with the 
recommendations for VR clinical trial methodology80, this human-centered iterative design process yielded 
a program that, in addition to gamification, provides backend mechanics giving PT providers the capability 
to control intensity, affected side/extremity emphasis, mirroring, and movement exaggeration to leverage 
the potential neuromodulatory effects of VR coupled with targeted pain PT.
(b) PRVR increases movement. A prospective, randomized crossover study led by Co-Investigator Tom 
Caruso, MD compared PRVR vs. SPR ages 6 and older, including adolescents (n=41) during a single session 
of outpatient PT with each patient serving at their own control 
(NCT03874507). Patients moved significantly more when participating in 
PRVR compared to SPR (1120.88 meters vs 672.65 meters p = 5.47E-08; 
Figure 5). When stratified by therapy target (upper vs lower) PRVR 
treatment was also associated with more movement of the appropriate 
limbs, lower (p < 0.001) and upper (p = 0.01). Pediatric users reported 
significantly less pain when using VR (88%) compared to adults (50%) and 
virtually all patients reported enjoying the VR experience (96% adult users; 
100% pediatric users). (Caruso et al., in preparation). These results suggest 
marked increases in movement, potential pain relief, and a fun experience 
using VR in PT and warrents examination for culmultative effects over 
mulitple treatment sessions. 
Feasibility and Acceptability Data. PRVR feasibility testing (Mayday Fund supported) included 17 
participants (13 female, 4 male), mean age 13.24 (range 7-17), completing a total of 63 sessions. Overall 
reports of immersion were high (M = 28.98, SD = 4.02 out of 40). Analysis of 45 sessions from 13 patients 
entered into the NVivo qualitative data analysis program revealed: 1) positive experience (i.e., enjoyed it, 
would like to utilize the VR program again, felt it was a helpful tool), 2) feeling distracted from pain while
engaged in VR, 3) increased physical function/mobility, and 4) reduced pain behaviors/symptoms during 
VR (Griffin et al., in submission). These results suggest that Fruity Feet has the right mix of immersion, fun 
and PT movement capabilities to provide targeted and effective pain physiotherapy in VR.
3. STUDY DESIGN
Recruitment. Potential participants were identified at their multidisciplinary evaluation at the Pediatric Pain 
Management Clinic and at participating private practices. Participants will be referred by their clinician and if 
interested will be put in contact with Dr. Simons, her co-investigators, or trained members of the research 
team.
Trained members of the research team may need to contact youth and caregivers to confirm eligibility after 
referral. Additionally, a study flyer will be posted on a bulletin board of all active clinical studies in patient 
waiting rooms and/or given to eligible participants if they would like.
For inclusion, the patients: 1) are 10-17 years old; 2) have musculoskeletal or neuropathic pain (e.g., localized 
[back, limb], diffuse)47 not due to an acute trauma (active sprain or fracture); 3) English language proficiency. 
Patient exclusion criteria are: 1) significant cognitive impairment (e.g., brain injury) and 2) significant medical 
or psychiatric problem that would interfere with treatment (e.g., seizures, psychosis, suicidality). 3) Presents 
with a condition that interferes with virtual reality usage (e.g., history of seizure, facial injury precluding safe 
placement of headset, visual impairment, significant hearing impairment impact ability to follow audio 
instructions). Identification of Eligibility: Patients and their parents who meet eligibility criteria will be 
referred to the study by their pain clinicians at clinic appointments. A trained member of the research team 
will reach out to the family after they are referred and they agree. 
Study Procedures. After the informed assent/consent, baseline will begin, and participants will complete 
baseline questionnaires. Discharge testing occurs at the end of 6-8 sessions or when the clinician believes they 
are finished with treatment. Discharge includes participant questionnaires. At 3 months follow-up, 
Figure 5. SPR vs PRVR total movement
for adult (n=24) and pediatric (n=17)

