The VIGOR Study - Virtual Immersive Gaming to Optimize Recovery in Low Back Pain
Phase: NA
Conditions: Chronic Low Back Pain, Fear of Pain, Fear of Injury
Sponsor: Virginia Commonwealth University

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DETAILED STUDY PROTOCOL 
 
Principal Investigators: 
James S Thomas (contact), PT, PHD 
 
 
Supported by: 
Eunice Kennedy Shriver National Institute of Child Health and Human Development 
Grant Number: 1R01HD088417-01A1 
FAIN: R01HD088417 
ClinicalTrials.gov Identifier: Approved 
IRB: 17F011 
 
 

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Tool Revision History 
Version Number: DRAFT V0-1 
Version Date: 14 April 2020 
Sponsor Approval Date: To be determined 
IRB Approval Date: To be determined 
Summary of Revisions Made:  
 
Added the following assessments:  
o 
PROMIS SF v1.0 – ED – Anxiety 8a (8 items) 
o 
PROMIS SF v1.0 – ED – Depression 8a (8 items) 
o 
PROMIS SF v1.0 – ED – Positive Affect 15a (15 items) 
o 
PROMIS – Meaning and Purpose Scale (adult version) 
o 
Life Fulfillment Scale 
 
Added references for new assessments 
 
Replaced “narcotics” with “opioids” 
 
Added Seizures and Motion Sickness to exclusion criteria 
 
Added racial and ethnic categories to Planned Inclusion Enrollment 
 
Added Numeric Pain Rating to every visit 
 
Added treatment tracking to pain medication tracking form 
 
Added tracking for all medications 
 
Removed Numeric Pain Rating Scale from visits when Pain, Medication, 
and Health Form are administered (NPRS is included in the PMH form) 
 
Significant revisions to Study Interventions – Virtual Environment (Section 
5.1) to reflect developments in virtual reality game programming and 
participant experience 
 
Added Timeline Between Visits Section 6.1.1 
 
Added an allowance of 30 additional days to the total intervention 
 
Added Seizures to the list of exclusion criteria 
 
Changed Quebec Task Force Inclusion Criteria to <4 
 
Added risks: nausea, motion sickness, fall risk 
 
Added “Working proficiency in English” to the inclusion criteria 
 
Revised and rearranged the descriptions of evaluations 
 
Removed the video link from the description of the Informed Consent 
process 
 
Removed muscle relaxant from the list of exclusion criteria 

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 
Added process and/or criteria to be used by the study team to determine 
if a participant is able to continue participation after an incident to Reasons for 
Early Termination (section 6.2.6) 
 
Removed agrees with statement “It is not really safe for a person with my 
back problem to be physically active,” and added Tampa Scale of 
Kinesiophobia score greater than 36 to inclusion criteria. 
 
  

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TABLE OF CONTENTS 
Page 
Tool Revision History ............................................................................................................... 2 
TABLE OF CONTENTS ........................................................................................................... 43 
STUDY TEAM ROSTER ....................................................................................................... 76 
PARTICIPATING STUDY SITES ........................................................................................ 76 
PRÉCIS .................................................................................................................................... 76 
1. STUDY OBJECTIVES .......................................................................................................... 99 
1.1 
Primary Objective ....................................................................................................... 99 
1.2 
Secondary Objectives .............................................................................................. 109 
2. BACKGROUND AND RATIONALE................................................................................. 109 
2.1 
Background on Condition, Disease, or Other Primary Study Focus ................ 109 
2.2 
Study Rationale ...................................................................................................... 1110 
2.2.1 Epidemiology of Low Back Pain ............................................................................. 1110 
2.2.2 Fear-Avoidance Model of Low Back Pain .............................................................. 1110 
2.2.3 Virtual Reality Games for Health Promotion and Rehabilitation ............................ 1111 
2.2.4 Mechanisms Underlying Proposed Game Intervention ........................................... 1211 
3. STUDY DESIGN ................................................................................................................ 1312 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS ........................................... 1312 
Planned Inclusion Enrollment ........................................................................................... 1312 
4.1 
Inclusion Criteria ..................................................................................................... 1413 
4.2 
Exclusion Criteria ................................................................................................... 1514 
4.3 
Study Enrollment Procedures .............................................................................. 1514 
5. STUDY INTERVENTIONS ............................................................................................... 1615 
5.1 
Interventions, Administration, and Duration ....................................................... 1615 
5.2 
Handling of Study Interventions ........................................................................... 1919 
5.3 
Concomitant Interventions .................................................................................... 1919 
5.3.1 Allowed Interventions ........................................................................................... 1919 
5.3.2 Prohibited Interventions ........................................................................................ 1919 
5.4 
Adherence Assessment ........................................................................................ 1919 
6. STUDY PROCEDURES ................................................................................................... 2121 
6.1 
Schedule of Evaluations ........................................................................................ 2121 
6.1.1 Time between visits ................................................................................................. 2121 

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6.1.2 Time between treatment weeks ................................................................................ 2222 
6.2 
Description of Evaluations  ................................................................................... 2323 
6.2.1 Screening Evaluation ............................................................................................ 2727 
6.2.2 Enrollment, Baseline, and/or Randomization (Visit 1) ......................................... 2828 
6.2.3 Blinding................................................................................................................. 2828 
6.2.4 Follow-up Visits.................................................................................................... 2929 
6.2.5 Completion/Final Evaluation ................................................................................ 3030 
6.2.6 Reasons for Early Termination ............................................................................. 3030 
7. SAFETY ASSESSMENTS ............................................................................................... 3131 
7.1 
Specification of Safety Parameters ..................................................................... 3232 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters .......................................................................................................................... 3333 
7.3 
Adverse Events and Serious Adverse Events ................................................... 3333 
7.4 
Reporting Procedures ............................................................................................ 3434 
7.5 
Follow-up for Adverse Events .............................................................................. 3534 
7.6 
Safety Monitoring ................................................................................................... 3534 
8. INTERVENTION DISCONTINUATION .......................................................................... 3535 
9. STATISTICAL CONSIDERATIONS ............................................................................... 3635 
9.2 
Sample Size and Randomization ........................................................................ 3636 
Treatment Assignment Procedures ................................................................................... 3737 
9.3  
Definition of Populations ....................................................................................... 3737 
9.4 
Interim Analyses and Stopping Rules ................................................................. 3837 
9.5 
Outcomes ................................................................................................................ 3838 
9.5.1 Primary Outcome .................................................................................................. 3838 
9.5.2 Secondary Outcomes ............................................................................................ 3838 
9.6 
Data Analyses ......................................................................................................... 3838 
10. DATA COLLECTION AND QUALITY ASSURANCE ............................................... 3939 
10.1 
Data Collection Forms ........................................................................................... 3939 
10.2 
Data Management .................................................................................................. 4040 
10.3 
Quality Assurance .................................................................................................. 4040 
10.3.1 
Training ............................................................................................................. 4040 
10.3.2 
Quality Control Committee............................................................................... 4040 
10.3.3 
Metrics .............................................................................................................. 4040 
10.3.4 
Protocol Deviations ........................................................................................... 4040 
10.3.5 
Monitoring ........................................................................................................ 4140 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY .................................................. 4140 

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11.1 
Institutional Review Board (IRB) Review ............................................................ 4140 
11.2 
Informed Consent Forms ...................................................................................... 4140 
11.3 
Participant Confidentiality ..................................................................................... 4141 
11.4 
Study Discontinuation ............................................................................................ 4241 
12. COMMITTEES ................................................................................................................. 4241 
13. PUBLICATION OF RESEARCH FINDINGS .............................................................. 4242 
14. REFERENCES................................................................................................................. 4242 
I. Procedures Schedule 
II. Informed Consent Form Template 
III. Other (add as many appendices as necessary) 

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STUDY TEAM ROSTER  
Principal Investigator: 
o   
 
James S. Thomas, P.T., Ph.D.  
o Virginia Commonwealth University; 740-593-4178 (T);  
jthomas32@vcu.edu  
 
 
Study Coordination and Data Collection Team 
 
Tiffany Amos, B.S. – Study Coordinator 
o 804-628-2902(T); tiffany.amos@vcuhealth.org 
 
Other Key Members 
 
Peter Pidcoe, Ph.D. - Bioengineer 
o Virginia Commonwealth University, 804-628-3655 (T); 
pepidcoe@vcu.edu 
  
 
 
PARTICIPATING STUDY SITES 
This is a single site study conducted at Virginia Commonwealth University.  
PRÉCIS  
A fundamental clinical problem in individuals with chronic low back pain is the 
significant alteration in movement patterns that restrict lumbar spine motion. This 
restriction of lumbar motion is particularly evident in patients with kinesiophobia; that 
is, a fear of movement due to possible injury or reinjury. For chronic back pain 
patients with kinesiophobia it is critical to develop an effective intervention to 
increase spine motion while minimizing concerns of pain and harm. Accordingly, we 
have developed an innovative suite of virtual reality games that track whole-body 
motion and are designed to encourage spinal flexion while reducing concerns of pain 
and harm among individuals with low back pain. Our games have two distinct 
advantages. First, within this game environment we can manipulate the target 
locations to encourage progressively larger amounts of lumbar spine flexion during 
game play. Second, virtual reality games are potent distractors that can reduce 
attention to pain.  
 
We have recently established safety and feasibility when played for 3 consecutive 
days. In the proposed study participants will complete 18 intervention visits over 9 
weeks with the number of sessions tapered across weeks (i.e., 3 sessions/week in 
weeks 1-3, 2 sessions/week in weeks 4-6, and 1 session/week in weeks 7-9).  
 
Our co-primary outcome variables will be change in pain and change in disability 
from baseline to 1-week post-treatment (Aim 1). We will also examine changes in 
expectations of pain/harm and lumbar flexion as potential mechanisms of change in 
pain and disability (Aim 2). Aim 3 will examine maintenance of treatment gains at 1-, 
6-, 12-, 24-, and 48-weeks post-treatment, additional measures of emotional 
functioning, pain vulnerability, and pain resilience, and real-world activity monitoring 

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(See Recruitment and Pre-Screening – Figure1).  
 
 
    Figure 1 
 
Study Title  
VIGOR - Virtual Immersive Gaming to Optimize Recovery in Low Back Pain  
Objectives  
The co-primary clinical outcomes are changes in pain and disability. Secondary 
objectives are to examine potential mechanisms of pre- to post-treatment changes in 
clinical outcomes and maintenance of treatment gains. 
Design and Outcomes  
VIGOR is a Phase II, double-blind, randomized, placebo-controlled trial to test the 
efficacy and safety of a novel, immersive, virtual reality intervention on outcomes of 
pain, disability, pain/harm expectancy, and lumbar flexion in individuals aged 18-60 
years of age with chronic low back pain. 
Individuals with chronic low back pain will be randomly assigned to play one of two 
versions of the virtual reality game suite for 9-weeks. In the experimental group, 
gameplay will promote progressive increases in lumbar flexion. The control group will 
play the same immersive video games, but the parameters will be modified such that 
RECRUITMENT AND PRE-SCREENING
ENROLLMENT, SCREENING, & RANDOMIZATION 
Enrollment (informed consent) 
Screening (medical history and physical exam, pain, disability, kinesiophobia) 
Randomization (assignment to treatment group) 
VIDEO GAME PLAY (18 sessions over 9 weeks) 
Control Group 
Experimental Group 
POST-TREATMENT ASSESSMENT 
(1-, 6-, 12-, 24-, and 48-weeks after last game session) 
 
Primary Clinical Outcomes (back pain, disability) 
Standardized Reaching Task (pain/harm expectations, lumbar flexion) 
Additional Measures (emotional functioning, pain vulnerability, pain resilience)  
Real-World Activity Monitoring (7 days of Actigraphy after laboratory session) 
PRE-TREATMENT BASELINE ASSESSMENT
Primary Clinical Outcomes (back pain, disability) 
Standardized Reaching Task (pain/harm expectations, lumbar flexion) 
Additional Measures (emotional functioning, pain vulnerability, pain resilience)  
Real-World Activity Monitoring (7 days of Actigraphy after laboratory session) 

