A Decentralized, Randomized, Controlled Trial to Study Health Outcomes of EaseVRx-8w+ for the Treatment of Chronic Lower Back Pain
Phase: NA
Conditions: Chronic Low-back Pain, Anxiety, Depression
Sponsor: AppliedVR Inc.

A Decentralized, Randomized, Controlled Trial of EaseVRx-8w+ for
Chronic Low Back Pain
Principal Investigator: Todd Maddox, PhD
Funded by: AppliedVR, Inc.
Protocol Version Number: v.3.0
Protocol Version Date: 14JUL2022
Summary of Changes from Previous Version:
Affected
Section(s)
Summary of Revisions Made
Rationale
Section 12.1
Update database lock date
Updated to reflect database lock
date in Statistical Analysis Plan
Update Informed Consent Form Version
Both the initial and most recently
revised version of the protocol have
the same version number. The
revised version will be listed as
version 2.0.
Update Statistical Analysis Plan
Updated to reflect randomization
ratio listed on Protocol
Add Request for Feedback Letter
Added letter to obtain consent from
participants to receive testimonials
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Table of Contents
1
STATEMENT OF COMPLIANCE
4
2
PROTOCOL VERSION HISTORY
5
3
PROTOCOL APPROVAL SIGNATURE PAGE
8
4
SIGNATURE PAGE
9
5
LIST OF ABBREVIATIONS
10
6
PROTOCOL SUMMARY
11
6.1
Synopsis
11
6.2
Schedule of Activities (SoA)
18
7
INTRODUCTION
19
7.1
Study Rationale
19
7.2
Background
19
7.3
Device Description
20
7.3.1
Indications for Use
20
7.3.2
System Description and Components
20
7.3.3
AppliedVR Software for EaseVRx
21
7.4
Study Interventions
22
7.5
Dosing and Administration
23
7.6
Technical Support
23
7.7
Risk/Benefit Assessment
24
7.7.1
Known Potential Risks
24
7.7.2
Known Potential Benefits
24
7.7.3
Assessment of Potential Risks and Benefits
24
8
STUDY OBJECTIVES AND ENDPOINTS
24
9
STUDY DESIGN
30
9.1
Overall Design
30
9.2
Scientific Rationale for Study Design
31
9.3
Justification for Dose
31
9.4
End of Study Definition
31
10
SELECTION OF STUDY POPULATION
32
10.1
Inclusion Criteria
32
10.2
Exclusion Criteria
32
10.3
Participant Recruitment and Screening
33
10.4
Informed Consent
33
10.5
Screen Failures
34
11
STUDY PROCEDURES
34
11.1
Baseline Survey
34
11.2
Enrollment & Randomization
35
11.3
Pre-Treatment Device Use Onboarding
35
11.4
Treatment Phase (Weeks 0-8) & Extended Use Period (weeks 9-16)
35
11.5
Day 56
36
11.6
Post-treatment Data Collection
36
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11.7
Healthcare Utilization Analysis
37
12
STUDY INTERVENTION
38
12.1
Measures to Minimize Bias: Randomization and Blinding
38
12.2
Study Intervention Compliance
38
13
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL
38
13.1
Discontinuation of Study Intervention
38
13.2
Participant Discontinuation/Withdrawal from the Study
38
13.3
Lost to Follow-Up
39
13.4
Equipment Return
39
14
STUDY ASSESSMENTS
39
14.1
Efficacy Assessments
39
14.2
Other Assessments
42
14.3
Healthcare Utilization Assessments
42
15
PROTOCOL DEVIATIONS
43
16
SAFETY REPORTING
43
16.1
Definitions
43
16.2
Assessment of Severity
44
16.3
Assessment of Relationship
45
16.4
Adverse Event Reporting
46
16.5
Serious Adverse Event Reporting
46
16.6
Determination and Reporting of Unanticipated Adverse Device Effects
46
16.7
Device Deficiency Reporting Procedures
47
17
STATISTICAL CONSIDERATIONS
47
18
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS
47
18.1
Study Discontinuation and Closure
47
18.2
Confidentiality and Privacy
48
18.3
Publication and Data Sharing Policy
48
18.4
Conflict of Interest Policy
49
18.5
Study Records Retention
49
19
REFERENCES
50
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1
STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical
Practice (ICH GCP) and the following:
•
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part
46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)
The protocol, informed consent form(s), and recruitment materials will be submitted to the Institutional
Review Board (IRB) for review and approval. Approval of both the protocol and the consent form must be
obtained before any participant is enrolled. Any amendment to the protocol will require review and
approval by the IRB before the changes are implemented to the study. In addition, all changes to the
consent form will be IRB-approved; a determination will be made regarding whether a new consent
needs to be obtained from participants who provided consent, using a previously approved consent
form.