 
12
participants complete self-report questionnaires. VR will supplement treatment and be used in session (either 
in-person or telehealth) and at home as part of their prescribed treatment homework. We will ask youth and 
caregivers to join a training session via zoom or in person so that trained members of the research team may 
orientate the family to the VR equipment and help them set it up in the environment in which they will be 
asked to use the VR by their clinician. 
Optional study procedures. 
Daily Diary Surveys: Answering questions in the daily diary will take approximately 3 minutes to complete. You 
will be asked to fill out the daily diary and given the option to answer weekly, daily, and/or when you have PT 
sessions during study treatment and for one week at 3-month follow-up if you choose. You will be 
compensated a $20 bonus as a thank you for your time if you choose to answer these surveys.  
Brief Informational Interview: This exploratory study seeks to gather reports from participants after 
undergoing virtual reality exposure, paying particular attention to the language individuals use to describe 
their experience. Thus, the study procedure may include an informal and semi-structured interview, that will 
take place in the clinic after VR exposure. Participants and their parents may be asked to reflect on their 
condition, and on their experience with the VR module. The interviews may be recorded and transcribed. 
Personally-identifying information will not be disclosed from these interviews. Audio devices will be kept in a 
locked office at Stanford University. 
Actigraph Watch: Participants can wear a small, electronic study device on your wrist that tracks your activity 
level and sleep. If they choose to participate in this activity, participants will be asked to wear this from the 
start of the study until the last study treatment session and responsible for returning this electronic study 
device at the end of the study treatment period. 
5. STUDY INTERVENTIONS  
5.1 
Interventions, Administration, and Duration  
Participants will complete their treatment sessions 1-hour each, delivered over ~6-12 weeks or until clinician 
believes the patient is done with treatment. VR will supplement treatment and be used in session (either in-
person or telehealth) and at home as part of their prescribed treatment homework.  
5.1.2 
Compensation  
All patients will be closely monitored by the PI, Laura Simons, as well as the treatment and research team. 
Patients are compensated for their time and contribution to this study, with increased compensation for the 
3 -month post-discharge follow-up. The following is the compensation timeline for all patients in the study:  
• 
Timepoint 1: $10.00 Amazon.com gift code at the start of treatment after baseline completion of 
questionnaires  
o $20 bonus if participants agree to participate in the daily surveys  
• 
Timepoint 2: $20.00 Amazon.com gift code after completion of treatment and end of treatment 
questionnaires 
• 
Timepoint 3: $30.00 Amazon.com gift code at the 3 month post-discharge follow-up for completion 
of questionnaires 
5.2 
Handling of Study Interventions  
All participants will receive an Oculus Quest 2 virtual reality headset for use during the study.   

 
13
5.4 
Adherence Assessment  
Patients will be closely monitored by the PI, Laura Simons, as well as the treatment and research team. 
Patients are compensated for their time and contribution to this study, with increased compensation for the 
3-month follow-ups. Follow-up will occur at 3-months for both treatment groups.
6. Description of Evaluations  
The Schedule of Evaluations will include Recruitment (referral), a Baseline Assessment (informed 
consent/assent, self-reported questionnaires), Discharge Assessment (self-report questionnaires), 
and a 3-month follow-up (self-report questionnaires).  
6.1 Screening Evaluation 
Screening 
The study team will recruit adolescent patients and a primary parent from the outpatient 
rehabilitation department the Department of Rehabilitation at Stanford Children’s Health (SCH) at 
the Pediatric Pain Management Clinic (PPMC). Youth patient and parent will be reffered by their 
clinician at the PPMC. If interested, the parent will tell their clinician that they are interested to 
allow researchers to contact them.  
 
Consenting Procedure 
Before obtaining formal written assent/consent from patients and their parents, clinical providers 
at the SCH will obtain consent to be approached by members of the research team. 
Study staff, which will include a clinical research coordinator (CRC) or postdoctoral fellow trained by 
Dr. Laura Simons, will conduct the consent and assent procedure. Eligible participants will be 
educated about study procedures or any changes in those procedures. Signed consent/assent forms 
will be kept in a locked secure database in IRB approved REDCap.  
6.2 Enrollment, Baseline, and Randomization 
Enrollment 
Study consenting/assenting and enrollment will take place via Zoom or in person. All procedures will 
be completed by a clinical research coordinator (CRC) and/or postdoctoral fellows.   
 