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only small excursions of lumbar flexion are needed to successfully complete 
gameplay. The co-primary clinical outcomes of changes in pain and disability will be 
assessed at 1-, 6-, 12-, 24-, and 48-weeks post-treatment. Additionally, individual 
differences in expected pain, expected harm, and lumbar flexion will be measured at 
pre-treatment baseline and at each of the follow-up intervals in the laboratory. 
Finally, participant activity in their natural environment will be monitored for 7 days 
following each follow-up laboratory visit using accelerometry.  
Interventions and Duration  
Participants will complete 18 intervention visits over 9 weeks with the number of 
sessions tapered across weeks (i.e., 3 sessions/week in weeks 1-3, 2 sessions/week 
in weeks 4-6, and 1 session/week in weeks 7-9).  
Sample Size and Population  
We will recruit 230 participants with chronic low back pain (CLBP) and fear of 
movement. We will include participants with CLBP between the ages of 18-60 and 
who report no health condition(s) that may restrict movement or preclude safe 
participation. Participants will be recruited from the general population and specific 
organizations such as Virginia Commonwealth University’s Medical Associates. 
Aim 1: Power analyses were conducted to determine the sample size needed to 
achieve clinically important differences in our co-primary clinical outcome measures 
of pain and disability. Based on the extant literature, we based our analyses on a > 
30% decrease in pain ratings1 (on the 0-10 NRS scale) and a 30% decrease in 
disability ratings on the RMDQ2 in the experimental group. Further, we predict a 10% 
decrease in pain and disability in the control group to account for potential placebo 
effects. The population standard deviations were set at 75% of the population mean 
values. The pre-post correlation was estimated as r=0.7. These population 
parameters translate into an effect size of f=0.30. Using these parameters, we drew 
10,000 samples from a normal population distribution. Based on these parameters, 
to achieve power of 80% and α=0.05 will require a total N=78.  
Aim 2 & 3: Power analyses were conducted to determine the sample size needed to 
address hypotheses 2.1, 2.2, and 3. Using the method described by Morris (2008),3 
we calculated effect size estimates from randomized clinical trials on the effects of 
graded activity or graded exposure interventions on changes in disability among 
individuals with CLBP.4-7 For our power analyses, we adopted the median estimated 
effect size: δ = .45, which corresponds to what would commonly be described as a 
medium effect size. Following Raudenbush and Liu’s (2000) recommendation,8 we 
set the residual error variance to 1 and estimated the between-subject slope 
variance to be 0.30. For power equal to .80 and α=0.05, a sample size of 209 
participants was indicated.  
Based on the sample size calculations, using a sex-stratified random allocation table, 
we need a minimum sample of 209 participants to address Aims 1-3. To allow for 
10% attrition from baseline to 48-week follow-up, we will recruit 230 participants.  
1. STUDY OBJECTIVES 
1.1 
Primary Objective 
The co-primary clinical outcomes are changes in pain and disability. We will examine 
immediate clinical outcomes as a function of treatment. Relative to the control group, 
participants in the experimental group will show greater reductions in pain and 

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disability at post-treatment relative to pre-treatment baseline (Hypothesis 1). To test 
Hypothesis 1, we will examine the Treatment by Time (baseline-post treatment) 
interaction in a LME model: a greater reduction in pain and disability in the 
experimental group than in the control group. The co-primary clinical outcomes of 
changes in pain and disability will be assessed at 1-, 6-, 12-, 24-, and 48-weeks post-
treatment. 
1.2 
Secondary Objectives 
Secondary objectives are to examine potential mechanisms of pre- to post-treatment 
changes in clinical outcomes and maintenance of treatment gains. Participants in the 
experimental group will exhibit greater pre- to post-treatment decreases in pain/harm 
expectancy and increases in lumbar flexion as compared to the control group 
(Hypothesis 2.1). Decreases in pain/harm expectancy and increases in lumbar 
flexion will be positively related to pre- to post-treatment reductions in pain and 
disability (Hypothesis 2.2). Examination of maintenance of treatment gains will occur 
at 1-, 6-, 12-, 24-, and 48-weeks post-treatment. Relative to the control group, 
participants in the experimental group will continue to show lower levels of pain and 
disability at each time point as well as increased activity in their natural environment 
(Hypothesis 3). 
2. BACKGROUND AND RATIONALE 
2.1 
Background on Condition, Disease, or Other Primary Study Focus 
Low back pain is the second most common reason for a visit to a physician, with 
direct medical costs exceeding $90 billion per year in the United States alone.9, 10 
These costs are driven primarily by 7-10% of patients who develop chronic low back 
pain (CLBP) that can last for many years.9-11 Fear of movement (i.e., kinesiophobia) 
due to expectations of pain and harm is an important risk indicator for the 
development of persistent pain and disability, with studies consistently showing that 
high fear is one of the strongest predictors of the transition from sub-acute to 
CLBP.12-15 Specifically, fear encourages the adoption of maladaptive movement 
patterns wherein tasks of daily living are performed with reduced lumbar spine 
flexion and compensatory increases of knee, hip, and shoulder flexion. Using our 
standardized reaching tasks, we have repeatedly demonstrated reduced lumbar 
spine flexion in fearful acute, sub-acute, and CLBP sufferers.16-20 While avoidance of 
lumbar flexion may benefit these CLBP sufferers in the short-term by reducing their 
fear of injury, in the long-term, limited lumbar flexion becomes an entrenched pattern 
that can lead to shortening of spinal peri-articular connective tissues, changes in 
surrounding muscles,21-23 and increased risk for chronicity. 
The current standard of care for individuals with high fear and CLBP is graded 
exposure therapy, which promotes gradual confrontation of avoided movements in 
order to reduce expectations of pain/harm.24 Although recent RCTs with CLBP 
patients indicate that this approach significantly reduces fear of movement, it has not 
led to greater reductions in disability when compared to standard therapy.4, 6 We 
posit that prior studies have not seen the full benefit of this approach because they 
have failed to make restoration of lumbar flexion an explicit focus of therapy. Without 
this goal, patients are able to complete the graded movement tasks using 
maladaptive movement patterns that can impede full recovery. Therefore, we 
hypothesize that explicit efforts to increase lumbar flexion are required to benefit 
those with CLBP who are typically viewed as having intractable pain and disability.25 

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With the support of an NIH R21, we completed a Phase I trial of an immersive virtual 
reality dodgeball game designed specifically to increase lumbar flexion among 
individuals with CLBP and high fear of movement. The results of this proof-of-
concept study demonstrated that 3 daily sessions of virtual dodgeball was safe, did 
not exacerbate existing back pain, was highly rated by participants, and increased 
lumbar spine flexion during gameplay. The current Phase II RCT will determine the 
efficacy of a 9–week course of treatment of virtual dodgeball to reduce pain and 
disability among individuals with CLBP and high fear of movement.  
2.2 
Study Rationale 
2.2.1 Epidemiology of Low Back Pain  
Low back pain (LBP) is one of the most common reasons for seeking medical care 
and accounts for over 3.7 million physician visits per year in the United States 
alone.9 It is the leading cause of pain in the U.S., affecting 28.1% of adults each 
year11 and 90% of adults in their lifetime.9, 26-31 Back pain is associated with $200 
billion in lost wages and productivity annually, and is the second leading contributor 
to annual disability costs of $300 billion.9-11 These costs are driven largely by 7-10% 
of patients who develop chronic low back pain (CLBP)that typically lasts for many 
years.26 According to Foster (2011), “Despite decades of research and improved 
quality of clinical trials, the reality is that the treatments we have to offer patients tend 
to produce small effects, often only in the short term and none appear to change 
effectively the longer-term prognostic paths or trajectories for patients.”27  
2.2.2 Fear-Avoidance Model of Low Back Pain 
The fear-avoidance model of low back pain explains why some people with acute 
musculoskeletal pain go on to develop chronic pain and disability.32, 33 Central to this 
model, individuals who have high kinesiophobia are prone to catastrophic thoughts 
(e.g., “The pain will get worse!”), are more likely to experience greater fear of 
movement and re-injury, and hence will engage in behavioral adaptations to avoid or 
escape pain. In contrast, individuals with low kinesiophobia have little fear of 
movement and re-injury, and therefore are more likely to confront potential or actual 
pain-provoking situations that are needed to progress towards recovery (e.g., return 
to daily activities, work, rehabilitation). While the fear-avoidance model posits a 
generic avoidance of all forms of movement that are perceived as threatening, we 
have repeatedly shown that individuals with high fear and LBP display very similar 
patterns of motor behavior – they specifically avoid flexion of the lumbar spine.16, 34, 35 
Over time, avoidance of lumbar spine motion increases the risk for re-injury due to 
shortening of peri-articular connective tissues and changes in the surrounding 
muscles.21-23 These changes increase the risk of injury when the individual is 
exposed to common, unexpected environmental challenges (e.g., slipping on ice). 
Thus, interventions for individuals with CLBP and high fear must explicitly address 
avoidance of lumbar flexion. 
 
2.2.3 Virtual Reality Games for Health Promotion and Rehabilitation  
Virtual reality (VR) games have been used to promote health education, disease 
management, distraction from discomfort, increased physical activity, and 
rehabilitation involving motor performance, such as following a stroke.36-38 Further, 
strong evidence has accumulated regarding the utility of VR gaming for short-term 
pain relief.39, 40 One of the clear positive benefits of games is that they motivate 

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players to compete and score points. Games also provide a level of distraction from 
the actual behavior being performed, and individuals are willing to engage in 
behaviors that might cause pain due to the competitive nature of the game.41 
Consistent with this notion, VR gaming has been shown to significantly reduce pain 
during burn debridement, wound dressings, painful activity, and uncomfortable 
medical procedures.39, 40 However, to date, VR gaming interventions have not been 
adapted to address CLBP,39, 40 and have not taken advantage of VR interface 
features (e.g., full-body control of avatars, real time feedback/reinforcement).  
2.2.4 Mechanisms Underlying Proposed Game Intervention 
Both Graded Activity (GA) and Graded Exposure (GE) are common approaches to 
the treatment of CLBP. Graded activity focuses on restoring function regardless of 
pain. The intervention begins with provision of a treatment rationale emphasizing the 
negative effects of inactivity and the positive effects of physical activity on well-being, 
and then uses a combination of activity quotas and positive reinforcement to promote 
increased activity over time. In contrast, GE focuses on reducing fear of pain and 
expectations of harm upon movement. Treatment begins with provision of a 
treatment rationale emphasizing the role of fear as an impediment to functional 
restoration, and then proceeds with development of an individualized hierarchy of 
feared movements to guide subsequent sessions of graded exposure. Systematic 
exposure to feared movement provides repeated opportunities to confront and 
correct patient misperceptions of the expected relationship between movement and 
risk of harm. RCTs have shown that both GA and GE produce significant reductions 
in pain and disability, and that these intervention effects do not differ significantly at 
post-treatment and 1-, 6-, and 15-month follow-up intervals.4, 6, 42 However, a 
systematic literature review concluded that GA is no more effective than other forms 
of exercise and that GE is no better than wait-list or usual care controls.43 We 
hypothesize that GA and GE approaches to CLBP fail to outperform other forms of 
exercise or usual-care controls because patients can complete the prescribed tasks 
with restricted lumbar spine motion simply by increasing motion at the ankles, knees, 
and hips. Indeed, continued restriction of lumbar spine motion may be a key 
impediment to optimal restoration of function as we have consistently demonstrated 
that pain-related fear is associated with restricted lumbar flexion among: 1) 
individuals with subacute LBP,16, 35 2) individuals with CLBP,18 3) asymptomatic 
individuals who have recently recovered from LBP,34 and 4) healthy individuals with 
experimentally-induced back pain.19 To address the ubiquitous and persistent 
problem of restriction of lumbar spine flexion among those with pain-related fear, we 
specifically designed a suite of virtual reality games (i.e. VR Dodgeball) that 
necessitate progressively larger excursions of the lumbar spine to successfully 
complete the games. Similar to GA, we believe that our intervention does not require 
an explicit focus on psychological factors related to avoidance behavior, but rather 
operates through a combination of acute distraction from pain, repeated 
reinforcement of movement goals with feedback of progress, and graded increases 
in expectations of spinal lumbar flexion across sessions. In a Phase I trial, we 
demonstrated that individuals with CLBP and pain-related fear who played virtual 
dodgeball had significant increases spinal motion across sessions. They also rated 
the game as highly enjoyable and had no adverse outcomes. With sufficient 
exposure to this intervention, we posit that individuals with CLBP and pain-related 
fear will develop an implicit understanding that lumbar spine motion is not dangerous 
and will generalize the unrestricted lumbar spine motion that is promoted by the 

