Conditions: Opioid Use Arthropathy of Knee Pain, Postoperative
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 63
Healthy volunteers: no

Brief summary:
This is a single-center, prospective, randomized, controlled study of the appliedVR RelieVRx headset in subjects undergoing Total Knee Arthroplasty (TKA). This study will evaluate two primary endpoints - effectiveness of a single use of RelieVRx in the reduction of acute postoperative pain by 20%; and overall effectiveness of RelieVRx as an opioid-sparing intervention, where opioid consumption is reduced by at least 20% over a 90-day postoperative period in the interventional, standard of care (SOC) plus RelieVRx group compared to the control, SOC group.

Detailed description:
This is a single-center, prospective, randomized, controlled study of the appliedVR RelieVRx headset in subjects undergoing Total Knee Arthroplasty (TKA). Patients will be randomized to one of the two groups after study enrollment, and patients in the test arm will be educated about the device preoperatively to facilitate its use in the acute post-operative period. The goals of VR will be presented in the context of an alternate method of pain control to opioids. This study will evaluate two primary endpoints - effectiveness of a single use of RelieVRx in the reduction of acute postoperative pain by 20%; and overall effectiveness of RelieVRx as an opioid-sparing intervention, where opioid consumption is reduced by at least 20% over a 90-day postoperative period in the interventional, standard of care (SOC) plus RelieVRx group compared to the control, SOC group.

Arms:
arm 1: Receive standard of care for pain management, do not receive RelieVRx headset arm 2: Receive standard of care for pain management, plus RelieVRx headset

Interventions: intervention 1: RelieVRx headset intervention 2: multi-modality pain management
Intervention descriptions: intervention 1: RelieVRx is a virtual reality therapy intended as adjunctive treatment for acute surgical pain intervention 2: combination of medications may be used such as a local anesthesia, ibuprofen, acetaminophen, gabapentin, ketamine, lidocaine, and opioids

Protocol document:
Prot_SAP_000.pdf: 
PI Name: Michael Suk, MD 
Research Protocol: July 25, 2019 
Version 1.2 (03/17/20) 
CONFIDENTIAL AND PROPRIETARY 
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Safety and Effectiveness of Virtual Reality utilizing RelieVRx for Total Knee 
Arthroplasty (TKA) for the Reduction of Acute Postoperative Pain and 
Opioid Use 
NCT04010266 
 
Principal Investigator: 
 
Michael Suk, MD, JD, MPH, MBA, FACS 
 
 
 
 
 
Chief Physician Officer, Geisinger System Services 
Chair, Musculoskeletal Institute & Department of 
Orthopaedic Surgery Geisinger Health System 
 
 
 
 
 
Address 100 N. Academy Ave., Danville, PA 17822 
 
 
 
 
 
Telephone 570-214-5605 
 
 
 
 
 
 
 
 
 
 


PI Name: Michael Suk, MD 
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TABLE OF CONTENTS  
1 
ABBREVIATIONS USED IN THE PROTOCOL ............................................................................ 4 
2 
ABSTRACT ....................................................................................................................................... 6 
3 
BACKGROUND AND SIGNIFICANCE .......................................................................................... 7 
4 
SPECIFIC AIMS ................................................................................................................................ 8 
4.1 
Specific Aim 1 ......................................................................................................................... 8 
4.2 
Specific Aim 2 ......................................................................................................................... 8 
4.3 
Specific Aim 3 ......................................................................................................................... 8 
5 
STUDY DESIGN ............................................................................................................................... 8 
5.1 
Description ............................................................................................................................... 8 
5.2 
Study Population ...................................................................................................................... 9 
5.2.1 
Approximate Number of Subjects ............................................................................ 9 
5.2.2 
Inclusion Criteria ...................................................................................................... 9 
5.2.3 
Exclusion Criteria ..................................................................................................... 9 
5.3 
Recruitment ............................................................................................................................ 10 
5.4 
Study Duration ....................................................................................................................... 10 
5.4.1 
Approximate Duration of Subject Participation ..................................................... 10 
5.4.2 
Approximate Duration of Study ............................................................................. 10 
5.5 
Procedures .............................................................................................................................. 11 
5.5.1 
Study Time and Events Table ................................................................................. 12 
5.6 
Study endpoints and statistical plan ....................................................................................... 14 
5.6.1 
Sample Size Considerations ................................................................................... 15 
5.7 
Data Management .................................................................................................................. 16 
5.7.1 
Data Collection and Storage ................................................................................... 16 
5.7.2 
Records Retention .................................................................................................. 17 