Consenting Procedure for Enrollment 
This study will follow the Informed Consent Process for Research according to the Stanford 
University Research Compliance Office. Each participant’s consenting process will be recorded by 
the study CRC in the “Screening and Enrollment Log” (MOP Supplemental Materials I) within an 
online REDCap eCRF. The signed consent/assent documents will be kept in a locked secure 
database in IRB approved REDCap. 
 
The informed consent process will take place via Zoom or in-person, and participants will have the 
opportunity to read the consent form and ask any questions they may have at the beginning of the 
data collection session. Signed consent/assent forms will be stored in a locked secure database. 
Participants will be reminded that their involvement in this study is completely voluntary, and that 
they can withdraw it any time without any negative repercussions whatsoever (e.g., with regard to 
clinical care or healthcare access). They will also be explicitly told that they may leave any question 
blank for questionnaires or unanswered for the clinical interview if they do not feel comfortable 
answering.  See Supplement Material for the consent and assent form. 
 
Non-English Speaking Participants – Individuals who do not speak or understand English will not be 
recruited to the study. While we recognize the limitations of this approach, practical 
considerations necessitate the inclusion of only those who are able to speak or understand English.  

 
14
 
Enrollment date will be recorded in the “Screening and Enrollment Log” eCRF, which will also 
include documentation of inclusion/exclusion criteria.  
 
Baseline Assessment (BAS): 
The BAS assessment will consist of self-report measures and a zoom or in-person training session. 
The child and parent baseline measures will be introduced by a CRC after they conduct the 
consent/assent process via Zoom or in person.  
VR orientation: We will ask youth and caregivers to join a brief zoom call so that trained members 
of the research team may orientate the family to the VR equipment and help them set it up in the 
environment in which they will be asked to use the VR by their clinician. 
See Supplemental Materials III for baseline self-report measures 
Discharge Assessment: 
The child and parent will complete discharge measures.  
See Supplemental Materials III for discharge assessment measures  
Follow-Up Assessments: 
The child and parent will complete follow-up measures.  
See Supplemental Materials III for follow-up assessment measures  
Optional Assessments: 
Daily Diary Surveys: Answering questions in the daily diary will take approximately 3 minutes to 
complete. You will be asked to fill out the daily diary and given the option to answer weekly, daily, 
and/or when you have PT sessions during study treatment and for one week at 3-month follow-up 
if you choose. You will be compensated a $20 bonus as a thank you for your time if you choose to 
answer these surveys.  
Brief Informational Interview: This exploratory study seeks to gather reports from participants after 
undergoing virtual reality exposure, paying particular attention to the language individuals use to 
describe their experience. Thus, the study procedure may include an informal and semi-structured 
interview, that will take place in the clinic after VR exposure. Participants and their parents may be 
asked to reflect on their condition, and on their experience with the VR module. The interviews may 
be recorded and transcribed. Personally-identifying information will not be disclosed from these 
interviews. Audio devices will be kept in a locked office at Stanford University. 
Actigraph Watch: Participants can wear a small, electronic study device on your wrist that tracks 
your activity level and sleep. If they choose to participate in this activity, participants will be asked 
to wear this from the start of the study until the last study treatment session and responsible for 
returning this electronic study device at the end of the study treatment period. 
See Supplemental Materials III for optional assessment measures  
Clinician Measures: 
Clinicians will answer brief surveys post VR exposure in session to document use of VR to ensure 
safety of participants.  
See Supplemental Materials III for clinician measures  
 7. SAFETY ASSESSMENTS  
As the study is being conducted within a healthcare facility all normal monitoring of safety will be 
in place. There are few additional safety risks introduced as part of the involvement in the study 