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game to their daily lives. In so doing, we expect that they will restore the normal 
patterns of spinal motion that are necessary to promote a lasting recovery. 
3. STUDY DESIGN 
The proposed project is a Phase II RCT in which CLBP participants will be randomly 
assigned to one of two intervention arms. Those assigned to the experimental group 
will play our immersive video games that encourage participants to produce 
progressively larger lumbar flexion excursions at each game level and across 
treatment sessions. Those in the control group will play the same immersive games 
but the parameters will be modified such that only small excursions of lumbar flexion 
are needed to successfully complete gameplay. Treatment frequency and duration is 
based on existing evidence that graded activity and graded exposure interventions, 
typically lasting 6-12 weeks with 8-18 treatments sessions, result in significant 
reductions in disability.44,43 Accordingly, participants in the proposed study will 
complete 18 intervention visits over 9 weeks with the number of sessions tapered 
across weeks (i.e., 3 sessions/week in weeks 1-3, 2 sessions/week in weeks 4-6, 
and 1 session/week in weeks 7-9). Our co-primary outcome variables will be change 
in pain and change in disability from baseline to 1-week post-treatment (Aim 1). We 
will also examine changes in expectations of pain/harm and lumbar flexion as 
potential mechanisms of change in pain and disability (Aim 2). Aim 3 will examine 
maintenance of treatment gains at 1-, 6-, 12-, 24-, and 48-weeks post-treatment.  
  
4. SELECTION AND ENROLLMENT OF PARTICIPANTS  
According to the most recent statistics from the U.S. National Health Interview 
Survey (NHIS), when collapsing across gender, approximately 29.2% of Whites, 
27.2.0% of Blacks/African Americans, and 27.4% of Hispanics reported low back 
pain in the previous three months. These data, shown in the table below are adapted 
from the Summary Health Statistics for U.S. Adults: National Health Interview Survey 
published in 2012. Although these national statistics indicate that low back pain is 
slightly more common amongst Whites as compared to African Americans and 
Hispanics, we will recruit our sample to ensure that it meets or exceeds the 
proportion of ethnic and racial minorities in the population according to 2010 U.S. 
Census figures. Specifically, we plan to enroll 16% Hispanic and 84% Non-Hispanic 
participants as well as 73% White, 17% African American, 7% Asian American, 2% 
American Indian/Alaskan Native, and 1% Native Hawaiian or Other Pacific Islander. 
Planned Inclusion Enrollment 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American 
Indian or 
Alaska 
Native 
1 
1 
0 
0 
2 
Asian 
8 
8 
0 
0 
16 
Native 
1 
1 
0 
0 
2 

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Hawaiian 
or Other 
Pacific 
Islander 
Black or 
African 
American 
16 
16 
4 
3 
39 
White 
71 
70 
15 
15 
171 
More than 
One Race 
0 
0 
0 
0 
0 
Unknown 
or Not 
Reported 
0 
0 
0 
0 
0 
Total 
97 
96 
19 
18 
230 
 
Using recruitment procedures that we have successfully employed in prior CLBP 
trials (R01 AT00697, R21AR064430, R21AR063909) as well as prior cohort 
studies,18, 35, 45-48 we will recruit 230 participants with CLBP and fear of movement. 
We will include participants with CLBP between the ages of 18-60 and who report no 
health condition(s) that may restrict movement or preclude safe participation. 
Participants will be recruited through advertisements and flyers posted in the local 
community, and via a combination of electronic, radio, print, and possibly television 
announcements in the local and surrounding communities. We may also recruit from 
local clinics. Finally, ResearchMatch.org will be used as a recruitment tool for this 
protocol. ResearchMatch.org is a national electronic, web-based recruitment tool that 
was created through the Clinical & Translational Science Awards Consortium in 2009 
and is maintained at Vanderbilt University as an IRB-approved data repository (see 
IRB #090207). 
 
4.1 
Inclusion Criteria 
Participants must meet all of the following inclusion criteria: 
 
18-60 years of age 
 
Low back pain that has been ongoing for at least half the days in the last 6 
months  
 
Average pain intensity of 3 or higher over the past week on a 0-10 Numerical 
Rating Scale  
 
Disability >4 on Roland and Morris Disability Questionnaire  
 
Tampa Scale for Kinesiophobia score >36 
 
Has sought care or consultation from a health care provider for back pain 
 
Meets category < 4 on the Classification System of the Quebec Task Force on 
Spinal Disorders,49 which reflects low back pain without neurological signs 

Working proficiency in English

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4.2 
Exclusion Criteria 
Candidates meeting any of the following exclusion criteria at baseline will be 
excluded from study participation:  
 
Has a personal history of the following neurological disorders: Alzheimer’s, 
Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Parkinson’s, Neuropathy, Stroke, 
Seizures 
 
Has a personal history of the following cardiorespiratory disorders: Congestive 
heart failure, heart attack in past 2 years 
 
Has a personal history of the following musculoskeletal disorders: Rheumatoid 
Arthritis, muscular dystrophy, pathologic fractures of the spine, avascular necrosis or 
osteonecrosis, severe osteoarthritis 
 
History of spine surgery or a hip arthroplasty 
 
Has active cancer 
 
Has a chronic disease that may restrict movement or preclude safe participation  
 
Has used opioids within 30 days prior to study enrollment 
 
Reports being pregnant, lactating, or that they anticipate becoming pregnant 
within 2-months 
 
Reports pending litigation related to CLBP 
 
Has current drug or alcohol use or dependence that, in the opinion of the PIs, 
would interfere with adherence to study requirements 
 
Has significant visual impairment that would prevent virtual reality headset use 
 
Has significant motion sickness that would prevent virtual reality headset use 
 
4.3 
Study Enrollment Procedures  
When an individual expresses interest in the study, he or she will be directed to 
complete an online or phone Prescreen Assessment Questionnaire (CRFs VIGOR 
Pre-Screen) after providing assent to the prescreen. If a potential participant passes 
the initial eligibility screening, the study coordinator will contact the potential 
participants by e-mail and/or by phone to schedule a full screening assessment (Visit 
0). At this time the study coordinator will verbally describe the study to the potential 
participant and answer any questions. The consent process will be conducted in a 
quiet, private room. During the consent process, potential participants will be 
informed about the study purpose and procedures and be given the opportunity to 
ask questions. They will be shown a video of the game to help them with the 
process. If they wish to continue, they will be asked to read and sign an informed 
consent document. Next, a member of the research team will review the signed 
consent form and will ask the participant to explain the procedures in their own words 
to ensure that they comprehend the study procedures before proceeding to the initial 
assessment. 
Participants will then complete the screening visit surveys. Based on the responses 
to the questions, interested individuals who meet the inclusion/exclusion criteria will 
be identified and then undergo a physical exam by a licensed physical therapist or 

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physician. Participants who remain eligible following the physical exam will then be 
formally enrolled into the study.  The study coordinator will then randomly assign 
them to their respective intervention group using a sex-stratified random allocation 
table. 
5. STUDY INTERVENTIONS  
5.1 
Interventions, Administration, and Duration  
Participants will complete 18 intervention visits over 9 weeks with the number of 
sessions tapered across weeks (i.e., 3 sessions/week in weeks 1-3, 2 sessions/week 
in weeks 4-6, and 1 session/week in weeks 7-9). 
Provision of Treatment Rationale: After completing all pre-treatment assessments, 
participants will be given a rationale for the intervention. This includes an educational 
component that will be used to correct biomedical misconceptions, explain how pain 
persists without underlying pathology, and describe the interaction among biological, 
psychological, and social factors in maintaining pain and disability. Further, as virtual 
dodgeball provides a unique platform to distract an individual from focusing on pain, 
the treatment rationale will be followed by 1) an initial exposure to the virtual 
dodgeball environment, 2) specific details on how the intervention is designed to 
promote increased spinal motion and decreased disability, and 3) an opportunity to 
play a practice level to review basic game constructs (e.g., scoring metrics, moving 
the avatar, sound and visual cues). 
Virtual Environment: A head mounted display (e.g., HTC Vive) will be used to provide 
a virtual environment for both the weekly standardized reaching tasks and for 
gameplay. The head mounted display is used to present the virtual world with a 
screen refresh rate of 90 Hz. The environmental parameters are controlled by 
custom software developed in the Unity game engine to manipulate and control all 
presented graphics and audio. During the initial testing session and at each post 
treatment follow-up (1,6,12, 24, & 48 weeks), the 6-DOF kinematic data from the 
clusters of light reflective markers placed on the participant is streamed to the game 
environment at 100 Hz using Vicon Tracker software allows for near real time 
presentation of the participant’s avatar. Motion Monitor software sets up bi-directional 
communication with the Unity game engine and records all kinematic data (e.g., joint 
excursions, joint moments) during the initial gaming session. This integration allows 
us to individualize the game experience to each participant. During the intervention 
visits, presentation of the participant’s avatar is controlled through the 6-DOF 
position data from the head mounted display, hand controllers, and Vive trackers 
attached to the thorax and pelvis of the participant.  

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As shown in Fig. 2, the participant will have a variety of immersive experiences 
across the 9 week intervention. The purpose of a suite of VR games is twofold. First, 
the games increase from difficulty across the intervention. That is the VR Dodgeball 
then has multiple opposing players launching virtual balls at higher velocities. Thus 
the suite is designed to provide a graded exposure in this cohort. Secondly, the use 
of multiple virtual environments within and across the suite of VR games is designed 
to encourage engagement with the protocol and to prevent boredom. In week one, 
they will engage inCannon Dodgeball, all balls are launched from the same position. 
In week two they will engage inDay Dodgeball increasing difficulty with the number of 
positions the ball can come from. Weeks 3-4 they will engage in night Dodgeball 
which gives less surrounding information making it more difficult to gage the speed of 
the ball.  Wekks 4-9 Dodgeball will be played on an alien planet, with atomosheric 
conditions like the moon, causing balls to be launched more straight at you. In all 
cases, the movement of the avatar will be controlled by the participant’s actual body 
movements.  
 
Participants will play variants of Virtual Dodgeball. All versions of VR Dodgeball 
consist of launched virtual balls that are directed at the participant’s avatar. The goal 
is to either block the launched virtual ball with the dodgeball held by the participant or 
to duck the launched virtual ball if it changes color to black and is accompanied by a 
quacking sound. In all variants of VR Dodgeball, there are 15 launched virtual balls 
per set, 2 sets per level, and 3 levels per game. Additionally, 3D sound is 
incorporated into the game in a number of ways, including crowd cheering, buzzers 
and referee whistles, and a duck quacking sound that occurs when a black ball is 
launched. Performance is updated in real-time and displayed on a virtual scoreboard 
in the basketball arena, and the participant will be awarded progressively more cash 
rewards for each successful block or dodge at each level of play (Level 1= 1¢, Level 
2=2¢, Level 3=5¢, Level 4=10¢). Successful contact of each highlighted ball 
presented between each set will result in a bonus 25¢ reward. Conversely, the 
participant loses cash rewards for each failure to block or duck the launched ball 
(N.B. a player starts the game with a cash balance on the scoreboard such that if 
 
Fig. 2. A participant with the head-mounted display and instrumented with the marker clusters (left). Matchality 
environments are illustrated in the second column: day one on earth (top), day two in orbit (middle), and day 3 on alien 
planet (bottom). Fishality environment is illustrated in the third column. Dodgeball variants are illustrated in fourth 
column: Cannon (top), standard (middle), alien planet (bottom). 