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6 
SAFETY MONITORING ................................................................................................................ 17 
6.1 
Adverse Event Reporting ....................................................................................................... 17 
6.2 
Definitions .............................................................................................................................. 17 
6.3 
Recording and Reporting ....................................................................................................... 19 
6.4 
Serious Adverse Event Reporting .......................................................................................... 19 
7 
PROTECTION OF HUMAN SUBJECTS ....................................................................................... 19 
7.1 
Informed Consent ................................................................................................................... 19 
7.2 
Protection of Human Subjects Against Risks ........................................................................ 20 
8 
PUBLICATION PLAN .................................................................................................................... 20 
9 
REFERENCES ................................................................................................................................. 21 
 


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1 
 ABBREVIATIONS USED IN THE PROTOCOL 
Abbreviation 
Term 
ACC 
AE 
AUC 
BMI 
CDC 
CMS 
DVT 
EHR 
EMR 
FDA 
Anterior Cingulate Cortex 
Adverse event 
Area under Curve  
Body Mass Index 
Center for Disease Control 
Centers for Medicare & Medicaid Services 
Deep Vein Thrombosis 
Electronic Health Record 
Electronic Medical Record 
Food and Drug Administration 
GIRB 
Geisinger IRB 
IRB 
LOS 
KOOS 
MME 
MRI 
MRN 
MRSA 
NPRS 
OUD 
PACU 
PDMP 
PE 
PI 
Institutional Review Board 
Length of Stay 
Knee Injury and Osteoarthritis Outcome Score 
Morphine Milligram Equivalents 
Magnetic resonance Imaging 
Medical Record Number 
Methicillin-Resistant Staphylococcus Aureus 
Numerical Pain Rating Scale 
Opioid Use Disorder 
Post Anesthesia Care Unit 
Prescription Drug Monitoring Program 
Pulmonary Embolism 
Principal Investigator 


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Abbreviation 
Term 
PT 
RA 
Physical Therapy 
Rheumatoid Arthritis 
RCT 
Randomized Controlled Trial 
SAE 
SOC 
TKA 
Serious adverse event 
Standard of Care 
Total Knee Arthroplasty 
VR 
VR-12 
Virtual Reality 
Veterans Rand 12 Item Health Survey 
 
 
 


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2 
ABSTRACT 
In 2016, the American Pain Society published guidelines on the management of postoperative 
pain based on a systematic review of the various interventions and management strategies. A key 
recommendation was that "clinicians offer multimodal analgesia, or the use of a variety of 
analgesic medications and techniques combined with non-pharmacological interventions, for the 
treatment of postoperative pain in children and adults (strong recommendations, high-quality 
evidence). [1] 
According to the August 21, 2013 Journal of Bone and Joint Surgery, one half of patients now 
receiving knee replacements are under 65 and demand for Total Knee Arthroplasty (TKA) is 
expected to exceed 3.5 million procedures per year by 2030. [2] 
Multimodal treatment plans provide an advantage for acute postoperative pain. Multi-modal pain 
treatment can also be improved by discharge to home and performing activities of daily living, 
physical therapy treatment within 24 hours of discharge and weight bearing as tolerated. The use 
of virtual reality (VR) has been shown to be a safe and effective adjunctive therapy for pain and 
low risk opioid sparing treatment. [3] 
We propose to study the effects of a VR-based pain management program, RelieVRx, in acute 
postoperative pain after orthopedic TKA surgery in 100 patients (50 patients in the standard of 
care plus RelieVRx test group and 50 patients in the standard of care control group). RelieVRx is 
a virtual reality therapy intended as adjunctive treatment for acute surgical pain. RelieVRx is 
intended to be a prescription therapy for the reduction and/or elimination of opiate use in patients 
suffering from acute surgical pain. Patients will be randomized to one of the two groups after 
study enrollment, and patients in the test arm will be educated about the device preoperatively to 
facilitate its use in the acute postoperative period. The goals of VR will be presented in the 
context of an alternate to opioids for pain control. Subjects will be assured they will receive SOC 
analgesic management in addition to the VR headsets. 
 