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2
PROTOCOL VERSION HISTORY
The table below is intended to capture changes of IRB-approved versions of the protocol, including a
description of the change and rationale. A Summary of Changes table for the current amendment is in
the Protocol Title Page.
Version
Date
Description of Change
Brief Rationale
1.0
02NOV2021
Original protocol
N/A
1.1
02FEB2022
Updated schedule of activities to
include PHQ-9 question 9
Changed order of enrollment
2) Removed wording about 1:1:1:1
ratio of randomization
3) Added screenshot of Curebase
sign up page
4) Added new demographic
message in Communication Plan
5) Added verbiage in
communication plan to confirm
that participants have received
their VR headset
6) Added option for participants to
receive text notifications during
the study in pre-screen survey
7) Added Pretreatment Survey
Completion screen
8) Updated Support Protocol &
Scripts
Ensures screening process is
reflected in the SoA
Moving the shipment survey
before the pre-treatment
BPIs allows for simpler CSV
data output
2) Randomization ratio is
2:1:2:1 on protocol
3) This is the account
creation page for Curebase
4) Allows us to confirm if the
participant has received the
headset and confirms the
start of the intervention
5) Ensures we receive
demographic information
from patients if they leave
the website
6) All study notifications will
be sent via email due to
complexity of study and text
message character limit. To
reduce the number of
notifications sent,
participants will have the
option to receive texts
7) Positive reinforcement for
participants to complete
pretreatment surveys
8) Updated questions and
answers to reflect flow of
study
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2.0
04MAR2022
(1) Change randomization
ratio to 1:1:1:1
(2) Updated name of PI from
Laura Garcia to Todd
Maddox
(3) Added new Study
Investigator Charisse
Sparks, M.D.
(4) Updated the number of
participants the study will
enroll from 800
participants to 1000
(5) Add exclusion criteria: only
one participant per
household allowed to
participate
(6) Add exclusion criteria:
recent or future medical
procedures
(7) Clarify language for
payment schedule
(1) Upon further
investigation, we
determined that a
randomization of
1:1:1:1 would better
suit the study and
would help us reach
the outcomes we
want to achieve. It
also allows for easier
recruitment of
participants and
randomization
through Curebase.
(2) PI Laura Garcia is no
longer part of
AppliedVR
(3) Charisse Sparks is
the new CMO for
AppliedVR and will
now be involved in
the study monitoring
(4) The increase in
number of
participants that will
enroll is necessary
due to the new
change in
randomization ratio
(5) Protects integrity of
study so that study
details are not
shared between
household members
(6) To adjudicate acute
versus chronic pain.
We are studying
chronic pain
therefore it is
necessary to exclude
acute pain diagnosis
(7) Provide clarification
that payment is tied
to survey completion
and not VR session
completion
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3
PROTOCOL APPROVAL SIGNATURE PAGE
Protocol Title:  A Decentralized, Randomized, Controlled Trial of EaseVRx-8w+ for Chronic Low Back Pain
Protocol Version/Date: v.1.0 / 02NOV2021
This protocol has been read and approved by:
SPONSOR:
Josh Sackman
Date
President and co-Founder
AppliedVR, Inc.
CRO:
Iman Ahmad
Date
Sr. Director, Clinical Affairs
MCRA, LLC
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PRINCIPAL INVESTIGATOR PROTOCOL
4
SIGNATURE PAGE
I have read and understand this protocol and will conduct the study in accordance with this protocol, all
attachments and amendments, applicable Food and Drug Administration regulations, HIPAA, IRB
requirements, and the policies of the institutions where the study will take place.
In my formal capacity as Investigator, my duties include ensuring the safety of the study participants
enrolled under my supervision and providing AppliedVR, Inc. with complete and timely information, as
outlined in the protocol. It is understood that all information pertaining to the study will be held strictly
confidential and that this confidentiality requirement applies to all study staff at this site.