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they failed on every launched or presented ball, their cash balance would be zero). 
The four versions of VR of dodgeball are described below. 
Dodgeball Cannon - This consists of a single cannon that is located on the opposite 
free throw line of the virtual gym in which VR Dodgeball is played. In this game, the 
participant only has to worry about a single opponent and the launch trajectory of 
virtual launched balls has been adjusted to increase the height of the parabolic flight 
pattern to make interception of the launched virtual ball less challenging. Thus, the 
Dodgeball Cannon is less difficult than the subsequent dodgeball versions. 
Dodgeball Day - In this classic version of VR Dodgeball the participant plays 
dodgeball against four virtual opponents. The participant is virtually located on one 
free-throw line and the four virtual opponents are located opposite the free throw line 
and have the ability to move 1 m fore-aft and 1 m left-right during gameplay. Virtual 
balls are launched in a randomized order from each of the four virtual opponents. If 
the launched ball is red, then the participant must attempt to block the ball with the 
ball held in their hands (corresponds to the virtual ball held in the virtual world). If the 
launched ball is black, the participant must attempt to duck to avoid the ball. There is 
a large scoreboard within the virtual gym that tracks participant performance and 
cash rewards earned during gameplay.  
Dodgeball Night - This game is identical to the game described above, only the gym 
lights have been removed and the opposing avatars and launched virtual balls glow 
in the dark. This variation of the game 1) increases the challenge by making the 
distance of the launched balls harder to judge and 2) increases immersion in the 
virtual space, and 3) enhances novelty to avoid boredom by altering the 
environment. 
Dodgeball Space - This game takes place on an alien planet with the gravitational 
constraints of the moon. The opposing players now are aliens and the physics of the 
ball launces has been adjusted to the reduced gravity of the moon. This again 
requires an adjustment by the participant to successfully control their avatar and in 
so doing helps to maintain challenge, immersion, and novelty. 
Shaping Lumbar Spine Motion  
Experimental Group: The location and presentation of static and dynamic virtual 
targets (dodge balls) will be manipulated to maximize lumbar flexion in the 
experimental group. The location of the virtual objects are set to necessitate 15, 30, 
45, & 60 degrees lumbar spine motion. After week 1 of gameplay, visual gain will be 
manipulated such that virtual objects will be farther away and at a lower height (5% 
adjustment) to necessitate greater lumbar flexion to successfully intercept the virtual 
objects.  In week 2 there will be a 10% adjustment (i.e, farther away and at a lower 
height), in week 3, and 15% adjustment will be made for weeks 4-9. 
Control Group: To ensure that lumbar flexion is minimized while playing the virtual 
reality games, we will manipulate the presentation of virtual targets (balls in 
Dodgeball) such that the participant will only need to flex the spine 15 degrees to 
successfully intersect the virtual objects (pilot data indicate that lumbar excursions in 
virtual dodgeball typically range from 15-60 degrees of lumbar flexion).  
At the end of each week, we will provide each participant with a graphic printout that 
indicates game performance such as hits, misses, points acquired across each 
week.  

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Schedule of Interventions 
 
Baseline Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week 
7 
Week 
8 
Week 
9 
Treatment # 
0 
1, 2, 3 4, 5, 6 7, 8, 9 10, 11 12, 13 14, 15
16 
17 
18 
Visit # 
1 
2, 3, 4 5, 6, 7 8, 9, 10 11, 12 13, 14 15, 16
17 
18 
19 
Intro 
x 
 
 
 
 
 
 
 
 
 
Dodgeball Cannon 
 
x 
x 
x 
 
 
 
 
 
 
Dodgeball Day 
 
 
 
 
x 
 
 
 
 
 
Dodgeball Night 
 
 
 
 
 
x 
 
 
 
 
Dodgeball Space 
 
 
 
 
 
 
x 
x 
x 
x 
Experimental Group  
% Gain Decrease
 
 
-5% 
-10% 
-15%
-15%
-15% 
-15%
-15% 
-15%
Experimental Group  
Gain
1 
1 
0.95 
0.90 
0.85 
0.85 
0.85 
0.85 
0.85 
0.85 
 
5.2 
Handling of Study Interventions  
The principal investigators, the statistician, and members of the data collection team 
will remain blinded to intervention assignment throughout the duration of the study. 
They will be given the identifying codes only at the end of the study when it is 
necessary to interpret the results. The un-blinded study coordinator, who is 
responsible for scheduling testing and treatment sessions, will greet participants and 
escort them to the testing lab; however, the study coordinator will not participate in 
the assessments of clinical outcomes or testing. 
5.3 
Concomitant Interventions  
Participants in the study will be permitted to use over the counter pain medications 
(e.g., Non-Steroidal Anti-Inflammatory Drugs, Acetaminophen, Aspirin), or to apply 
heat or ice to manage back pain symptoms. All concomitant pain management 
interventions will be recorded at the beginning of each visit.  
5.3.1 Allowed Interventions 
Although participants who report using pain interventions other than over-the-counter 
pain relievers or heat/ice will be allowed to remain in the study, they will be excluded 
from the per-protocol analyses. 
5.3.2 Prohibited Interventions 
None. 
5.4 
Adherence Assessment  
Adherence: Adherence to all scheduled intervention contacts is recorded by the 
study coordinator in a tracking system. Reports on adherence will be reviewed during 
regular meetings of a Recruitment, Adherence, and Retention Committee, which is 
composed of the PIs and the study coordinator. If a study participant misses a 
scheduled treatment, every effort will be made to re-schedule that treatment in the 
proposed weekly time frame. For the per-protocol analyses, successful adherence 
will be defined as >70% attendance (i.e., 13 out of the 18 treatments). To allow for 
flexibility in participant scheduling due to events that may conflict with scheduled 
visits (e.g., acute illness), the total length of the 9 week intervention period can be 

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extended by up to 30 days (i.e., total intervention = 9 weeks + 30 days).  
Retention: Retention is enhanced by the addition of more frequent follow-up 
assessments as well as use of incentive payments at each participant visit. 
Specifically, participants will receive remuneration for performance at each gameplay 
session. In addition, attendance at post-treatment follow-up sessions at 1-, 6-, 12-, 
24-, and 48-weeks will be encouraged by incentive payments of $100 per session 
attended.  
 
 

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6. STUDY PROCEDURES  
6.1 
Schedule of Evaluations 
 
Prescreen 
Screen 
Enrollment & 
Baseline
Treatment 
Post-Treatment 
Assessments
Post-Treatment 
Assessments
Assessment 
 
Visit 0 
Visit 1 
Visits 2-19 
Visit 20 
Visits 21-24 
Numeric Pain Rating Scales  
7-day & 24-hour
x 
x 
x 
x* 
x 
x 
Roland-Morris Disability Questionnaire 
x 
x 
x 
x 
x 
Fear Question 
x 
x 
 
 
 
 
Medical History - Back Pain 
x 
x 
Medication Log 
x 
x 
x 
x 
x 
Informed Consent Form 
x 
Inclusion/Exclusion Criteria 
x 
Enrollment/Randomization 
x 
Medical History 
x 
Physical Exam Form 
x 
Adverse Events 
x 
x 
x 
x 
Numeric Pain Rating Scale - Right Now 
x 
x 
x 
x 
Standardized Reaching Paradigm
• Pain & Harm Expectancy 
• Lumbar Spine Flexion
 
 
x 
x* 
x 
x 
Tampa Scale for Kinesiophobia 
 
x 
x 
x 
Center for Epidemiologic Studies - 
Depression
 
 
x 
 
x 
x 
Pain Catastrophizing Scale 
 
x 
x 
x 
Pain Resilience Scale 
 
x 
x 
x 
Pain Self Efficacy Questionnaire 
 
x 
x 
x 
Brief Pain Inventory - Short Form 
 
x 
x 
x 
PROMIS-Anxiety 
x 
x 
x 
PROMIS-Depression 
x 
x 
x 
PROMIS-Positive Affect 
x 
x 
x 
PROMIS – Meaning and Purpose Scale 
x 
x 
x 
Life Fulfillment Scale 
x 
x 
x 
Profile of Mood States 
x 
x 
x 
Real World Activity Monitoring 
x 
x 
x 
Treatment Evaluation Inventory - Short 
Form
 
 
x 
 
x 
 
Patient Global Impression of Change 
x 
x 
*assessed at the first visit of each week 
Note: Prescreening, Visit 0 screening, Visit 1 baseline, and Visit 2 first intervention can all occur 
on the same day. 
6.1.1 Time between visits 
 
Prescreening to Screening is ≤ 30-days 

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 
Screening to Baseline V1 is ≤ 7-days 
 
Baseline V1 to Intervention V2 is ≤ 7-days 
 
Intervention W1 V2 (T1), V3(T2), V4(T3) are 2-3-days apart (encompassing ≤ 
7-days) 
 
Intervention W2 V5 (T4), V6 (T5), V7 (T6) are 2-3-days apart (encompassing 
≤ 7-days) 
 
Intervention W3 V8 (T7), V9 (T8), V10 (T9) are 2-3-days apart 
(encompassing ≤ 7-days) 
 
Intervention W4 V11 (T10), V12 (T11) are 2-6-days apart (encompassing ≤ 7-
days) 
 
Intervention W5 V13 (T12), V14 (T13) are 2-6-days apart (encompassing ≤ 7-
days) 
 
Intervention W6 V15 (T14), V16 (T15) are 2-6-days apart (encompassing ≤ 7-
days) 
 
Intervention W7 V17 (T16) is 6-10-days after previous Intervention V16 
 
Intervention W8 V18 (T17) is 6-10-days after previous Intervention V17 
 
Intervention W9 V19 (T18) is 6-10-days after previous Intervention V18 
 
Final Intervention V19 to First Post-Intervention Assessments V20 7-days +/- 
3-days 
 
Final Intervention V19 to Post-Intervention Assessment V21 is 6-weeks +/- 1-
week 
 
Final Intervention V19 to Post-Intervention Assessment V22 is 12-weeks +/- 
1-week 
 
Final Intervention V19 to Post-Intervention Assessment V23 is 24-weeks +/- 
1-week 
 
Final Intervention V19 to Post-Intervention Assessment V24 is 48-weeks +/- 
1-week 
 
6.1.2 Time between treatment weeks 
 
Intervention V4 to V5, V7 to V8 are 2-3-days apart 
 
Intervention V10 to V11, V12 to V13, V14 to V15 are 2-6-days apart 
 
Intervention V16-V17 is 6-10-days apart 
 
Note: To allow for flexibility in participant scheduling due to events that may conflict 
with scheduled visits (e.g., acute illness), the total length of the intervention period 
(i.e., V2 T1 through V19 T18) can be extended by up to 30 days.  
 