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3 
BACKGROUND AND SIGNIFICANCE 
Pain following orthopedic injuries and operations, including over 6.6 million orthopedic 
surgeries anticipated in 2020 [1], is significant and sustained during the entire period of recovery. 
This recovery period can be quite long depending on the specific orthopedic operation and 
underlying disease or comorbidities. Treatment and management of this pain is traditionally 
based primarily around utilizing pharmacological management. 
Opiates are commonly prescribed as part of post-operative pain management which can lead to 
Opioid Use Disorder (OUD). These agents can yield both inconsistent and sub-optimal results 
[4] and greatly increase the risk of the patient developing an opioid addiction or OUD. Data from 
the U.S. Center for Disease Control (CDC) revealed that even a single day of opioid therapy can 
predict up to a 6% increase in the risk of the patient developing a dependency within a year [5].   
Two retrospective cohort studies found opioid therapy prescribed for acute pain was associated 
with greater likelihood of long-term use. One study evaluated opioid-naïve patients who had 
undergone low-risk surgery, such as cataract surgery and varicose vein stripping [5]. Use of 
opioids within 7 days of surgery was associated with increased risk for use at 1 year. The second 
study found that among patients with a workers’ compensation claim for acute low back pain, 
compared to patients who did not receive opioids early after injury (defined as use within 15 
days following onset of pain), patients who did receive early opioids had an increased likelihood 
of receiving five or more opioid prescriptions 30–730 days following onset that increased with 
greater early exposure [6]. While new opioid guidelines, such as the 2016 CDC opioid guidelines 
[7] or 2018 Centers for Medicare and Medicaid Services (CMS) rules [8], are limiting the 
number of opioids available to opioid “naïve” patients to an initial 7-day supply, regardless of 
dose, a lack of alternative pain management solutions exist.  
Unlike VR, opioids have a significant adverse event profile that includes hypotension, 
respiratory depression or arrest, aspiration, or vomiting. Although both risks and costs are often 
considered manageable, it is imperative to devise alternatives to address pain after surgery that 
are cost-effective and improve the risk benefit profile well above standard of care.  
It is hypothesized that the anterior cingulate cortex (ACC) plays a significant role in both the 
detection and response to pain. Indeed, functional MRI (fMRI) studies with VR have shown 
diminished pain-related brain activity in five regions associated with pain sensation. Regarding 
emotion, it has been demonstrated that emotions can modulate pain by activation/deactivation of 
the amygdala. Negative emotions, such as anxiety and depression, can facilitate pain while 
positive emotions can inhibit the pain-control pathway. 
 


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To reduce addiction, low risk, non-opioid pain analgesics are in great need and virtual reality 
(VR) shows great promise as a solution. Therapeutic VR has emerged as an effective, non-
pharmacological treatment modality for pain [4]. Users of VR wear a pair of goggles with a 
close-proximity screen that creates a sensation of being transported into immersive, three-
dimensional worlds. A hypothesis for the mechanism of action for VR suggests that by 
stimulating the visual cortex while simultaneously engaging other senses, VR is able to limit the 
user’s processing of pain signals [4].  
4 
SPECIFIC AIMS 
4.1 
SPECIFIC AIM 1 
Among standard of care (SOC) plus RelieVRx (SOC+RelieVRx) group, compare pain scores 
before and after use of RelieVRx. Hypothesis: Acute postoperative pain scores will decrease by 
at least 20% or 2 points on a 0-10 Numerical Pain Rating Scale (NPRS) after each use of 
RelieVRx.  
4.2 
SPECIFIC AIM 2 
Compare pain scores between the SOC group and SOC+RelieVRx group. Hypothesis: 
Cumulative pain scores will be comparable among the SOC+RelieVRx group and SOC group.  
4.3 
SPECIFIC AIM 3 
Compare opioid use between the SOC group and SOC+RelieVRx group. Hypothesis: Opioid 
consumption will be reduced by at least 20% over a 90-day postoperative period in the 
SOC+RelieVRx group compared to the SOC group.  
5 
STUDY DESIGN 
5.1 
DESCRIPTION 
This is a prospective, randomized, controlled study of the appliedVR RelieVRx pain 
management solution in subjects undergoing Total Knee Arthroplasty (TKA).  
Patients at each study site will be randomized by computer 1:1 to either the SOC (control) group 
or the SOC+RelieVRx (test) group. The SOC+RelieVRx group will receive education and 
hands-on experience with the VR headset and RelieVRx pain management solution at a routine 
preoperative patient education class or during the history and physical encounter visit through a 
predetermined script to make the patient feel comfortable using the device on their own. The 
goals of VR will be presented in the context of an alternate method of pain control to opioids. 
Subjects will be assured they will receive SOC analgesic management in addition to the 
headsets. The participating surgeons and anesthesiologists at Geisinger Medical Center will 


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adhere to a standardized medication regimen for anesthesia and pain relief prescriptions in order 
to minimize confounding between the groups due to differences in pain medication treatment 
plans.  
5.2 
STUDY POPULATION 
5.2.1 Approximate Number of Subjects 
Approximately 100 Geisinger subjects who have TKA surgery at Geisinger will participate in 
this study (50 will be in the SOC group and 50 will be in the SOC+RelieVRx group).      
5.2.2 Inclusion Criteria 
For inclusion, the study subjects should fulfill the following criteria:  
1. ≥ 18 years old 
2. Willing and able to read, comprehend, and sign the study informed consent form in 
English prior to study specific procedure 
3. Scheduled for Total Knee Arthroplasty (TKA) surgery 
4. Score of 1-3 based on the American Society of Anesthesiologists Physical Status 
Classification System  
5. Attended the pre-op Total Joint Arthroplasty Patient Education class (Proven Recovery 
Program©) 
6. Agrees to be enrolled in Force Therapeutics, a web-based, digital rehabilitation and 
education program 
7. Has family member, friend, or community support during post-surgical recovery period 
5.2.3 Exclusion Criteria 
For exclusion criteria, subjects should not enter the study if any of the following exclusion 
criteria are filled:  
1. Diagnosed with chronic pain syndrome 
2. Body Mass Index (BMI) ≥ 40 
3. Current tobacco user at time of surgery 
4. Uncontrolled sleep apnea 
5. Bilateral TKA 
6. Current or recent history (in past year) of substance abuse disorder 