 
15
procedures. If any risk arises as part of completing study assessments or participating in the 
treatment, there are physical therapists and medical personnel immediately available to assess the 
situation and provide assistance.  See Appendix B and Appendix C for Adverse and Serious Adverse 
Event Reporting forms.  
7.1 
Specification of Safety Parameters 
N/A 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
N/A  
7.3 
Adverse Events and Serious Adverse Events  
For the purposes of this study, the following AE definitions are used:  
 
Adverse Event (AE): Any unfavorable or unintended sign (including an abnormal laboratory finding), 
symptom or disease temporally associated treatment interventions, regardless of whether it is 
considered related to the treatment. AEs are categorized according to the following scale:  
 
Severity Ratings 
Adverse Events (AEs) will be rated on the following three-point scale, to the determine the severity 
of  
• 
Mild: An experience that is transient and requires no special treatment or intervention. 
The experience does not generally interfere with usual daily activities. 
• 
Moderate: An experience that is alleviated with simple therapeutic treatments. This 
experience impacts usual daily activities. Includes laboratory tests alterations indicating 
injury, but without long-term risk.  
• 
Severe: An experience that requires therapeutic intervention unrelated to clinical trial 
treatment intervention. The experience interrupts usual daily activities. If hospitalization 
is required for treatment, this will be classified as an SAE.  
 
Relatedness Ratings 
Adverse Events (AEs) will be rated on the following three-point scale, to the degree to which the 
event appears to be related to the study intervention: 
• 
0, Unrelated 
• 
1, Possibly Related 
• 
2, Definitely Related 
 
Expectedness Ratings 
Adverse Events (AEs) will be assessed as to wither they were expected to occur or unexpected, 
meaning not anticipated based on current knowledge found in the protocol or based on the treating 
clinician’s experience: 
 
• 
Unexpected: the nature or severity of the event is not consistent with information about 
the condition under study or intervention in the protocol, consent form, or clinician’s 
experience 
• 
Expected: the event is known to be associated with the intervention or condition under 
study.   
 
Unanticipated Problem (UP): an unanticipated problem involving risk to human participants or 
others, is one that (1) was unforeseen at the time of its occurrence, (2) is related or possibly related 

 
16
to participation in the research, and (3) indicates that participants or others are at an increased risk 
of harm. 
 
 
 
Serious Adverse Events (SAE): Any AE that result in any of the following outcomes:  
• 
Death 
• 
Suicide/Homicide Attempt 
• 
Life-Threating event  
• 
Event requiring inpatient hospitalization 
• 
Persistent or significant escalation of disability/incapacity  
 
There is no evidence that participation in this treatment trial will increase risk of a serious adverse 
event (SAE). 
7.4 
Reporting Procedures 
AEs will be identified at any time during participation in this treatment study. Reports of AEs to the 
Get Living Study team will be assessed and noted. The study team will be informed to notify the PI 
of any AEs identified during treatment or throughout the duration of enrollment in the study. 
Parents of patients will also be asked to notify the study team if an AE has occurred. During follow-
up contact, the study staff will ask patient and parent if any AEs have occurred since the end of 
treatment. The known potential risks will be described in informed consent documents and 
protocol. 
 
All AEs and SAEs will be monitored on a continual basis and documented, by participant, in the 
respective eCRFS on REDCap. All AEs and SAEs will also be collated across participants into a Master 
Sheet for presentation to the Safety Monitoring Committee (SMC) at quarterly meetings.  In 
addition, all SAEs and UPs are reported according to the Stanford Medical IRB reporting guidelines 
(within 10 working days of occurrence). Follow-up remediation will occur within five days of the 
IRB’s response or decision. All AEs will be reviewed quarterly by the PI and SMC. 
 
SAEs and specific treatment intervention-associated AEs will be reported to the PI, Dr. Laura Simons, 
and responsible study staff within 24 hours. All SAEs and UPs will be reported to the NIAMS within 
48 hours of the investigator becoming aware of the event. There are no SAEs anticipated for this 
research study. 
 