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6.2 
Description of Evaluations  
Numeric Pain Rating Scales - Right now, 7-day & 24-hour: To assess pain, separate 
ratings of back pain intensity “right now”, over the preceding 24 hours, and over the 
preceding 7 days will be measured using an 11-point numerical rating scale (NRS) 
with anchors of 0 (No pain) and 10 (Pain as bad as you can imagine). This scale will 
quantify the study candidates rating of their low back pain symptoms. 
Roland-Morris Disability Questionnaire: To assess physical functioning will be using 
the Roland-Morris Disability Questionnaire (RMDQ).50,51 The RMDQ includes 24 
yes/no items that are designed to assess physical disability related to CLBP. This 
form quantifies the self-report level of disability. 
Fear Question:  Candidates will be screened for participation in the pre-screening 
and the full screening by indicating whether or not they agree with the statement “It is 
not really safe for a person with my back problem to be physically active.” An 
affirmative response will indicate a fear of movement.  
Medical History – Back Pain: This form documents the candidate’s history of back 
pain. 
Medication Log: To assess pain, participants will be asked to report current 
frequency and dosage of medications used for back pain. Additionally, all medication 
use will be documented in this form.  
Informed Consent Form: Subjects must provide written informed consent prior to 
beginning the screening process and prior to implementation of any study 
procedures. 
Inclusion/Exclusion Criteria: This form will document whether the study candidate 
meets all of the inclusion and exclusion criteria. 
Enrollment/Randomization: This form will note the enrollment and randomization 
dates. 
Medical History: To monitor safety, participants will complete a brief health screening 
at the beginning of each game session to determine if there are any changes in back 
pain or radiating symptoms. 
Physical Exam Form: This form documents the study candidate’s physical exam 

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findings. 
Adverse Events: A structured safety monitoring system will be established to both 
assure real-time participant care and unbiased monitoring of adverse events (AE). 
For ongoing participant safety, events will be assessed by the PIs and co-
investigators to determine if they are Serious, Unexpected, and/or On-site. If so, an 
event evaluation form will be completed that will include a description of the event, a 
classification of seriousness, assessment of potential relationship to the intervention, 
assessment of need for change in the consent or the study activities, a summary of 
known prior health issues, event outcome, and a classification of the main organ 
system involved. 
Standardized Reaching Paradigm (Pain & Harm Expectancy, Lumbar Spine Flexion):  
Lumbar Spine Flexion: Movement of light-reflective marker clusters attached to 
the head, upper arms, forearms, hands, trunk, pelvis, thighs, shanks, and feet will 
be measured and recorded using a 10-camera Vicon Bonita system. This 
optoelectric-based kinematic system can track the three-dimensional coordinates 
of light reflective marker clusters attached to the participant with a spatial 
resolution of 0.1 mm. Kinematic data will be sampled at 100Hz. Participants point 
with their hand to 4 virtual targets co-located in the mid-sagittal plane. Location of 
the targets are 
adjusted to the 
individual as 
illustrated in Fig. 3.  
This method: 1) 
allows for 
comparison of 
movement patterns 
across individuals, 
2) challenges 
participants with 
tasks that require 
progressively more 
lumbar spine 
flexion, and 3) is 
sensitive to changes 
in LBP patients.16, 18, 
34, 35, 45 Participants 
will perform five 
reaching trials to 
each virtual target 
location with each 
hand, pause at the target for 2 seconds, and then return to an upright posture. 
These tasks will be repeated 1-, 6-, 12-, 24-, and 48-weeks post-treatment. 
Instructions will emphasize that participants should reach for the targets as fast 
as possible in a way that is “natural and comfortable for them” so as not to bias 
participants with a perceived correct way to move. Moreover, performing the 
reaching tasks at a rapid pace challenges the participant by increasing the 
loading required to perform the tasks. While forward excursions of the trunk must 
be counterbalanced by backward movement of the lower extremities, the targets 
are located such that they do not require an individual to move anywhere near 
euler 
 
Fig. 3 Target locations will be determined for each participant based 
on their hip height, trunk length, and arm length. The high target is 
located such that the subject could, in theory, reach the target by 
flexing the hips 15° with the shoulder flexed 90° and the elbow 
extended. The middle and low targets could be reached by flexing 
the hips 30° and 60°, respectively. NOTE: Target locations are 
determined mathematically (i.e., participants are not actually placed 
in the positions illustrated). 

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the limits of available range of motion of the lumbar spine, pelvis, knee, and 
ankle in this paradigm. Thus, participants can reach these targets using an 
infinite combination of joint excursions. Even though the reaching task requires 
no lifting and the loads on the lumbar spine are small, we have shown that 
individuals with elevated levels of kinesiophobia exhibit reduced lumbar spine 
flexion at this combination of target height and reaching speed.16, 18, 34, 35, 45 The 
time series joint angle data are calculated from the 3-D segment coordinate data 
using an Euler angle sequence of: 1) flexion-extension, 2) lateral bending, and 3) 
axial rotation52 using Motion Monitor software. This is defined as the change in 
joint angle (i.e., the difference between the joint angles at the beginning of the 
trial before the go signal and those extracted 100 ms after target contact). The 
standardized reaching paradigm will be used to assess lumbar flexion and 
expectations of pain and harm at pre-treatment baseline and will be repeated at 
1-, 6-, 12-, 24- and 48-weeks after the last treatment session.  
Pain & Harm Expectancy: Consistent with our prior work,20, 46, 47, 53 expectations 
of pain and harm will be measured during standardized reaches performed at 
pre-treatment baseline, the first visit of each week of interventions, and post-
treatment. Specifically, for each target height, prior to the first reaching trial, 
participants will be asked to rate the level of “expected pain” and “expected 
harm” using a visual analog scale displayed through the head mounted display 
(e.g., HTC Vive). The scale will consist of a 10 cm horizontal line with no 
numbers, marks, or descriptive vocabulary along its length. For expected pain 
ratings, the scale will be anchored with the descriptors “No pain” and “Worst pain 
imaginable”, respectively, at each end of the line. For expected harm, the scale 
will be anchored with “Not at all concerned” and “Extremely concerned” regarding 
potential harm to the back during task performance. Participants will indicate their 
response by moving a virtual sliding scale. Expectations of pain/harm will be 
used as dependent variables in Aim 2. 
 
Tampa Scale for Kinesiophobia: This is used to assess candidate’s level of fear of 
movement due to perceived risk for back injury or re-injury. It is one of two pain 
vulnerability measures assessed in the study and is included among our additional 
analyses. 
Center for Epidemiologic Studies – Depression: We will administer the Center for 
Epidemiological Studies-Depression (CES-D) scale 54 to assess symptoms of 
depression that often accompany chronic pain. The CES-D is included among our 
additional analyses as a measure of emotional functioning.  
Pain Catastrophizing Scale: This survey is used to identify characteristics of 
rumination, magnification, and helplessness in the face of ongoing or intense pain. It 
is one of two pain vulnerability measures assessed in the study and is included 
among our additional analyses. 
Pain Resilience Scale: This survey is used to measure behavioral perseverance as 
well as cognitive and affective positivity in the face of intense or prolonged pain.  It is 
one of two pain resilience measures assessed in the study and is included among 
our additional analyses. 
Pain Self Efficacy Questionnaire: This survey is used to measure the respondent’s 
confidence in their ability to carry out daily and enjoy daily activities despite pain. It is 

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one of two pain resilience measures assessed in the study and is included among 
our additional analyses. 
Brief Pain Inventory – Short Form: We will use the Brief Pain Inventory55 pain 
interference subscale as one of two measures to assess physical functioning. The 
pain interference subscale includes 7 items that assess the degree to which back 
pain has interfered with general activity, mood, walking, work, relations with others, 
sleep, and enjoyment of life. 
PROMIS-Anxiety: We will administer the PROMIS56 Anxiety scale as a measure of 
psychological distress that may accompany chronic pain, particularly among those 
with low back pain and fear of movement. The PROMIS-Anxiety scale is included 
among our additional analyses as a measure of emotional functioning. 
PROMIS-Depression: We will administer the PROMIS Depression scale as a 
measure of negative affect that often accompanies chronic pain. The PROMIS 
Depression scale is included among our additional analyses as a measure of 
emotional functioning. 
PROMIS-Positive Affect: We will administer the PROMIS Positive Affect scale as a 
measure of positive affect that may be reduced in chronic pain, and possibly 
enhanced by successful intervention. The PROMIS Positive Affect scale is included 
among our additional analyses as a measure of emotional functioning. 
PROMIS-Meaning and Purpose: We will administer the PROMIS Meaning and 
Purpose57 scale as a measure of positive engagement in daily living, which may be 
impaired in chronic pain and possibly enhanced by successful intervention. The 
PROMIS Meaning and Purpose is included among our additional analyses as a 
measure of emotional functioning. 
Life Fulfillment Scale: This Life Fulfillment Scale58 will be administered as a measure 
of positive cognitive and emotional adaptation, and is included among our additional 
analyses of emotional functioning. 
Profile of Mood States: The Profile of Mood States questionnaire will be administered 
to assess positive and negative affective states. The Profile of Mood States is 
included among our additional analyses as a measure of emotional functioning. 
Real World Activity Monitoring: Following pre-treatment baseline and each of the 
post-treatment assessments, the participant will be given an activity monitor to wear 
on the non-dominant wrist for 1-week and returned to the laboratory by pre-paid 
postage. The total number of steps/day will be the primary dependent variable to 
determine the effects virtual dodgeball on activity levels measured in a natural 
environment (Aim 3). We will also examine ancillary outcomes of physical activity 
intensity by examining step cadence and using standard thresholds to aggregate 
data into sedentary, light, moderate, and vigorous activity.59 
Treatment Evaluation Inventory – Short Form: To assess participant acceptance of 
the intervention, we will administer a modified version of the Treatment Evaluation 
Inventory, Short Form60 at Visit 1 and again at Visit 20 (i.e., 1-week follow-up). 
Patient Global Impression of Change: This scale is used to quantify a participant’s 
perception of their level of positive, negative, or no change as a function of 
participating in the intervention. It will be included among our additional analyses. 
 

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6.2.1 Screening Evaluation 
Consenting Procedure 
The consent process will be conducted in a quiet, private room. During the consent 
process, potential participants will be informed about the study purpose and 
procedures and be given the opportunity to ask questions. They will be shown a 
video of the game to help them with the process. If they wish to continue, they will be 
asked to read and sign a single informed consent document. Next, a member of the 
research team will review the signed consent form and will ask the participant to 
explain the procedures in their own words to ensure that they comprehend the study 
procedures before proceeding to the initial assessment. Informed consent must be 
obtained before participants are screened. A copy of the signed and dated consent 
form will be given to participants, and the original document will be electronically 
stored on a secure server. 
Pre-Screening 
The purpose of pre-screening is to determine if the research candidates will qualify 
for the research. This web-based survey will take approximately 15-minutes to 
complete and includes the following forms: 
 
Numeric Pain Rating Scales 7-day & 24-hour 
 
Roland-Morris Disability Questionnaire 
 
Fear Question 
 
Medical History – Back Pain 
Screening (Visit 0) 
The purpose of the screening visit is to 1) describe the study protocol to candidates 
and begin the informed consent process, and 2) determine if study candidates will 
qualify for the study. The screening visit will take approximately two hours. During 
the screening visit the study coordinator will complete, in cooperation with the study 
candidate, the following: 
 
Numeric Pain Rating Scales 7-day & 24-hour 
 
Roland-Morris Disability Questionnaire 
 
Fear Question 
 
Medical History – Back Pain 
 
Medication Log 
 
Quebec Task Force Classification 
 
Informed Consent Form 
 
Inclusion/Exclusion Criteria Form 
 
Enrollment & Randomization Form 
 
Medical History 
 
Physical Exam 
Re-screening participants may be considered and reviewed by the PIs on a case-by-
case basis. Screening must occur within 30-days of prescreen completion. Visits 1 
and 2 (Baseline and Intervention 1) may occur on the same day as screening and 
must occur within 7 days of screening. If these deadlines are not met the participants 
will be assigned a new PID, re-screened, and re-consented. 

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6.2.2 Enrollment, Baseline, and/or Randomization (Visit 1) 
Enrollment 
A single informed consent form that describes both screening and study procedures 
will be used. The date of enrollment in The VIGOR Study will be defined as the date 
all of the screening criteria are met and the individual agrees to participate. The 
enrollment date will be recorded on a case report form along with the allowable 
window between screening and randomization. 
 