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7. Uncontrolled diabetes (HbA1c ≥ 7.0) 7.8 at time of surgery 
8. History of Pulmonary Embolism (PE) or Deep Vein Thrombosis (DVT) 
9. Currently being treated with blood thinners at time of surgery 
10. Diagnosis of Rheumatoid Arthritis (RA) 
11. Has Methicillin-resistant Staphylococcus aureus (MRSA) 
12. Currently pregnant/breastfeeding or planning to in the next 3 months 
13. Comorbidities including neurological, psychosocial, sensory, or other disorders that may 
impact pain perception 
14. Diagnosis of epilepsy, dementia, migraines, or other neurological disorders that may 
prevent VR usage, and/or other medical conditions predisposed to nausea and dizziness 
15. Hypersensitivity to flashing lights or motion  
16. Claustrophobia 
17. Lack of stereoscopic vision  
18. Severe hearing impairment 
19. Injury to eyes, face, or neck that prevents comfortable VR usage 
5.3 
RECRUITMENT 
The primary and collaborating investigator(s) will identify potential subjects in their respective 
clinics that have elected to undergo primary TKA. These patients will also be pre-screened via 
manual chart review of their electronic health record (EHR) by the research team. Patients 
meeting the inclusion/exclusion criteria will be approached by an IRB approved study 
team member (e.g. primary and collaborating physicians, research project manager and/or project 
coordinator) during their orthopaedic clinic visit, orthopaedic health and physical, and/or Total 
Joint Class. Before asking for patient consent, the study will be explained in its entirety and the 
patient will have ample opportunity to ask any questions or express any reservations.  
5.4 
STUDY DURATION 
5.4.1 Approximate Duration of Subject Participation 
Subjects will participate in the study for approximately 4 months.  
5.4.2 Approximate Duration of Study 
This study will be completed in approximately two years. The end of the study is the last visit of 
the last subject or end of collection of data from the patient’s electronic medical record (EMR).   


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5.5 
PROCEDURES 
Standard of Care: Both the SOC+RelieVRx group and the SOC group will be enrolled in the 
Geisinger ProvenRecovery Program©, which includes a “My Rapid Recovery Kit” containing 
care instructions for mobility and nutrition, an antiseptic body wash to lessen the chances of 
infection, a spirometer to measure lung capacity, and immunonutrition drinks to avoid 
malnutrition and dehydration. Surgery through ProvenRecovery© is opioid avoiding and in 
many cases opioid free. During surgery, a patient’s pain is controlled by targeting only the 
surgical area. Known as multi-modality pain management, this technique allows for effective 
pain control of just one area and eliminates additional pain sources. A combination of non-opioid 
medications is used, depending on the surgery, such as a local anesthesia, ibuprofen, 
acetaminophen, gabapentin, ketamine, and lidocaine. 
Intervention: For all participants who are randomly assigned to the SOC+RelieVRx group, the 
RelieVRx headset will be provided by a study team member during the preoperative period, 
along with instructional materials. While in the hospital, use of the VR headset will be offered 
either in addition or as an alternative to SOC pain medication. The headset will be provided pre-
operatively, but patients will not be instructed to use the device until after their surgery. Patients 
will be instructed to use the device on the day of surgery after they are discharged from the Post 
Anesthesia Care Unit (PACU) to the inpatient unit, or at least 4 hours post-surgery. The device 
will then go with the patient upon discharge for use through the entire treatment period (i.e. 14 
days). Participants will use the RelieVRx headset for 14 days postoperatively a maximum of 3 
times per 24-hour period (morning, noon, and evening) for not more than 30 minutes 
consecutively. The patients will be instructed not to use the device while ambulating. 
Assessments: In inpatient postoperative periods, pain will be assessed as per routine with a 
Numerical Pain Rating Scale (NPRS) of 0-10, where zero equals the lowest pain level and 10 
equals the highest. This will be administered every 4 hours during the patient’s hospital stay, and 
each time the patient requests pain medication, either intravenous or oral. After patients are 
discharged from the hospital, they will be asked to complete a paper or online REDCap diary to 
track their pain levels, opioid/non-opioid pharmacotherapy, and device use from home. The daily 
log will capture the NPRS at the same time each evening (± 2 hours). Participants will be asked 
to record their NPRS at least 2 hours after taking any pain medication. In the SOC+RelieVRx 
group, NPRS also will be recorded before (within 15 minutes prior to use) and immediately after 
each use of the RelieVRx device. Analgesic medication use will be recorded in terms of 
medication type, dose, and time of administration.  
All participants will be enrolled in Force Therapeutics, a web-based, digital rehabilitation and 
education program. The patient is automatically enrolled when surgery is scheduled, and patient 