Protocol Title:  A Decentralized, Randomized, Controlled Trial of EaseVRx-8w+ for Chronic Low Back Pain
Protocol Version/Date: v.1.0 / 02NOV2021
Principal Investigator:
Todd Maddox, PhD
(Print Name)
(Signature)
(Date)
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5
LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
Adverse Event
ADE
Adverse Device Effect
AVR
AppliedVR, Inc.
BPI
Brief Pain Inventory
CAP-6
Concerns About Pain
CBT
Cognitive Behavioral Therapy
CDC
Center For Disease Control and Prevention
CDRH
FDA Center for Devices and Radiological Health
CFR
Code of Federal Regulations
CID
Clinically Important Difference
CLBP
Chronic Low Back Pain
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
Sars-cov-2 Coronavirus
CRF
Case Reporting Form
FDA
Food And Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
ICH GCP
International Conference on Harmonisation Good Clinical Practice
IDE
Investigational Device Exemption
IRB
Institutional Review Board
JMIR
Journal Of Medical Internet Research
MCRA
Company Name: Regulatory Consultants
MHLC-C
Multidimensional Health Locus of Control
ODI-2.1b
Oswestry Disability Index
OUD
Opioid Use Disorder
PGIC
Patient Global Impression of Change
PHI
Protected Health Information
PHQ-9
Patient Health Questionnaire (9 Question Instrument)
PI
Principal Investigator
PMID
PubMed Identification
PROMIS
Patient-Reported Outcomes Measurement Information System
PSEQ-10
Pain Self-Efficacy Questionnaire (10 Question Instrument)
PUI
Perceptual User Interface
RCT
Randomized Controlled Trial
ROM
Read Only Memory
SAE
Serious Adverse Event
SUS
System Usability Scale
TMF
Trial Master File
UADE
Unanticipated Adverse Device Effect
USA
United States of America
VR
Virtual Reality
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6
PROTOCOL SUMMARY
6.1
SYNOPSIS
Title:
A Decentralized, Randomized, Controlled Trial of EaseVRx-8w+ for Chronic Low Back
Pain
Study Sponsor
AppliedVR, Inc.
16760 Stagg Street, Unit 216
Van Nuys, CA 91406
Phone: 1-844-204-9093
Study
Investigators
Todd Maddox, PhD (Principal Investigator)
Charisse Sparks, MD
Liesl Oldstone, PhD
Beth Darnall, PhD
Investigational
Device
EaseVRx is a prescription-use immersive virtual reality system intended to provide a
combination of biopsychosocial pain education, diaphragmatic breathing training,
relaxation exercises, and executive function games for participants diagnosed with
chronic low back pain (CLBP). The device is intended for in-home use for the
reduction of pain and pain interference associated with CLBP.
Study Purpose
The aim of this randomized controlled trial (RCT) is to assess outcomes for virtual
reality therapy (including pain intensity, pain interference, anxiety, depression,
physical function, sleep, behavioral skills development, health outcomes and
satisfaction) along with healthcare utilization and costs in participants with CLBP.
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Study Design
This is a decentralized, randomized controlled trial with four parallel study arms
comparing change from pre-treatment to end-of-treatment to 12-months
post-treatment in the EaseVRx-8w, EaseVRx-8w plus extended on-demand and
Control groups.
After consenting to join the study, participants will be randomized and allocated to
one of four treatment programs. Study devices will be delivered to the participant's
home with instructions for use via FedEx with complementary remote technical
support.
•
participants in the EaseVRx-8w arm will participate in an 8-week
interventional program and continue to be followed for 24 months after
completion of treatment
•
participants in the EaseVRx-8w plus extended on-demand arm will enroll in an
8-week interventional program and be offered an extended 8-week
on-demand period, and continue to be followed for 24 months after the
completion of treatment
•
participants in the first control arm will receive 2D Sham VR virtual reality
content during the 8-week interventional program and continue to be
followed for 24 months after the completion of treatment
•
participants in the second control arm will receive 2D Sham VR virtual reality
content during the 8-week interventional program and be offered an
extended 8-week on-demand period, after which they will continue to be
followed for 24 months after the completion of treatment
All trial participants will be monitored for pain intensity and pain interference,
physical function, behavioral skills development, health outcomes and satisfaction.