CRF: Randomization and Enrollment Form 
Baseline Assessments 
Participants enrolled in the study will complete the following baseline assessments at 
Visit 1:  
 
Numeric Pain Rating Scales 7-day & 24-hour 
 
Roland-Morris Disability Questionnaire 
 
Medication Log 
 
Adverse Events Log 
 
Numeric Pain Rating Scale – Right Now 
 
Standardized Reaching Paradigm (Pain & Harm Expectancy, Lumbar Spine 
Flexion) 
 
Tampa Scale for Kinesiophobia 
 
Center for Epidemiologic Studies – Depression 
 
Pain Catastrophizing Scale 
 
Pain Resilience Scale 
 
Pain Self Efficacy Questionnaire 
 
Brief Pain Inventory – Short Form 
 
PROMIS-Anxiety 
 
PROMIS-Depression 
 
PROMIS-Positive Affect 
 
PROMIS-Meaning and Purpose Scale 
 
Life Fulfillment Scale 
 
Profile of Mood States 
 
Real World Activity Monitoring 
 
Treatment Evaluation Inventory – Short Form 
 
Randomization 
The study coordinator will use a sex-stratified random allocation table, created by the 
study statistician, to assign participants to a treatment group. A maximum of 7-days 
will be permitted between enrollment and randomization or initiation of the study 
intervention.  
6.2.3 Blinding 
The principal investigators, the statistician, and members of the data collection team 
will remain blinded to intervention assignment throughout the duration of the study. 
They will be given the identifying codes only at the end of the study when it is 
necessary to interpret the results. The un-blinded study coordinator, who is 
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escort them to the testing lab; however, the study coordinator will not participate in 
the assessments of clinical outcomes or testing.  
6.2.4 Follow-up Visits 
Treatment visit assessments for each visit 2-19 include the following:  
 
Numeric Pain Rating Scales 7-day & 24-hour 
 
Medication Log 
 
Adverse Events Log 
 
Numeric Pain Rating Scale – Right Now 
 
Standardized Reaching Paradigm (Pain & Harm Expectancy, Lumbar Spine 
Flexion) 
Assessments at first post-treatment follow-up visit, Visit 20, include: 
 
Numeric Pain Rating Scales 7-day & 24-hour 
 
Roland-Morris Disability Questionnaire 
 
Medication Log 
 
Adverse Events Log 
 
Numeric Pain Rating Scale – Right Now 
 
Standardized Reaching Paradigm (Pain & Harm Expectancy, Lumbar Spine 
Flexion) 
 
Tampa Scale for Kinesiophobia 
 
Center for Epidemiologic Studies – Depression 
 
Pain Catastrophizing Scale 
 
Pain Resilience Scale 
 
Pain Self Efficacy Questionnaire 
 
Brief Pain Inventory – Short Form 
 
PROMIS-Anxiety 
 
PROMIS-Depression 
 
PROMIS-Positive Affect 
 
PROMIS-Meaning and Purpose Scale 
 
Life Fulfillment Scale 
 
Profile of Mood States 
 
Real World Activity Monitoring 
 
Treatment Evaluation Inventory – Short Form 
 
Patient Global Impression of Change 
Assessments at post-treatment follow-up visits 21-24 include: 
 
Numeric Pain Rating Scales 7-day & 24-hour 
 
Roland-Morris Disability Questionnaire 
 
Medication Log 
 
Adverse Events Log 
 
Numeric Pain Rating Scale – Right Now 
 
Standardized Reaching Paradigm (Pain & Harm Expectancy, Lumbar Spine 
Flexion) 
 
Tampa Scale for Kinesiophobia 
 
Center for Epidemiologic Studies – Depression 
 
Pain Catastrophizing Scale 
 
Pain Resilience Scale 

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 
Pain Self Efficacy Questionnaire 
 
Brief Pain Inventory – Short Form 
 
PROMIS-Anxiety 
 
PROMIS-Depression 
 
PROMIS-Positive Affect 
 
PROMIS-Meaning and Purpose Scale 
 
Life Fulfillment Scale 
 
Profile of Mood States 
 
Real World Activity Monitoring 
 
Treatment Evaluation Inventory – Short Form 
 
6.2.5 Completion/Final Evaluation 
Assessments to be performed at the participant’s final visit include: 
 
Numeric Pain Rating Scales 7-day & 24-hour 
 
Roland-Morris Disability Questionnaire 
 
Medication Log 
 
Adverse Events Log 
 
Numeric Pain Rating Scale – Right Now 
 
Standardized Reaching Paradigm (Pain & Harm Expectancy, Lumbar Spine 
Flexion) 
 
Tampa Scale for Kinesiophobia 
 
Center for Epidemiologic Studies – Depression 
 
Pain Catastrophizing Scale 
 
Pain Resilience Scale 
 
Pain Self Efficacy Questionnaire 
 
Brief Pain Inventory – Short Form 
 
PROMIS-Anxiety 
 
PROMIS-Depression 
 
PROMIS-Positive Affect 
 
PROMIS-Meaning and Purpose Scale 
 
Life Fulfillment Scale 
 
Profile of Mood States 
 
Real World Activity Monitoring 
 
Patient Global Impression of Change 
All assessments will be performed for participants who discontinue study intervention 
early. 
 
6.2.6 Reasons for Early Termination 
A subject would be discontinued from the study intervention if a medical condition 
develops that precludes the continuation of the treatment intervention. For 
participants who discontinue The VIGOR Study prior to completing all scheduled 
treatment sessions (regardless of the reason), we will make every attempt to obtain 
the outcome measurements. If the study participant is unwilling or unable to undergo 
the laboratory-based tests (e.g., difficulty tolerating the protocol, experienced an 
adverse event to a lab test) we will still attempt to obtain the clinical outcome 

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measures. In instances where an adverse event does occur, we will follow-up with 
participants until the event is resolved or until the IRB deems it unnecessary to 
continue to follow the participant. 
 
If the participant complains of any sudden onset of muscle or joint pain, the current 
session will be terminated, and the Principal Investigator will be contacted to 
complete an assessment.  If he is unavailable, one of the other clinicians on the 
study team will be contacted to provide a clinical assessment of the participant. They 
will then consult with the PI to assess if the participant should continue to stay on 
protocol. If an exclusion criterion is identified from the presenting signs and 
symptoms, the participant will then be withdrawn from the study. If the presenting 
signs and symptoms do not meet the exclusion criteria, the participant will be invited 
to return for their next scheduled visit when the sudden onset of symptoms has 
abated. Upon return, the PI or a clinician on the study team will again assess the 
participant and make a clinical judgement about their fitness to continue with the 
intervention. However, if the participant has a second episode of sudden onset of 
joint or muscle pain, they will be immediately withdrawn from the study. 
 
 
 
7. SAFETY ASSESSMENTS  
Threats to Individual Privacy and Data Confidentiality: To minimize risk to participant 
privacy, all study procedures are conducted in private testing rooms by qualified 
study personnel and the collection of sensitive information is limited to the minimum 
necessary to conduct the necessary screening and testing. To minimize risk to 
participant confidentiality, we will use secure web-based applications (i.e., REDCap) 
to collect and manage participant information and all data will be stored with unique 
identification codes such that no personal identifying information will be available in 
the study files. All data collection forms are electronic Case Report Forms (eCRF). 
As source documents, all forms are signed or electronically verified and dated by a 
study staff member. In case of interruption of internet connectivity during data 
collection, participants will complete a paper version of the eCRF and the Study 
Coordinator or Research Assistant will transfer all data from the paper forms to the 
database. Every 2-weeks a Research Assistant will perform a quality assurance 
check by comparing data entered into the database from paper-based forms. All 
paper data collection forms will be kept in locked file cabinets located in locked 
testing rooms.  
Voluntary Reaching Task: Bending of the trunk could possibly aggravate current low 
back pain symptoms; however, these reaching tasks have been chosen because 
they mimic everyday activities and are within the available range of motion of 
individuals with low back pain. The reaching tasks minimize potential risks to the 
participant in that they do not require any lifting; thus, spine loads are minimal. Risk 
is further minimized because we inform all participants that they are free to stop at 
any time if they find the procedure too uncomfortable. We have been conducting this 
reaching protocol with back pain participants for more than a decade and we have 
never had any incidents of injury or sustained aggravation of back pain symptoms. 
Virtual Reality Game Play: Consistent with our Phase I trial, prior to testing 
participants will be fully informed of the game procedures, including information on 
the available rewards for performance. The movements required during video game 
play will be very similar to those required to perform the reaching tasks and will be 
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minimizes potential risks to the participant in that they do not require any lifting; thus, 
spine loads are minimal. We further minimize risk by informing the participants that 
they are free to stop at any time if they find the procedure too uncomfortable. Finally, 
each session will begin with the participant starting with the most basic movement 
task to encourage success and to allow for the adaption of movement patterns while 
reducing the risk of exacerbating back pain symptoms.  
Some participants could feel nauseated from being in the virtual reality environment, 
but this is minimized by having precise synchronization of motion of the headset and 
the graphics presented to the participant. Care is also taken to avoid rapid changes 
in the visual scenes that can induce motion sickness. Finally, we are pre-screening 
our applicants to ensure they are not highly susceptible to motion sickness.  
There is a risk of falling as vision of the real world is fully occluded by the virtual 
reality headset. Risk of falling is minimized by having the participant first stand in the 
testing area and then put on the headset. None of the virtual reality activities require 
steps to be taken; in fact, we will instruct participants to move their feet as little as 
possible. Further, the headset will be removed while the participant is still in the 
testing environment; hence, at no time will participants be ambulatory while their real 
world vision is obstructed. Additionally, the testing area is an open space with a level 
surface, minimizing the risk of injury if a participant should fall. Two research staff 
members will conduct every appointment which allows one to run the software and 
the other to monitor the study subject. 
In keeping with Virginia Commonwealth University Institutional Review Board and US 
Department of Health and Human Services, Office for Human Research Protections 
requirements, all study personnel who interact with participants or have access to 
research data will maintain valid certification of training in the protection of human 
research participants. 
7.1 
Specification of Safety Parameters 
At each visit the study staff will use the Adverse Event Log to ask the study 
participants if they have had any change in general health since the last visit. If fever 
or unexplained weight loss is reported, suggesting systemic infection / disease may 
be causing their low back pain, the clinician will do a basic physical exam and 
specifically assess for the possibility they have other systemic illness. They will be 
advised to seek medical care and research participation may be delayed, temporarily 
discontinued, or permanently suspended at the discretion of the examining clinician 
and in consultation with the Medical Directors if needed. 
Before each treatment the study staff will use the Contraindications Form to inquire 
about change in back related signs indicative of increased severity of symptoms. 
Specifically if they have any new symptoms such as weakness, numbness, or 
difficulty walking. If the study participant reports yes on any of these items the 
clinician will do a basic physical exam and assess neurological function by checking 
myotomes, dermatomes, and reflexes to determine whether the study participant 
now presents with hard neurological signs (e.g., loss of motor function, significant 
changes in reflexes), or symptoms of other systemic disease. If the participant does 
present with hard neurological signs or serious systemic disease, they will be 
encouraged to seek consultation with their personal physician, and they will be 
excluded from further participation from the study.  
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Adverse Events, logged, and reported per requirements of the Virginia 
Commonwealth University IRB and NIH. In the case of dismissal from the protocol 
for the above stated reasons, the Medical Safety Committee will meet to determine 
whether the AE was caused by the intervention (Definite, Probable, Possible, 
Unknown) and an adverse event report will be filed according to the specific 
requirements of the Virginia Commonwealth University IRB and NIH. 
Adverse events will be entered directly into RedCap™, an electronic data 
management system and assessed twice monthly by the unmasked study 
coordinator using Tables 4, 5, and 6 located in Appendix A.  Adverse events will be 
recorded and these will be monitored at each study visit to be entered by the RAs. 
The study coordinator will routinely assess recruitment, participant status, upcoming 
visits, and outstanding assessments.  All Adverse Events will be assessed, 
classified, and reported according to Appendix A. 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
All Adverse Events will be reported to the Study Coordinator who will complete an 
Adverse Event Form and collaborate with study staff involved in the AE. If applicable, 
the Medical Director will review the AE and determine the Common Terminology 
Criteria for Adverse Events (CTCAE) scale. The Study Coordinator then compiles 
masked AE reports for the PIs to review. Twice monthly, adverse events and serious 
adverse events will be assessed by the unblinded study coordinator. Potential 
unanticipated side effects of the interventions will be monitored at each study visit 
and entered by a research assistant into the database. A tracking report will be 
developed as part of the database to allow the coordinator to assess recruitment, 
participant status, upcoming visits, and outstanding assessments. Annually, an AE 
summary report will be generated and provided to the Independent Monitors for 
review and forwarded to the NICHD. At each periodic review, AEs will be reported to 
the IRB. 
All adverse events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of 
study participation will be recorded. At each study visit, the investigator will inquire 
about the occurrence of AE/SAEs since the last visit. Events will be followed for 
outcome information until resolution or stabilization. 
7.3 
Adverse Events and Serious Adverse Events  
Adverse events: A structured safety monitoring system will be established to both 
assure real-time participant care and unbiased monitoring of adverse events (AE). 
For ongoing participant safety, events will be assessed by the PIs and co-
investigators to determine if they are Serious, Unexpected, and/or On-site. If so, an 
event evaluation form will be completed that will include a description of the event, a 
classification of seriousness, assessment of potential relationship to the intervention, 
assessment of need for change in the consent or the study activities, a summary of 
known prior health issues, event outcome, and a classification of the main organ 
system involved. (See Protection of Humans Subjects for definitions of adverse 
events). 
Adverse Events include any reaction, side effect, or other untoward medical event, 
regardless of the relationship to the study intervention. For ongoing participant 