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participation is reinforced in the patient education class. This will allow for the easy collection of 
patient-reported outcome measures, such as VR-12 and KOOS Jr., after discharge. Outcomes 
data also may be collected via OBERD, a software system for patient-reported outcomes already 
in use at the study clinics. To assess opioid use, the investigators will query Pennsylvania's 
Prescription Drug Monitoring Program (PDMP) database. To maintain compliance with ABC-
MAP Act 191 of 2014, study investigators will query the PDMP only for their existing patients. 
The RelieVRx devices will collect information related to device usage (i.e. frequency and 
duration of use, experiences selected, etc.). Patients who are not using their RelieVRx device as 
prescribed and/or not completing the prescribed questionnaires in Force may be contacted via 
phone or email by the study team to further encourage participation. Participants will be asked to 
return their device to the study team at a routine postoperative clinic visit. 
Outcome measures include: 
• Pain will be assessed via the standard Geisinger Numerical Pain Rating Scale (NPRS) 
ranging 0-10 (0 = least amount of pain, 10 = worst amount of pain).   
o Every 4 hours during patient’s hospital stay 
o Daily for the remainder of the first 14 postoperative days 
o Before (within 15 minutes prior to use) and immediately after each use of their 
device 
• Physical function will be assessed by the KOOS Jr. (Knee Osteoarthritis Outcome) 
• Analgesic medication use will be assessed in three ways:  
o Reviewing inpatient use as recorded in EMR 
o Extrapolating total milligrams of morphine equivalent doses filled from PDMP 
database through 90-days postoperative 
o Patient self-reported consumption 
• Quality of life will be assessed using the Veterans RAND 12 Health Survey (VR-12) – 
physical component score 
• PACU length of stay (LOS) 
• Hospital LOS 
• Time to initial ambulation 
• Clinic and emergency department visits within 90-days postoperative 
• Inpatient readmissions for uncontrolled pain within 90-days postoperative 
• Surgical complications, such as infection or delayed healing, within 90-days 
postoperative 
5.5.1 Study Time and Events Table    
 


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Study Procedures 
Pre-
surgery 
Day of 
Surgery 
Inpatient stay 
(multiple times 
per day) 
Daily for 14 days 
postoperative 
(multiple times 
per day)*  
14, 30, 60, 90 
days 
postoperative* 
Review inclusion/exclusion 
X 
 
 
 
 
Demographics, 
medical history 
X 
 
 
 
 
Informed consent 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
Device set-up and 
orientation1 
X 
 
 
 
 
Surgery2 
 
X 
 
 
 
NPRS pain score 
X 
X 
X 
X 
X 
KOOS Jr. and VR-12 
X 
 
 
 
X 
Analgesic medication use 
X 
X 
X 
X 
 
Opioid use 
X 
X 
X 
X 
X 
LOS, time to initial 
ambulation, ED visits, 
readmissions 
 
 
 
 
X 
Device utilization statistics3 
X 
X 
 
X 
 
AE / Complication Reporting 
X 
X 
X 
X 
X 
 
1 RelieVRx group only 
2 Corresponds to pre-surgery, day of surgery, and inpatient stay timepoints on the billing determination 
* Data collected from patient at home via phone or online; not an in-person visit 