Additionally, to assess resource use associated with CLBP, participant data will be run
through a secure Datavant matching process to be linked to their healthcare claims
data if it is available in the Komodo data set. The claims will provide descriptive
characterizations of resource use and healthcare costs associated with CLBP. For
participant-level changes in resource use, and for comparisons between study arms,
only the participants with complete claims files will be assessed. Claims-matched
data will capture all interactions with the healthcare system that generate an
insurance claim record, which includes such things as physician visits, interventions
such as steroid injections, surgery or physical therapy, emergent use of services,
medications, and diagnostic procedures. Claims adjudication often lags a few
months, so the most robust analyses of utilization will be performed about 6 months
after the time point of interest. Health economic modeling will be performed after 1
year to assess the cost and economic outcomes of the EaseVRx intervention.
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The Komodo claims data provides a real-world source of utilization and cost
parameters associated with claims of CLBP.  As such, it can be used more broadly to
either compare the study participants' resource use and costs to the broader
population of participants with CLBP, or a “synthetic arm” can be constructed using
available demographic data to match any of the study arms.
Study Duration
This study is expected to take approximately 36 months for completion.
Number of
Participants &
Sites
This study will enroll approximately 1000 participants using a fully decentralized
direct-to-participant trial design without any central data collection sites.
Randomization
Scheme
Enrolled participants will be randomized 1:1:1:1 and assigned to one of four
treatment arms:
•
56-day skills-based VR program (EaseVRx-8w)
•
56-day skills-based VR program followed by an extended 56-day on-demand
period (EaseVRx-8w plus extended on-demand)
•
56-day control (Sham VR)
•
56-day control followed by an extended 56-day on-demand period (Sham VR
plus 8w extended on-demand)
Evaluation
Schedule
Participants in all 4 treatment arms will be evaluated at the following timepoints:
pre-treatment, 2x/week during treatment, immediately post-treatment (day 56 in all
arms), 4-weeks post-treatment, 8-weeks post-treatment, 12-weeks post-treatment, 6
months post-treatment, 12 months post-treatment, 18 months post-treatment, 24
months post-treatment.
Intended
Participant
Population
Mixed community-based sample and physician-referred sample of individuals aged
18 and older with a diagnosis of CLBP (defined as moderate to severe pain lasting
longer than three months). Participant recruitment methods will aim to guarantee
data collection from the following groups:
•
At least 250 of the approximately 1000 recruited participants will be ≥ 65+
years old.
•
At least 250 of the approximately 1000 recruited participants will be of lower
education and socioeconomic status (based on education level, employment
status and annual household income).
Enrollment
Target
Approximately 1000 participants
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Inclusion
Criteria
In order to be eligible to participate in this study, participants must meet all of the
following criteria:
1.
Male and female adults aged 18-85.
2.
Self-reported chronic low back pain that will be confirmed with claims
data when available.
3.
Pain duration of at least three months.
4.
Average pain intensity score of ≥ 4 and average pain interference score
of ≥ 4 on the 0-10 Brief Pain Inventory (BPI) Pain Scale for the past
month at screening.
5.
Fluency in English.
6.
Willing and able to comply with all study procedures including all
required restrictions for the duration of study participation.
7.
Able to give voluntary, written informed consent to participate and have
signed an Informed Consent Form specific to this study.
8.
Access to Internet for the duration of their study participation (24
months).
9.
Access to a smartphone or computer for the duration of the study.
10.
Availability of a physical mailing address that is not a PO box address for
receipt of the device.
11.
Completed the Baseline Survey plus at least two of the five sets of
participant surveys that are administered during the 10-day
pretreatment assessment period.
12.
Able to provide photo ID.
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Exclusion
Criteria
Participants who meet any of the following criteria will be excluded from
participating in this study:
1.
Unable to understand the goals of the study due to cognitive difficulty.
2.
Any medical condition that may prevent the use of virtual reality (e.g.,
current, or prior diagnosis of epilepsy, seizure disorder, hypersensitivity to
flashing light or motion, migraines, any medical condition predisposing
participant to nausea or dizziness, dementia, absence of stereoscopic vision
or severe hearing impairment).
3.
Injury to eyes, face, or neck that prevents comfortable use of VR.
4.
Index back pain is linked to a cancer-related diagnosis.
5.
Possible suicidal ideation as indicated by the 9th item of the Participant
Health Questionnaire-9 (PHQ-9).
6.
Previous participation in the 2020 AVR EaseVRx pivotal study.
7.
Receiving worker’s compensation and/or involved in any active litigation
related to an injury.