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safety, any adverse events will be characterized within 24 hours by the study team to 
determine if it was Non-series/Serious, Unexpected/Expected, and Off-site/On-site.  
Non-serious adverse events will be defined as conditions that may be unpleasant 
and bothersome to the participant (e.g., mild nausea) that do not require 
discontinuing the study intervention or components of the intervention. All adverse 
events will be documented for review by the Independent Monitoring Committee 
(IMC) and reported to the IRB. Serious events includes any event that is 1) life 
threatening, 2) may result in prolonged, permanent, or severe disability, 3) may 
worsen a pre-existing condition, or 4) requires inpatient hospitalization or surgical 
procedure, or a treatment to prevent a serious event. All serious adverse events will 
require immediate notification of a Physician, 24 hour notification of the IRB, and an 
assessment of the implications for the continuation of the study and/or modification 
of the consent form.  
Unexpected adverse events are defined as events that are not listed in the consent 
form. Monitoring for unexpected serious adverse events attributable to the 
intervention is the responsibility of the investigators. Specific reporting and review 
requirements are defined for unexpected events, so that, if an unexpected event is 
found to be related to the intervention, the protocol and consent can be modified.  
We will utilize the NCI Common Terminology Criteria for adverse Events which are a 
descriptive terminology that can be utilized for Adverse Event (AE) reporting and 
provides a grading (severity) scale for each AE. AEs will be labeled according to 
severity, which is based on their impact on the patient.  
Attribution: An assessment of the relationship between the AE and the intervention 
will be performed using the NCI guidelines which do not define an AE as necessarily 
“caused by a therapeutic intervention”, after naming and grading the event, the 
clinical investigator will assign an attribution to the AE as unrelated, unlikely, 
possible, probable, or definite. 
Note that back pain is not considered an adverse event within this research. 
7.4 
Reporting Procedures 
The site staff must immediately report to the coordinating center PI any serious 
adverse event, whether or not considered study related, including those listed in the 
protocol and must include an assessment of whether there is a reasonable possibility 
that the study caused the event within 48 hours of PI awareness of the event.  
They must also report any unanticipated problems within the same timeframe. The 
Site staff must also report any protocol deviations or violations to the coordinating 
center PI within 7 days of awareness. Participating centers must also submit all 
reports to their local IRB in accordance with their institutional policies. 
SAEs that are unanticipated, serious (Grade 3), and possibly related to the study 
intervention will be reported to the Independent Monitors, IRB, and NICHD in 
accordance with requirements.  
Unexpected fatal or life-threatening AEs related to the intervention will be reported to 
the NICHD Program Officer and Independent Monitoring Committee within 2 days 
and to the IRB within 1 day. Other serious and unexpected AEs related to the 
intervention will be reported to the NICHD Program Official within 7 days.  

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Other anticipated or unrelated SAEs will be handled in a less urgent manner but will 
be reported to the Independent Monitor(s), IRB, NICHD, and other oversight 
organizations in accordance with their requirements. In the annual AE summary, the 
Independent Monitor(s) Report will state that they have reviewed all AE reports. 
7.5 
Follow-up for Adverse Events 
In instances where an adverse event does occur, we will follow-up with participants 
until the event is resolved or until the IRB deems it unnecessary to continue to follow 
the participant. 
7.6 
Safety Monitoring  
We have developed a Data Safety and Monitoring Plan which oversees the progress 
of the proposed study and establishes Independent Monitoring Committee (IMC). 
Membership in the IMC will be determined in collaboration with the NICHD program 
officer and the principal investigators and will include individuals that have expertise 
in chronic low back pain, biomechanics, clinical trials, and biostatistics.  
The goals of the Data and Safety Monitoring Plan include 1) evaluation of the 
progress of the study, including periodic assessments of participant recruitment, 
accrual, retention, and timeliness; participant risk versus benefit; and other factors 
that can affect study outcome, and 2) consideration of factors external to the study, 
such as scientific developments that may have an impact on the safety of 
participants or the ethics of the study. A structured safety monitoring system will be 
established to both assure real-time participant care and unbiased monitoring of 
Adverse Events (AE). 
The IMC will be scheduled to meet annually to conduct safety reviews. These 
meetings will cover all aspects of study progress, including participant recruitment, 
accrual, and retention; a review of data collection forms for assurance of data quality 
and timeliness; consideration of participant risk versus benefit; and other factors that 
can affect study outcome including a review of incidents of protocol deviation and 
actions taken in response to such deviations. In addition, these meetings will address 
any factors external to the study (e.g., recent scientific developments) that may have 
an impact on the safety of participants or the ethics of the study. 
In addition to scheduled annual meetings, the IMC will also be consulted on an as-
needed basis in the case of unanticipated serious adverse events or otherwise 
difficult situations that may arise. In such cases IMC members will discuss and 
implement the appropriate course of action to remedy any critical incident that may 
occur during the course of the study. A journal will also be maintained during the 
project to record the nature of any such critical incident, personnel involved, solutions 
considered, and the final action implemented to resolve the incident. Reporting of 
such critical incidents will be made to the Virginia Commonwealth University IRB as 
well as the NICHD. The IMC will also have responsibility to make recommendations 
to NICHD, the IRB, and the PIs concerning continuation or conclusion of the study, 
or possible modification of the ongoing protocol. 
8. INTERVENTION DISCONTINUATION  
A subject would be discontinued from the study intervention if a medical condition 
develops that precludes the continuation of the treatment intervention. For 
participants who discontinue The VIGOR Study prior to completing all scheduled 
treatment sessions (regardless of the reason), we will make every attempt to obtain 

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the outcome measurements. If the study participant is unwilling or unable to undergo 
the laboratory-based tests (e.g., difficulty tolerating the protocol, experienced an 
adverse event to a lab test) we will still attempt to obtain the clinical outcome 
measures. In instances where an adverse event does occur, we will follow-up with 
participants until the event is resolved or until the IRB deems it unnecessary to 
continue to follow the participant.  
9. STATISTICAL CONSIDERATIONS  
The co-primary clinical outcomes are changes in pain and disability. We will examine 
immediate clinical outcomes as a function of treatment. Relative to the control group, 
participants in the experimental group will show greater reductions in pain and 
disability at post-treatment relative to pre-treatment baseline (Hypothesis 1). To test 
Hypothesis 1, we will examine the Treatment by Time (baseline-post treatment) 
interaction in a LME model: a greater reduction in pain and disability in the 
experimental group than in the control group. The co-primary clinical outcomes of 
changes in pain and disability will be assessed at 1-, 6-, 12-, 24-, and 48-weeks post-
treatment. 
Secondary objectives are to examine potential mechanisms of pre- to post-treatment 
changes in clinical outcomes and maintenance of treatment gains. Participants in the 
experimental group will exhibit greater pre- to post-treatment decreases in pain/harm 
expectancy and increases in lumbar flexion as compared to the control group 
(Hypothesis 2.1). Decreases in pain/harm expectancy and increases in lumbar 
flexion will be positively related to pre- to post-treatment reductions in pain and 
disability (Hypothesis 2.2). Examination of maintenance of treatment gains will occur 
at 1-, 6-, 12-, 24-, and 48-weeks post-treatment. Relative to the control group, 
participants in the experimental group will continue to show lower levels of pain and 
disability at each time point as well as increased activity in their natural environment 
(Hypothesis 3). 
This project is a Phase II RCT in which CLBP participants will be randomly assigned 
to one of two intervention arms. Those assigned to the experimental group will play 
immersive games that will encourage progressively larger lumbar flexion excursions 
at each game level and across treatment sessions. Those in the control group will 
play the same immersive games, but the parameters of the game will require smaller 
excursions of lumbar flexion to successfully complete gameplay. Treatment 
frequency and duration is based on existing evidence that graded activity and graded 
exposure interventions, typically lasting 6-12 weeks with 8-18 treatments sessions, 
result in significant reductions in disability.44,43 Accordingly, participants in this study 
will complete 18 visits over 9 weeks with the number of sessions tapered across 
weeks (i.e., 3 sessions/week in weeks 1-3, 2 sessions/week in weeks 4-6, and 1 
session/week in weeks 7-9). Our co-primary outcome variables will be change in 
pain and change in disability from baseline to 1-week post-treatment (Aim 1). We will 
also examine changes in expectations of pain/harm and lumbar flexion as potential 
mechanisms of change in pain and disability (Aim 2). Aim 3 will examine 
maintenance of treatment gains at 1-, 6-, 12-, 24-, and 48-weeks post-treatment. 
9.2 
Sample Size and Randomization 
We will recruit 230 participants with chronic low back pain (CLBP) and fear of 
movement. We will include participants with CLBP between the ages of 18-60 and 
who report no health condition(s) that may restrict movement or preclude safe 
participation. Participants will be recruited from the general population and specific 

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organizations such as Virginia Commonwealth University’s University Medical 
Associates. 
Aim 1: Power analyses were conducted to determine the sample size needed to 
achieve clinically important differences in our co-primary clinical outcome measures 
of pain and disability. Based on the extant literature, we based our analyses on a > 
30% decrease in pain ratings1 (on the 0-10 NRS scale) and a 30% decrease in 
disability ratings on the RMDQ2 in the experimental group. Further, we predict a 10% 
decrease in pain and disability in the control group to account for potential placebo 
effects. The population standard deviations were set at 75% of the population mean 
values. The pre-post correlation was estimated as r=0.7. These population 
parameters translate into an effect size of f=0.30. Using these parameters, we drew 
10,000 samples from a normal population distribution. Based on these parameters, 
to achieve power of 80% and α=0.05 will require a total N=78.  
Aim 2 & 3: Power analyses were conducted to determine the sample size needed to 
address hypotheses 2.1, 2.2, and 3. Using the method described by Morris (2008),3 
we calculated effect size estimates from randomized clinical trials on the effects of 
graded activity or graded exposure interventions on changes in disability among 
individuals with CLBP.4-7 For our power analyses, we adopted the median estimated 
effect size: δ = .45, which corresponds to what would commonly be described as a 
medium effect size. Following Raudenbush and Liu’s (2000) recommendation,8 we 
set the residual error variance to 1 and estimated the between-subject slope 
variance to be 0.30. For power equal to .80 and α=0.05, a sample size of 209 
participants was indicated.  
Based on the sample size calculations, using a sex-stratified random allocation table, 
we need a minimum sample of 209 participants to address Aims 1-3. To allow for 
10% attrition from baseline to 48-week follow-up, we will recruit 230 participants. 
Treatment Assignment Procedures 
Randomization & Stratification: The study statistician will use the R statistical 
language to block randomize treatments stratified by sex. Then the study coordinator 
will assign subjects to the treatment arms.  
  
Masking or Blinding: The principal investigators, the statistician, and members of the 
data collection team will remain blinded to intervention assignment throughout the 
duration of the study. They will be given the identifying codes only at the end of the 
study when it is necessary to interpret the results. The un-blinded study coordinator, 
who is responsible for scheduling testing and treatment sessions, will serve to 
receive the study patients and escort them to the various testing and treatments sites 
to minimize the interaction between patients; however, the study coordinator will not 
participate in the assessments.  
9.3  
Definition of Populations 
Intention to Treat Analysis (ITT): We will include all randomized study participants 
who have at least baseline endpoint assessments in our ITT analysis. The ITT 
analysis is our primary method for assessing outcomes, and how it is performed will 
be determined based on the pattern of missingness. If the missingness is deemed 
MCAR, the LOCF method will be used: simply the most recent valid observation will 
be "carried forward" to replace the subsequent missing observations. If the 
missingness is deemed MAR, missing observations will remain as missing, and 

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maximum likelihood estimation, the default estimation algorithm of LMER, will be 
used to estimate these observations. If the missingness is found to be MNAR, 
multiple-imputed data will be used to construct LMER models. 
 