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5.6 
STUDY ENDPOINTS AND STATISTICAL PLAN 
This study will evaluate two primary endpoints – effectiveness of a single use of RelieVRx in the 
reduction of acute postoperative pain by 20%; and overall effectiveness of RelieVRx as an 
opioid-sparing intervention, where opioid and non-opioid consumption is reduced by at least 
20% over a 90-day postoperative period in the SOC+VR group compared to the SOC group. 
Acute effectiveness will be evaluated using NPRS data collected before and after each use of 
RelieVRx (up to 3 times per day) over the 14-day postoperative period. NPRS is measured on a 
scale of 0-10, with 0 being the least amount of pain and 10 being the most. Because pain levels 
will vary by time of day administered and are expected to peak in the first 24-72 hours 
postoperatively and drop afterward, acute effectiveness will be evaluated at all stages of 
recovery. The expected 20% reduction after single use will be scaled relative to the pre-use pain 
score [e.g. users reporting a pre-VR pain level of 8 would need to report post-VR pain levels of 
6.4 (8 * 80%) on average; users reporting pre-VR pain of 5 would need to report pain levels of 4 
post-VR, etc.]. Each SOC+VR patient will use VR up to 44 times over the 14-day recovery 
period, requiring linear mixed model analysis to assess acute changes in pain scores while 
accounting for stage of recovery and other covariates, such as age, preoperative health status and 
opioid use, and postoperative complications. For interim and final endpoint analyses, pain %-
change scores will be calculated for each use and averaged for each patient across the 72-hour 
acute postoperative period, the following week, after 10 days, and overall. These averages will 
be evaluated using one-sample unpaired t-tests (or the nonparametric one-sample Wilcoxon 
signed-rank test, as needed for non-normal data).  
Overall effectiveness will be evaluated by tracking daily opioid usage 90 days postoperatively in 
both SOC and SOC+VR groups. Average MMEs (Morphine Milligram Equivalents) per day will 
be compared using unpaired Student’s t-test (or the nonparametric Wilcoxon rank-sum test) in 
interim and final endpoint analyses. In addition, changes in usage over time will be evaluated 
using linear mixed models (or nonlinear models, given data shape), accounting for variations in 
recovery time across patients and other covariates, such as other analgesic medications used 
postoperatively, preoperative opioid use, and dosage changes. A sub-analysis will compare usage 
in the 14-day acute postoperative recovery period. 
The secondary endpoint of this study is a comparison of the cumulative experience of pain over 
the 14-day acute postoperative period between SOC and SOC+VR groups. In order to quantify 
pain that fluctuates over time, NPRS pain scores will be plotted for each patient over the acute 
postoperative period, using straight-line interpolation between measurements. This approach will 
allow for incorporation of all data collected (even if some patients participate more than others), 
and will avoid overemphasis on a single outcome measure (e.g. pain on day 14). Percent-area-
under-the-curve (VAS-%AUC) measurement will be calculated for each patient by adding the 


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areas of consecutive trapezoids defined by time on the x-axis and pain level measurements on the 
y-axis (e.g. 100% would indicate pain scores of 10 across the entire time period; 50% would 
indicate a linear reduction from 10 to 0 over the same time period). In interim and final endpoint 
analyses, NPRS-%AUC accumulated to date will be compared between groups using an 
unpaired Student’s t-test (or nonparametric equivalent). In addition, linear mixed models will be 
used to compare cumulative pain between SOC and SOC+VR groups over time, as well as pain 
experienced in the inpatient postsurgical period and following days. 
Additional outcome data will be compared between groups in preliminary analyses using chi-
squared tests (for categorical variables), unpaired Student’s t-tests (for single-measure normal 
continuous data), or nonparametric equivalent (for non-normal data), as appropriate. For 
measures collected at multiple time points, %AUC values will be calculated per patient and 
compared using aforementioned tests. In final analyses, outcomes will be compared using linear 
mixed models, allowing for data missing at random and evaluation of covariates.  
When approximately 25% of the total required sample has been collected, patient data will be 
summarized to verify adequate study power, and interim analyses will be conducted. In order to 
preserve a Type I error rate of 5% (i.e., α = 0.05) for final analyses, interim analyses will be 
conducted with p-value threshold of 0.001, as suggested using the Hybittle-Peto method, 
meaning that only effects where d > 2.0 will be significant. Additional patients may be recruited 
as needed to ensure sufficient study power, and fewer patients may be recruited if interim 
analyses demonstrate highly significant effects. All statistical analyses will be performed with 
SAS (SAS 9.4, SAS Institute, Cary, NC), Stata (SE 14.2, StataCorp, LLC, College Station, TX), 
or R (R 3.5.2, The R Foundation, Vienna, Austria) statistical software, with p-values of <0.05 
considered statistically significant. 
5.6.1 Sample Size Considerations 
This study has been designed with consideration for power requirements of both primary and 
secondary endpoint evaluations, as well as requirements for a noninferiority trial evaluating the 
overall effectiveness of RelieVRx as an opioid-sparing product. 
Primary Endpoints 
Preliminary data collected at Geisinger Medical Center (Danville, PA) between March 2017 and 
December 2018 from 1,052 patients who underwent total joint arthroplasty showed an average 
postoperative pain score of 8.50 following the procedure, and 6.16 on day 2 (SD = 2.0; change d 
= 1.2, or a 28% pain reduction) under SOC. 
To assess the acute effectiveness endpoint of 20% average reduction in pain scores, each one-
sample t-test only requires data from 13 patients to demonstrate a significant difference from 
zero, assuming 20% attrition, a Type I error rate of 5% and a Type II error rate of 20% (i.e., 80% 