7.5 
Follow-up for Adverse Events 
All AE’s will be reported to the IRB of record within five days. Follow-up remediation will occur within 
five days of the IRB’s response or decision. 
7.6 
Safety Monitoring  
Oversight of this clinical trial is provided by the Principal Investigator (PI), Dr. Simons. The Study 
Monitoring Committee (SMC) will involve the following individuals:  
 
- 
 (Medical Expertise) – Institute of Creative Technologies, USC 
- 
 (VR in Pain Expertise) – College of Engineering at U of Washington 
- 
, PT M (Psychology Expertise) – Ottawa Hospital Rehabilitation Centre 
 
This is a multi-site clinical trial involving low risk. The individuals listed above, along with Dr. 
Simons and the Institutional Review Board (IRB), will be responsible for the duties involved with 
this data monitoring.  

 
17
 
Conflict of Interest for Monitoring Bodies. Members of the SMC will have no direct involvement 
with the PI or the administration of the intervention. Each member will sign a Conflict of Interest 
(COI) Statement which includes current affiliations, if any, with any steering committees or 
advisory councils associate with study, pharmaceutical, and biotechnology companies (i.e. 
stockholder, consultant), and any other relationship that could be perceived as a conflict of 
interest related to the study and/or associate with commercial or non-commercial interests 
pertinent to the study objectives.  
 
Protection of Confidentiality. Only de-identified and re-coded data will be presented during open 
sessions with the SMC. All data, whether in a report or discussed during SMC meetings are kept 
confidential. Participant identities will be kept confidently unless there are serious safety concerns 
in which the PI and SMCs involved may request and necessitate the identification of some or all 
data.  
 
Monitoring Entity Responsibilities. The following are details of members of the study monitoring 
entity’s responsibilities:  
- 
Review of Study Documentation: The CRC will be responsible for reviewing the Data Safety 
Monitoring Plan (DSMP), informed consent/assent documents, protocol amendments, and 
updates to the Manual of Operating Procedures (MOP) and Clinical Protocol for this trial on a 
weekly basis. The CRC will notify the PI immediately with any PDs and approvals for 
amendments to the protocol. The PI will have access to all these documents at all times and 
will be responsible for meeting with the SMC on a quarterly basis.  
 
- 
Subject Accrual: Review of subject accrual rates and compliance with inclusion/exclusion 
criteria will be conducted by the PI and SMC on a quarterly basis to ensure a sufficient number 
of participants are enrolled, properly screened for eligibility, and targeted goals outlined in the 
grant proposal are being met.  
 
- 
Enrollment: Review of the status of enrolled subjects will be monitored on a regular basis by 
the CRC and the PI. Quarterly updates will be monitored by the PI and SMC to ensure target 
enrollment is being met per grant proposal. Monthly enrollment reports will be provided to 
the NIAMS via NCR by the CRC. 
 
- 
Adherence Data: Data on adherence to treatment protocol will be collected on a weekly basis 
by the CRC and reviewed quarterly by the PI and SMC.  
 
- 
AEs and Rates: Adverse Events and the rate of occurrence will be tracked and noted per 
occurrence and the PI will be notified. Unless indicated necessary, AEs will be reviewed 
quarterly by the PI and SMC.  
 
- 
SAEs: Serious Adverse Events will be monitored in real-time and the PI will be notified within 
24 hours of occurrence by the treatment team. The PI, SMC, NIAMS/NCR, and IRB will review 
this SAE and take appropriate action for the safety of the patient. It will be evaluated at the 
time of occurrence whether the participant will be withdrawn from the study.  
 