8.
Current or recent participation (i.e., within the last 2 months) in any other
research study involving a drug, device, vaccine, or other interventional
treatment product; or plans to participate in another research study over the
next 24 months.
9.
Participation of two or more members in one household
10. Recent or future medical procedures scheduled related to any current
diagnosis
Primary
Objective
The primary objective of this study is to evaluate the following:
Primary Endpoint: Assess the impact of skill-based VR on pain Intensity or
Interference compared to sham VR.
•
Assess the effect of EaseVRx vs. Sham VR on group score change from baseline
to end of treatment on pain intensity
•
Assess the effect of EaseVRx vs. Sham VR on group score change from baseline
to end of treatment on pain interference
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Secondary
Objectives
The secondary objectives of this study include the following:
1.
Assess the effect of EaseVRx vs. Sham VR by comparing:
•
Percentage of participants with a ≥ 30% change in pain intensity
measured with the Brief Pain Inventory (BPI) from pre-treatment to
end-of-treatment (8 weeks) for each group
•
Percentage of participants with a ≥ 30% change in pain interference
measured with the BPI (as represented by a single composite score
derived from 7 pain interference questions) from pre-treatment to
end-of-treatment (8 weeks) for each group
2.
Assess the effect of EaseVRx vs. Sham VR by comparing:
•
Change in Oswestry Disability Index (ODI-2.1b), PROMIS Sleep
Disturbance, PROMIS Depression and PROMIS Anxiety from
pre-treatment to end-of-treatment (8 weeks) for each group
3.
Assess effect of EaseVRx vs. Sham VR by comparing participant satisfaction
at end-of-treatment (8 weeks) for each group
Exploratory
Objectives
The exploratory objectives of this study include the following:
1.
Assess the impact of skill-based VR in follow-up pain adjusting for baseline
pain.
2.
Assess the impact of skill-based VR based on clinical importance changes in a
responder framework. This endpoint is included to provide sensitivity around
the secondary endpoint.
3.
Assess the impact of skill-based VR on changes in healthcare utilization and
outcomes throughout an 8-week intervention and follow-up period.
4.
Assess effect of EaseVRx vs. Sham VR by comparing change in Concerns
About Pain (CAP-6); and behavioral skills from pre-treatment to
end-of-treatment for each group.
5.
Assess effect of EaseVRx vs. Sham VR by comparing participant Global
Impression of Change (PGIC) and system usability (as measured with the
System Usability Scale; SUS) at end-of-treatment for each group.
6.
Assess effect of EaseVRx vs. Sham VR by comparing change in all objectives
from pre-treatment to end-of-treatment, 4 weeks post treatment, 8 weeks
post treatment, 12 weeks post treatment, 6 months post treatment, 12
months post treatment, 18 months post treatment and 24 months post
treatment in the EaseVRx-8w and EaseVRx-8w plus extended on-demand
groups.
Clinical
Research
Organization
(CRO)
MCRA, LLC
803 7th Street NW
Washington DC 20001
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Virtual Trial
Platform
Curebase Inc.
340 S Lemon Ave #3356
Walnut, CA 91789
United States
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6.2
SCHEDULE OF ACTIVITIES (SOA)
VISITS
Pre-Treatmen
t
Treatment
Post-Treatment (PT)
Day
- 101
Day
-9
to 0
Wks.
1-8
Day
56
4 Wks.
(84
+7 days) 1
8 Wks.
(112
+7 days) 1
12 wks.