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power). In order to observe significance of a lower threshold (e.g., a 10% reduction in pain level 
on average), data from 43 patients using VR will be required, assuming 20% attrition, a Type I 
error of rate 5% and 80% power. 
To assess the overall effectiveness for reducing opioid usage by at least 20%, this study assumes 
an average MME per day of 12.5mg (SD = 3) across all users, although continuous opioid users 
may report averages higher than 50mg/day. Observing a 20% relative reduction in opioid usage 
in the SOC+VR group compared to SOC (2.5mg) will require 64 patients total (32 per group), 
assuming 25% attrition, a Type I error rate of 5% and 80% power. If interim data analysis 
reveals unexpectedly high variability in opioid consumption, a revised power calculation based 
on new data may increase data collection requirements to address this question. 
Secondary Endpoint 
Using aforementioned preliminary data, two patients groups were created with simulated VAS-
%AUC data (with day 14 VAS means of 6.16 and 4.93, SD = 2.0; or, a 20% greater reduction at 
day 14) corresponding to a 7% difference in VAS-%AUC (0.86 versus 0.79; SD = 0.1; difference 
d = 0.7). Assuming 25% attrition, the study will require 92 patients total (46 per group). Data 
from at least 68 patients is needed to observe a statistically significant VAS-%AUC difference 
between SOC and SOC+VR of 7% in an unpaired t-test, with a Type I error rate of 5% and 80% 
power. 
 
5.7 
DATA MANAGEMENT 
5.7.1 Data Collection and Storage 
The following data points will be recorded via direct data collection, retrospective EMR review, 
and/or the Pennsylvania Prescription Drug Monitoring Program (PDMP) database: 
• Medical Record Numbers (MRN) (Will not be included in final data set) 
• Name (Will not be included in final data set) 
• Patient contact information (e.g. phone, email) (Will not be included in final data set) 
• Date of birth 
• Patient demographics such as gender, race/ethnicity, and BMI 
• Medical history relevant to inclusion/exclusion 
• Date(s) of clinic visits 
• Outcome measures (see section 5.5. for complete list) 


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The study coordinator(s) will randomly assign study ID numbers in place of MRNs. All study 
data will be stored on a secure Geisinger Health System server, and hard copy data will be 
double locked and accessible only to the study investigators. Only group-level information 
without personal identifiers will be included when presenting results or submitting manuscripts 
for publication. An IRB approved study team member will share the dataset with appliedVR via 
a secured e-mail.   
The RelieVRx devices will collect information related to device usage (i.e. frequency and 
duration of use, features utilized, completion rates). When connected to WiFi, the devices will 
automatically and securely transmit de-identified logs of headset usage. This data contains no 
PHI, is encrypted in transit, transmitted as frequently as every 5 minutes, and stored in 
appliedVR's secure and compliant cloud environment. Data will be aggregated and sent in a 
compatible format to Geisinger to be analyzed and cross referenced with patient study ID 
numbers. 
5.7.2 Records Retention 
Records of the data generated within the course of this study will be kept indefinitely and may be 
used for future research studies that have been reviewed and approved by the IRB. 
6 
SAFETY MONITORING  
6.1 
ADVERSE EVENT REPORTING 
Clinical adverse events (AEs) will be monitored throughout the study. All AEs will be reported 
to the institutional review board (IRB) regardless of whether they are considered study related.  
The date and time of onset and outcome, course, intensity, action taken, and causality to study 
treatment will be assessed by the study PI.  In the event of a serious AE (SAE), this will be 
reported to the Geisinger IRB (GIRB) according to the GIRB guidelines. All other AEs will be 
summarized and submitted to GIRB during continuing review. 
6.2 
DEFINITIONS 
An adverse event (AE) is any untoward, undesired, or unplanned event in the form of signs, 
symptoms, disease, or laboratory or physiologic observations occurring in a person given a test 
article or in a clinical study. The event does not need to be causally related to the test article or 
clinical study.  
A serious adverse event (SAE) is an AE that: 
• Results in death. 
• Is life-threatening (see below). 
• Requires inpatient hospitalization or prolongation of an existing hospitalization (see below). 