- 
PDs: Major PDs will be communicated to the PI immediately. All events will be communicated 
to the NIAMS via NCR within 48 hours of the PI becoming aware of the event. 
8. INTERVENTION DISCONTINUATION  
Patients and their parents have the right to withdraw consent/assent or discontinue participation at 
any time without penalty or any impact on the child’s care. Because this is an exploratory clinical 

 
18
trial, we will not discontinue participation based on missed attendance to treatment sessions. There 
will be no temporary discontinuations from treatment or study participation. The PI may withdraw 
a patient/parent dyad from the study for one or more of the following reasons:  
• 
Failure to follow instructions of the PI or study staff. 
• 
The PI decides that continued participation would be harmful (e.g., patient reports 
increased emotional or physical distress from exposure therapy) 
Patients and parents will be asked permission to use data collected form the study if they are asked 
to discontinue or decide to withdraw from the study.  
9. STATISTICAL CONSIDERATIONS  
9.1 
General Design Issues  
To characterize feasibility of a future hybrid effectiveness-dissemination trial of PRVR in 
routine physiotherapy practice. Hypotheses: PRVR participants will have (1) high patient-
reported treatment satisfaction and high clinician-rated patient engagement scores; Clinicians 
will report high clinical proficiency and self-efficacy in using PRVR.  
 
Analysis Plan: Satisfaction. We will examine mean satisfaction scores, clinician rated 
engagement scores, and clinician proficiency and efficacy with PRVR clinical use. 
Adherence/retention. We will examine mean adolescent adherence to survey completion, 
percent of patients who dropout prior to treatment completion, and VR side effects reported. 
Health care costs and pain medication use. We will examine health care and pain medication 
use by calculating totals via healthcare cost surveys and compared across timepoints. 
10. DATA COLLECTION AND QUALITY ASSURANCE 
10.1 
Data Collection Forms  
The majority of the research data, including self-reported questionnaires, informed consent forms, 
appointment tracking, case report forms, adverse events, serious adverse events, protocol 
deviations, and unanticipated problems will be sourced and captured electronically by participant 
via REDCap. If participants opt to complete daily diaries, daily check-in surveys will be collected 
electronically by participant via LifeData. Data collection will occur either in-person on an 
encrypted study iPad, or at home via electronic surveys. 
 
REDCap’s features include research data collection instruments (surveys and forms), and an e-
Consent Auto-Archiver Framework. The e-Consent Framework platform will be used to consent 
patients on site using a computer-based consent form rather than traditional paper 
documentation. 
 
LifeData is a mobile application to collect experience sampling, ecological momentary assessment, 
and electronic check-ins. This app will be used to easily push notifications to child and parent 
devices to collect Daily Check-in data.  
 
Word document versions of the REDCap data collection instruments can be found in the MOP 
Supplemental Materials Section: 
 
 
 
 
 
Supplemental Materials I: Electronic Case Report Form (eCRF) Templates 
 
 
 
Supplemental Materials II: Research Consent and Assent Forms 
 
 
 
Supplemental Materials III: Self-Reported Questionnaires 
 

 
19
The CRC will be responsible for maintenance of all data collection forms, and will include any updates 
in the monthly report to the NIAMS via NCR.  
10.2 
Data Management  
All questionnaire data collected for the study will be exported into SPSS, SAS or R via REDCap. 
Treatment session audio/video recordings may be recorded digitally and saved on the secure, 
private drive on the server and only personnel associated with the study will have access to the 
files. 
10.3 
Quality Assurance  
10.3.1 Training 
Stanford University uses the “CITI” training program (Collaborative Institutional Training Initiative; 
https://www.citiprogram.org/). All staff must pass required tests on each module. A refresher 
course must be passed every 3 years.  
Per NIH requirements, all staff will be trained in Good Clinical Practice (GCP), consistent with 
principles of the International Conference on Harmonisation (ICH) E6 (R2). The CRC will be 
responsible for maintaining documentation of all CITI and GCP training certifications. 
An outpatient team of licensed Physical Therapists at each clinical site will provide study intervention 
sessions, trained in this modality of treatment by Laura Simons, PhD with ongoing consultation from 
Amy Weisman PT, DPT (expert in physical rehabilitation for chronic pain) and Maria Menendez, MD 
(expert in virtual reality intervention administration). 
The PI will be responsible for and oversee all training of research personnel in GCP and the delivery 
of study interventions. All members of the research team will be trained on the contents of this 
document (MOP) and relevant study materials prior to beginning work on the study. 
 