(140
+7 days) 1
6 months
(238
+30 days) 1
12 months
(420
+30 days) 1
18 months
(602
+30 days)1
24 months
(784
+30 days) 1
Pre-Screener
X
Suicidality Screener - 9th item of
PHQ-9
X
Demographic survey
X
Informed Consent via Curebase
X
Identity Verification
X
Brief Pain Inventory (BPI) pain
intensity/interference
X
X2
X3
X
X
X
X
X
X
X
X
Oswestry Disability Index
X
X
X
X
X
X
X
X
X
PROMIS Sleep Disturbance
X
X
X
X
X
X
X
X
X
PROMIS Depression
X
X
X
X
X
X
X
X
X
PROMIS Anxiety
X
X
X
X
X
X
X
X
X
Concerns About Pain
(CAP-6) Scale
X
X
X
X
X
X
X
X
X
Behavioral Skills Use
X
X
X
X
X
X
X
X
X
Participant’s Global Impression of
Change Scale (PGIC)
X
X
X
X
X
X
X
X
Pain Self-Efficacy Questionnaire
(PSEQ-10)
X1
X1
X1
X1
X1
X1
X1
X1
X1
Multidimensional Assessment of
Interoceptive Awareness (Ver 2)
X1
X1
X1
X1
X1
X1
X1
X1
X1
Multidimensional Health Locus of
Control
X1
X1
X1
X1
X1
X1
X1
X1
X1
VR Sickness Questionnaire
X4
X4
X4
X4
participant Satisfaction
X
System Usability Scale (SUS)
X
Benefits Screening
X
Shipping Address Survey
X
EaseVRx User Experience
Questionnaire
X
X5
Randomization (performed within
Curebase portal)
X
Ship Intervention kit to
participants
X
Technical onboarding
X
Record VR compliance/use data6
X
X
X5
X5
Collect study intervention kit
X
Perceived Treatment Assignment
X
Healthcare utilization data analysis
X7
X7
X7
X7
X7
X7
X7
X7
1 OPTIONAL survey offered next day.
2 Two out of five BPI survey instances to be completed over 9-day pre-intervention period.
3 Research staff will monitor participants’ progress through twice weekly BPI surveys.
4 VR Sickness Questionnaire will be administered once per week during treatment and once per week for the 16-week arms.
5 For participants assigned to extended 56-day on-demand period only.
6Device use to be monitored on a weekly basis when participants connect the device to Wi-Fi. For participants who do not
connect their headset to Wi-Fi, compliance will be assessed post-intervention when the headset has been returned.
7Komodo data analysis to begin after all participants have completed Day 56 and will be ongoing through 24-month
post-treatment visit.
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7
INTRODUCTION
7.1
STUDY RATIONALE
The aim of this randomized controlled trial (RCT) is to assess the impact of using virtual reality therapy in
pain management outcomes – including pain intensity and pain interference levels, back pain function,
sleep disturbance, anxiety, depression, behavioral skills development, health outcomes and satisfaction
in a cohort of participants with chronic pain of the lower back.
7.2
BACKGROUND
Chronic pain is one of the most common reasons adults seek medical care1: chronic pain affects between
50 and 116 million Americans, more so than cancer, diabetes, and cardiovascular disease combined1-4.
Other estimates suggest that up to 40% of American adults suffer from chronic pain, ranging from mild
to severe5. Pain treatment and management are traditionally based around utilizing pharmacological
management tools, which typically involve opioids. Although some non-opioid pharmaceuticals and
non-pharmacological therapies are becoming available, there is still a significant unmet need for
integrative, easily accessible, non-opioid solutions for chronic pain.
Approximately 25 million American adults are living with moderate to severe chronic pain (i.e., pain
scoring 4-7 on a Visual Analog Scale and lasting over 3 months) that limits their activities and diminishes
their quality of life6, 7. Close to 85% of these participants do not find meaningful relief from current
non-opioid treatments (i.e., they do not experience a long-term ≥ 50% reduction in their pain levels)8.
Opioids are commonly prescribed for pain treatment and management. These agents can yield both
inconsistent and sub-optimal results9 and greatly increase the risk of the participant developing an
opioid addiction or Opioid Use Disorder (OUD). Data from the U.S. Centers for Disease Control (CDC)
revealed that even a single day of opioid therapy can predict up to a 6% increase in the risk of the
participant developing a dependency within a year10.
To reduce addiction and provide relief for the millions of chronic pain sufferers, new low-risk, non-opioid
pain analgesics are needed. On-demand digital therapeutics may provide home-based access to pain
education and skills-based pain self-management. Particularly during the COVID-19 pandemic,
home-based behavioral pain care has gained interest, importance, and engagement among participants.
Home-based digital pain treatment options include those involving therapist instruction, as well as fully
automated behavioral programs. For the latter, the portfolio of self-treatment options includes computer
applications for symptom tracking, education, and treatment; web-based programs that include
self-paced multisession skills-based pain management learning modules; and virtual reality (VR)
immersive treatment11.