Per-Protocol Analysis (PPA): For the PPA we will exclude study participants who: 1) 
fail to attend 13 out of 18 treatment sessions; 2) develop an exclusionary medical 
condition while on study protocol, or 3) receive interventions outside of the Allowed 
(Section 5.3.1) during treatment. Finally, we will assess how comparable estimated 
parameters vary between ITT and PPA analyses. 
 
9.4 
Interim Analyses and Stopping Rules 
No interim analyses are planned as they relate to either the primary or secondary 
outcome data. An individual subject would be discontinued from the study 
intervention if a medical condition develops that precludes the continuation of the 
treatment intervention. Additionally, the study will be stopped if the IMC, in 
consultation with NICHD, decides that the risks associated with the treatment 
interventions (i.e., excessive SAEs) outweigh the potential benefits of the knowledge 
gained from continuing the study. 
 
9.5 
Outcomes  
9.5.1 Primary Outcome  
The co-primary clinical outcomes are pain and disability, which will be assessed at 
pre-treatment baseline (visit 1) and at 1-, 6-, 12-, 24-, and 48-weeks post-treatment 
(i.e., visits 20-24).  
9.5.2 Secondary Outcomes  
Secondary outcomes include expected pain, expected harm, and lumbar flexion 
during standardized reaching, which will be measured at pre-treatment baseline (visit 
1), at the beginning of each week during treatment (visits 2, 5, 8, 11, 13, 15, 17, 18, 
19), and at 1-, 6-, 12-, 24-, and 48-weeks post-treatment (i.e., visits 20-24).  
9.6 
Data Analyses  
We will analyze all outcome variables (pain, disability, pain/harm expectancy, and 
lumbar flexion) using linear mixed-effects (LME) models with treatment 
(Experimental, Control) as a between-subject fixed effect and time (pre-treatment, 1, 
6, 12, 24, and 48 weeks) as a within-subject fixed effect. Given the expected 
findings, both linear and quadratic time effects will be tested in every model. We will 
also include demographic covariates (e.g., age, BMI) and potential confounders 
(e.g., radiating versus non radiating pain) as well as sex stratification in the LME 
models. Any variables that differ at baseline will be included in the statistical models 
as potential confounders.  
Intention-to-treat analyses are commonly conducted to analyze randomized clinical 
trial data in the presence of missing values. While various imputation strategies have 
been proposed to estimate missing data, such as last observation carried forward, 
use of LME models to analyze longitudinal data renders these strategies largely 
unnecessary. We will also conduct equivalent per-protocol analyses that will include 
only successfully adhered participants (i.e., attending > 70% of gaming sessions).  
 
Aim 1. Examine immediate clinical outcomes as a function of treatment. Relative to 

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the control group, participants in the experimental group will show greater reductions 
in pain and disability at post-treatment relative to pre-treatment baseline (Hypothesis 
1).  
 
To test Hypothesis 1, we will examine the Treatment by Time (baseline-post 
treatment) interaction in a LME model: a greater reduction in pain and disability in the 
experimental group than in the control group. 
Aim 2. Examine potential mechanisms of pre- to post-treatment changes in clinical 
outcomes. Participants in the experimental group will exhibit greater pre- to post-
treatment decreases in pain/harm expectancy and increases in lumbar flexion as 
compared to the control group (Hypothesis 2.1). Decreases in pain/harm expectancy 
and increases in lumbar flexion will be positively related to pre- to post-treatment 
reductions in pain and disability (Hypothesis 2.2). 
Aim 3. Examine maintenance of treatment gains at 1-, 6-, 12-, 24-, and 48-weeks 
post-treatment. Relative to the control group, participants in the experimental group 
will continue to show lower levels of pain and disability at each time point as well as 
increased activity in their natural environment (Hypothesis 3). 
To address aims 2 & 3 we will build and test linear mixed-effects models for each of 
the outcome variables. For hypotheses 2.1 and 3, pain, disability, pain/harm 
expectancy, and lumbar flexion will be the outcome variables, while time (linear and 
quadratic), treatment group, and the interactions of time and treatment group will be 
the primary predictor variables. For hypothesis 2.2, pain/harm expectancy and 
lumbar flexion will serve as the outcome variables, while time (linear and quadratic), 
treatment group, the time-by-group interactions, pain, and disability will be predictor 
variables. For hypothesis 3, planned comparisons will be conducted to compare the 
control and experimental groups at each time period for pain, disability, and activity 
levels in the natural environment. As noted above, covariates will be added to 
analyses as needed. The significance level for every omnibus test will be set to 0.05, 
while Holms procedure will be used to control familywise type-I error rate for post-
tests at .05. 
Checking Assumptions: Assumptions of LME models will be checked by conducting 
analyses of model residuals. Violations of normality will be addressed by 
transforming the data, while outliers or influential cases will be handled by 
conducting sensitivity analyses. In contrast to the standard repeated measures 
analyses of variance, with their rigid assumptions about the error covariance 
structure, LME models permit numerous alternative error covariance structures. This 
allows for modeling of data that exhibit both heteroscedasticity and autocorrelation, 
which is likely to characterize the data collected for this study. 
Additional Analyses: We will use the same analytic framework to analyze additional 
measures of core outcome domains, including emotional functioning (e.g., CES-D, 
POMS-2, PROMIS measures), pain vulnerability (TSK, PCS), pain resilience (PRS, 
PSEQ), and patient global impression of change (PGIC).  
 
10. DATA COLLECTION AND QUALITY ASSURANCE 
10.1 
Data Collection Forms  
All data collection forms are paper-based or electronic (eCRF) with the exception of 

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the prescreen survey which is always an online form, but can be completed by study 
staff as a source document during a phone interview. As source documents, all 
forms are signed or electronically verified and dated by a study staff member. Forms 
are identified with Participant Identification Numbers with no personal identifying 
information. The Study Coordinator or Research Assistant transfers all data from the 
paper forms to the database. Every 2-weeks a Research Assistant performs a quality 
assurance check by comparing paper-based forms to data entry in the database.  
All paper data collection forms will be kept in a locked file cabinet in the Study 
Coordinator's office or the respective offices or laboratories of the PIs. Data will also 
be entered into an electronic database. The data management system has been 
developed by the Virginia Commonwealth University Office of Research and 
Sponsored Programs. Specifically, we will use REDCap™, a web application for 
building and managing online surveys and databases. Subjects will be identified by a 
unique identification number and no personal identifying information will be stored in 
the study database or used in any of the analyses files.  
10.2 
Data Management  
This is a single site study and as such Virginia Commonwealth University will serve 
as the Coordinating Center and is responsible for all data management. 
10.3 
Quality Assurance  
10.3.1 Training 
Prior to data collection, the following will take place:  
1. The Steering Committee will review and approve all protocols.  
2. All study personnel will be trained in all study procedures for which they are 
responsible.  
10.3.2 Quality Control Committee  
This is a single site study and the Steering Committee will be responsible for 
overseeing quality control.  
10.3.3 Metrics 
The PIs will monitor treatment administration records on a monthly basis to 
determine whether study participants are receiving appropriate treatments as 
prescribed. 
10.3.4 Protocol Deviations 
A list of potential protocol deviations will be created and maintained for tracking by 
the Steering Committee. Each protocol violation report will include a description of 
the violation, the type of deviation that occurred, whether the date the deviation 
occurred, and whether the IRB was notified. The Steering Committee will review 
protocol deviations on an as needed basis to determine if subjects should continue in 
the study, the impact on the procedures, and the next steps for subject continuation. 
Examples of protocol violations include enrollment of an ineligible subject, 
randomization of an ineligible subject, failure to collect all screening tests, serious 
adverse events not reported in a timely fashion, breach of confidentiality, subject lost 
to follow-up, and visits outside of time window. 

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10.3.5 Monitoring 
The Steering Committee will be responsible for study monitoring. This committee will 
review and approve the study protocol prior to initiation of enrollment, will review 
SAEs and AEs at least twice annually and will be alerted to any interim concerns. 
Should any SAEs occur, they will be reported within 24 hours to the PIs.  
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 
Institutional Review Board (IRB) Review  
This protocol and the informed consent document and any subsequent modifications 
will be reviewed and approved by the Virginia Commonwealth University IRB.  
11.2 
Informed Consent Forms 
An initial screening will be conducted with all participants to describe the research 
study and determine their interest. For subjects who are interested in potentially 
volunteering for the study the study coordinator and/or principal investigators will 
meet with interested candidates. At this time individuals interested in participating 
can ask questions about the study. If they wish to be considered for the study they 
will then be asked to read and sign an informed consent document. A signed consent 
form will be obtained from each participant. 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 and this fact will be 
documented in the participant’s record. The principal investigators will work with the 
Virginia Commonwealth  University IRB on an as needed basis to make provisions 
for special populations. 
11.3 
Participant Confidentiality  
Data from self-report instruments and physical assessments are the primary source 
of research material. Measures will be taken to ensure the confidentiality of 
participant responses. Only those persons directly involved with conducting the study 
will be able to link the participant names with their information. All participants will be 
provided with a random ID number and no personal identifiers will be kept with the 
raw data. All informed consent documents will be filed separately so that there is no 
direct connection between participant names and any of their data. All hard copy 
data will be kept in locked filing cabinets. Physical and questionnaire data will be 
stored digitally using filenames corresponding to the participants ID number only. No 
identifying information will be used in any publications or presentations that result 
from this research. The code linking the random ID number with the participants 
name and contact information will be maintained through the follow-up period of the 
last enrolled subject (i.e., ~August 2023), at which point it will be destroyed. 
All health-related data will be kept confidential by the investigators involved in this 
study. Specifically, only the investigators in the study will have access to patient 
data. Published or presented data will not identify patients in any way. Patients will 
not be audiotaped or videotaped. Data, forms, reports, and other records that leave 
the site will be identified only by a participant identification number (Participant ID, 
PID). All records will be kept in a locked file cabinet. All computer entry and 
networking programs will be done using PIDs only. Additionally, while every effort will 
be made to keep study-related information confidential, there may be circumstances 
where this information must be shared with: 1) Federal agencies, for example the 
Office of Human Research Protections, whose responsibility is to protect human 

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subjects in research; and 2) Representatives of Virginia Commonwealth University 
VCU, including the Institutional Review Board, a committee that oversees the 
research at VCU. 
11.4 
Study Discontinuation  
The study may be discontinued at any time by the IRB, the NICHD, the OHRP, or 
other government agencies as part of their duties to ensure that research 
participants are protected.  
12. COMMITTEES 
Steering Committee: The VIGOR Study Steering Committee, which is charged with 
the overall governance of study conduct, consists of James S. Thomas, PhD, PT, 
and Christopher R. France, PhD. The Steering Committee approves the final 
protocols and manuals of operations, supervises the overall execution of the trial, 
generates and approves study policies, considers modifications of the protocol and 
study operations, and plans and drafts study-related publications. The Steering 
Committee appoints and charges the subcommittees described below. All major 
scientific decisions are determined by consensus of the Steering Committee.  
Medical Safety Committee: The VIGOR Study Medical Safety Committee, which 
consists of James S. Thomas, PhD, PT, Christopher R. France, PhD, Tim Law, D.O. 
and Study Coordinator Tiffany Amos, reviews masked study data related to the 
overall safety of study participation, develops safety reports for the Data and Safety 
Monitoring Board, addresses IRB issues (related to participant safety) that may arise, 
reviews clinical practice-related issues and oversees the clinical safety of all study 
participants.  
Data Safety and Monitoring Board: A Data Safety Monitoring Board (DSMB) that 
consists of an Independent Monitoring Committee IMC (IMC) monitors all aspects of 
the study, including those that require access to any blinded data.  
Recruitment, Adherence, and Retention Committee: The VIGOR Study Recruitment, 
Adherence and Retention Committee (James S. Thomas, PhD, PT, Christopher R. 
France, PhD., and members of the Study Coordination and Data Collection Team) 
refines and optimizes protocols and strategies for recruitment, adherence and 
retention of study participants. The Committee oversees recruitment progress, 
intervenes in cases of under-recruitment, and reports recruitment progress to the 
Steering Committee. 
13. PUBLICATION OF RESEARCH FINDINGS  
This study is governed by a Steering Committee and publication of the results of this 
trial will be governed by the policies and procedures developed by the Steering 
Committee.  
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