The PI and CRC will hold primary responsibility for study data quality control. To address quality 
control methods, all data will be entered into REDCap using standardized electronic case report 
forms (eCRFs).  
 
10.3.2 Quality Control Committee  
The PI and research coordinator will be hold primary responsibility for study data quality control. To 
address quality control methods, chart data will utilize standardized collection forms.  For data entry 
of study information, a portion of files will be re-entered by a separate person, to check for 
consistency.  If consistency is low, the entire data set will be re-entered.  
10.3.3 Metrics 
All self-report outcome measures have demonstrated psychometric soundness, including reliability 
and validity. 
10.3.4 Protocol Deviations 
Each protocol deviation (PD) will be captured and documented, by participant, in the Protocol 
Deviation Tracking Log eCRF (MOP Appendix E). All PDs will be collated and reviewed by the CRC and 
study PI. 
A major protocol deviation or violation includes any procedure that differs from the IRB-approved 
protocol that was intended to eliminate an immediate hazard to the participant, was harmful, or is 
possible serious or continue non-compliance by a study staff member.   
Major protocol deviations will be communicated to the PI immediately. All events will be 
communicated to the NIAMS via NCR within 48 hours of the PI becoming aware of the event.  

 
20
Protocol deviations/violations that occur but do not affect participant safety will be submitted as 
part of the quarterly reports distributed to the SMC and subsequently shared with the NIAMS. 
10.3.5 Monitoring 
The study will be monitored by the research coordinator regularly throughout the collection of data. 
Oversight of this clinical trial is provided by the Principal Investigator (PI), Dr. Simons and a Study 
Monitoring Committee (see section 7.6).  
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 
Institutional Review Board (IRB) Review  
This protocol and the informed consent document (MOOP Supplemental Materials II) and any 
subsequent modifications will be reviewed and approved by the Stanford IRB responsible for 
oversight of the study.  
11.2 
Informed Consent Forms 
A signed consent form will be obtained from each parent participant, and a signed assent form for 
each child participant. For participants who cannot consent for themselves, such as those with a 
legal guardian (e.g., person with power of attorney), this individual must sign the consent form. 
The consent form will describe the purpose of the study, the procedures to be followed, and the 
risks and benefits of participation. A copy will be given to each participant or legal guardian and 
this fact will be documented in the participant’s record. Per IRB requirements, any participant who 
turns 18 years of age while actively enrolled during the course of study will be contacted and 
consented as an adult. 
 
11.3 
Participant Confidentiality  
Any data, specimens, forms, reports, video recordings, and other records that leave the site will be 
identified only by a participant identification number (PID) to maintain confidentiality. All records 
will be kept in a locked file cabinet. All computer entry and networking programs will be done using 
PIDs only. Information will not be released without written permission of the participant, except as 
necessary for monitoring by IRB, the FDA, the NIAMS, and the OHRP. 
11.4 
Study Discontinuation  
The study may be discontinued at any time by the IRB, the NIAMS, the OHRP, the FDA, or other 
government agencies as part of their duties to ensure that research participants are protected.  
12. COMMITTEES 
Steering committee – Study PI, Co-Investigators, and Research Coordinator for this study will meet 
monthly to discuss study progress relative to milestones, coordinate efforts, and review any protocol 
deviations or other issues requiring adjustment.  
Safety Monitoring Committee – The Study PI and Study Monitoring Committee (Section 7.6) will 
meet quarterly to review study accrual, status of enrollment, adherence to data regarding study visit 
and intervention, and adverse events.  
13. PUBLICATION OF RESEARCH FINDINGS  
As an NIH-funded Clinical Trial this study will be registered at, and will submit summary results 
information to, ClinicalTrials.gov for public posting. Publication of the results of this trial will be 
governed by the policies and procedures developed by the Steering Committee.  

 
21
As an NIH-funded Clinical trial, mandatory submission of the final manuscript will be made to the 
NIH National Library of Medicine PubMed central for archiving upon acceptance for publication. 
 
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