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7.3
DEVICE DESCRIPTION
7.3.1
INDICATIONS FOR USE
EaseVRx is an investigational, prescription-use immersive virtual reality system intended to provide
adjunctive treatment based on cognitive behavioral therapy skills and other evidence-based behavioral
methods for participants (age 18 and older) with a diagnosis of chronic lower back-pain (defined as
moderate to severe pain lasting longer than three months). The device is intended for in-home use for
the reduction of pain and pain interference associated with chronic lower back pain.
7.3.2
SYSTEM DESCRIPTION AND COMPONENTS
EaseVRx is an investigational medical device with preloaded software content on a proprietary hardware
platform that delivers cognitive behavioral skills training and other behavioral methods to participants
diagnosed with chronic pain. It is an immersive VR system that delivers the VR content while
incorporating biopsychosocial pain education, diaphragmatic breathing training, mindfulness exercises,
relaxation exercises, and executive functioning games. The medical device integrates an all-in-one
head-mounted display with a Software Application and a Breathing Amplifier™ to enable the
diaphragmatic breathing exercises. The device is intended to be self-administered, unsupervised in the
participant’s home while the participant is in a seated position. The device is powered by a rechargeable
lithium battery. Each device is intended for a single participant. The medical device is meant for repeated
use.
There are two main components of the EaseVRx system, as follows.
Head-Mounted Display (HMD)
The all-in-one mounted display consists of an off-the-shelf VR headset, modified with a Breathing
Amplifier™ accessory (See Figure 1 below). The headset is a standalone VR system comprised of the
following:
•
Adjustable straps to allow the user to comfortably use the headset
•
Mounted high resolution display
•
Positional audio speaker system
•
Buttons to power on/off, control volume, and navigate content
•
Integrated microphone for use with some content
•
Breathing Amplifier™ modification to direct breath toward microphone
A Breathing Amplifier™ is added to the headset by the Sponsor, AppliedVR, Inc., hereafter AppliedVR.
This mechanical attachment is designed to enhance the user’s engagement in certain content by
amplifying the user’s exhalation into the on-board microphone input to generate a visualization of the
user’s breath within the VR content.
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Figure 1: (Left): EaseVRx Headset
(Right): Drawing depicting buttons and their
locations
Figure 2: Breathing Amplifier™ Component of EaseVRx
Head-Mounted Display (HMD) Off-the-shelf Software
HMD off-the-shelf software comprises of the following:
•
General operating system: off-the-shelf operating system modified by AppliedVR to support and
execute the functions of EaseVRx
•
Bootloader: off-the-shelf firmware component that turns on the HMD and verifies that critical
software components for operation are present and activated
•
Perceptual User Interface (PUI): off-the-shelf component that acts as a user interface “wrapper”
around the general operating system
•
System ROM: off-the-shelf general computing component that contains the necessary software
and firmware for the device image, and drivers to handle HMD specific functions such as
buttons, light sensors, and lens display
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7.3.3
APPLIEDVR SOFTWARE FOR EASEVRX
The EaseVRx software is designed to provide cognitive behavioral therapy (CBT) and other behavioral
methods within an immersive VR environment. EaseVRx software is installed on a general operating
HMD system. The breathing shield component of EaseVRx acts as a mechanical amplifier enabling the
software to visualize the exhalation.
EaseVRx runs on an off-the shelf general computing operating system, Android, that was modified by
AppliedVR to support EaseVRx’s delivery of cognitive behavioral therapy, hereby referred to as “content.”
Users receive EaseVRx pre-installed with all necessary content. EaseVRx does not require any participant
information in order to initiate treatment, nor is there anything for a participant to install. Upon
receiving the device, a participant only needs to power the device on and follow the instructions on the
display to initiate sessions.
7.4
STUDY INTERVENTIONS
The study intervention will include evidence-based digital devices that offer non- pharmacological
solutions to managing pain.
Skills-Based VR (EaseVRx)
Participants allocated to the two EaseVRx arms will use a multi-modal, skills-based, self-management VR
program, called EaseVRx (AppliedVR; Los Angeles, CA), that incorporates the evidence-based principles
of CBT and mindful meditation. EaseVRx combines biopsychosocial education, pain education, breathing
training, relaxation exercises, and executive functioning games to provide a mind-body approach toward
living better with chronic pain. The standardized, reproducible, 56-day program delivers a combination of
skills training and CBT-related treatments through scheduled daily virtual experiences. Each VR
experience lasts between 2-16 minutes, with an average duration of 6 minutes. The VR treatment
modules are designed to minimize triggers of emotional distress or cybersickness. For the proposed
study, participants in the skills-based VR arm will be instructed to complete the full 56-day treatment
using a Pico G2 4K VR headset. There are 5 types of modules, as follows:
•
Interoceptive modules: an entirely new and powerful element added to the treatment program
to help understand and perceive what is going on inside the body, and to provide a
biofeedback-like platform in which the changes in the observed environment reflect a
progressively enhanced state of relaxation.