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• Results in a persistent or significant disability or incapacity (see below). 
• Results in cancer. 
• Results in a congenital anomaly or birth defect. 
• Additionally, important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition.  Examples of such events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
Life-threatening refers to immediate risk of death as the event occurred per the reporter. A 
life-threatening experience does not include an experience, had it occurred in a more severe 
form, might have caused death, but as it actually occurred, did not create an immediate risk of 
death. For example, hepatitis that resolved without evidence of hepatic failure would not be 
considered life-threatening, even though hepatitis of a more severe nature can be fatal. Similarly, 
an allergic reaction resulting in angioedema of the face would not be life-threatening, even 
though angioedema of the larynx, allergic bronchospasm, or anaphylaxis can be fatal. 
Hospitalization is official admission to a hospital. Hospitalization or prolongation of a 
hospitalization constitutes criteria for an AE to be serious; however, it is not in itself considered 
an SAE. In absence of an AE, a hospitalization or prolongation of a hospitalization should not be 
reported as an SAE by the participating investigator. This is the case in the following situations: 
• The hospitalization or prolongation of hospitalization is needed for a procedure required by 
the protocol. 
• The hospitalization or prolongation of hospitalization is part of a routine procedure followed 
by the center (e.g., stent removal after surgery).  This should be recorded in the study file. 
In addition, a hospitalization for a preexisting condition that has not worsened does not constitute 
an SAE. 
Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions. 
If there is any doubt about whether the information constitutes an SAE, the information is treated 
as an SAE. 
A protocol-related adverse event is an AE occurring during a clinical study that is not related 
to the test article but is considered by the investigator or the medical monitor (or designee) to be 


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related to the research conditions, i.e., related to the fact that a subject is participating in the 
study. For example, a protocol-related AE may be an untoward event occurring during a washout 
period or an event related to a medical procedure required by the protocol. 
Other Reportable Information.  Certain information, although not considered an SAE, must be 
recorded, reported, and followed up as indicated for an SAE.  This includes:  
• Pregnancy exposure to a test article, except for exposure to prenatal vitamins.  If a pregnancy 
is confirmed, use of the test article must be discontinued immediately.  Information about 
pregnancy exposure includes the entire course of pregnancy and delivery, and perinatal and 
neonatal outcomes, even if there are no abnormal findings.  Both maternal and paternal 
exposure are considered other reportable information.  For exposure involving the female 
partner of a male subject, the necessary information must be collected from the subject, while 
respecting the confidentiality of the partner. 
• Lactation exposure to a test article with or without an AE.    
• Overdose of a test article as specified in this protocol with or without an AE.  Baby formula 
overdoses without any AEs are excluded. 
• Inadvertent or accidental exposure to a test article with or without an AE. 
6.3 
RECORDING AND REPORTING 
A subject’s AEs and SAEs will be recorded and reported from the signing of the informed 
consent form through 1 year post-operative. 
6.4 
SERIOUS ADVERSE EVENT REPORTING 
Michael Suk, MD, JD, MPH, MBA, FACS, Chief Physician Officer, Geisinger System Services 
Chair, Musculoskeletal Institute & Department of Orthopaedic Surgery Geisinger Health System, 
will notify GIRB of all study SAEs in accordance with policy guidelines. If an SAE has not 
resolved at the time of the initial report, a follow-up report including all relevant new or 
reassessed information (e.g., concomitant medication, medical history) will be submitted to 
GIRB. An SAE will be followed until either resolved or stabilized.   
7 
PROTECTION OF HUMAN SUBJECTS 
7.1 
INFORMED CONSENT 
The investigator will provide for the protection of the subjects by following all applicable 
regulations. The informed consent form will be submitted to the IRB for review and approval.  
Before any procedures specified in this protocol are performed, a subject must: 
• Be informed of all pertinent aspects of the study and all elements of informed consent.  


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• Be given time to ask questions and time to consider the decision to participate. 
• Be allowed to visually and manually inspect the device. 
• Voluntarily agree to participate in the study.  
• Sign and date an IRB-approved informed consent form. 
7.2 
PROTECTION OF HUMAN SUBJECTS AGAINST RISKS 
The investigator will provide for the protection of the subjects by following all applicable 
regulations. Anticipated risks in this study are minimal. The major risk to human subjects is the 
accidental disclosure of PHI. In this regard, the assignment of a study ID number to each 
individual participant and the protocol of providing only the necessary associated clinical 
information to the remainder of the research team will mitigate this risk. All data will be coded 
and encrypted while being transferred. 
8 
PUBLICATION PLAN  
After clinical trials are completed, we intend to submit, together with our collaborators, results of 
the evaluations of RelieVRx for publication in order to promptly disseminate information on its 
efficacy. appliedVR will also prepare all study data for de novo submission to the FDA to obtain 
Class II review and clearance.  


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9 
REFERENCES 
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2. Journal of Bone and Joint Surgery, August 21, 2013. Cisternas MG, MGC Data Svcs, 
Murphy L. Croft JB. Helmick CG.  Racial Disparities in Total Knee Replacements among 
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9.The Veterans Rand 12 Item Health Survey (VR-12) AAOS.org – Medicare Health 
Outcomes Survey, NCQA permission granted March 2011. 
10. KOOS Jr., Hospital for Special Surgery, developer Stephen Lyman PhD (HSS 
validation cohort and FORCE-TJR registry) – Non-proprietary and free to use.