•
Education modules: helps the user understand why the VR exercises are relevant to their pain as
well as specific topics often used in pain psychology treatments. They learn about the
neurobiology of pain, the role of mood and stress in pain, pain catastrophizing, activity pacing
and goal setting. The goal is for the user to create self-management steps and a toolkit of
strategies they can use to manage their response to pain.
•
360-degree video modules: high quality 360-degree videos with voiceovers, music, breathing
effects, and sound effects are designed to maximize relaxation and engagement of participants.
•
Game modules: games are designed to maximize distraction and engagement, increasing the
cognitive load on participants, and decreasing their perception of pain.
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•
Dynamic breathing modules: based on evidence-based biofeedback training designed to
enhance awareness of one’s physiological response to pain and to self-regulate that response. In
a virtual world, the user experiences a gamified biofeedback session where they are introduced
to awareness of their breath via visualization in the virtual environment in the form of air
bubbles. In multiple sessions, the user receives increasingly challenging tasks to practice
diaphragmatic breathing while interacting with the virtual environment. The user is also asked to
pace their breath according to an expanding and contracting ring in the environment to slow
their breath and create physiological changes associated with relaxation. The user’s exhale is
measured by the microphone embedded in the Pico G2 hardware, offering biodata-enabled
immersive therapeutics.
Sham VR
In an ongoing systematic literature review using Cochrane criteria, few VR studies have been found that
adequately blind participants to the treatment procedure. VR-CORE guidelines suggest using an active
control in VR clinical trials and promote the use of non-immersive, 2D content within a VR headset as an
optimal control. Thus, participants in the Sham VR group will receive the same Pico G2 4K headset as
participants in the immersive VR groups, but rather than view 360-degree, 3D, interactive content
specially selected for efficacy, they will only have access to 2D nature footage with neutral music layered
on top that is selected to be neither overly relaxing nor distracting. The experience of Sham VR is similar
to watching a large-screen TV, but it is not interactive. The advantage of Sham VR is that it controls for
the novelty and immersion of the hardware and isolates the effect of VR skill-based training.
7.5
DOSING AND ADMINISTRATION
Weeks 1-8:
All participants will receive a VR headset and will be instructed to use VR once a day for 8 weeks.
Weeks 9-16:
For the 2 groups that are assigned to the arms with an extended 56-day on-demand period, participants
will have the option of accessing VR for an additional 8-week period at their discretion. These groups will
be instructed to use VR on an as-needed basis (i.e., there will be no set requirement for daily use as with
the initial 8-week treatment phase).
7.6
TECHNICAL SUPPORT
Participants in both arms will receive remote technical support from the research and operations team.
The idea is that issuing devices is usually insufficient to achieve behavior change; supporting those
devices with high-touch yet scalable care is a vital component.
Participants will be provided with device use instructions as well as emails describing the study details.
Instructional videos will be made available to participants, and access to remote technical support will be
provided.
Participants will receive a telephone number, email, and will have access to contact support staff as
needed. The Research support staff will also reach out if there is a lack of survey completion.
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7.7
RISK/BENEFIT ASSESSMENT
7.7.1
KNOWN POTENTIAL RISKS
Short-term risks associated with the study may include minor psychological distress from questionnaires
regarding health, and small risk of VR-related “cybersickness,” which involves transient symptoms related
to entering VR environments (vertigo, nausea, headache). Risks for cybersickness are mitigated by the
design of the VR programs in this study. Previous research with this program demonstrates that less than
10% of participants reported cybersickness that prevented them from using Virtual Reality 11, 12.  There
are no anticipated long-term risks from participating in this study.
7.7.2
KNOWN POTENTIAL BENEFITS
Potential immediate benefits include reduction of pain due to chronic low back pain (CLBP) and global
improvements in psychological health. Potential long-term benefits include improved functionality,
development of behavioral coping skills, reduced opioid use, and improved global physical health.
7.7.3
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS
Virtual reality hardware and software have advanced significantly in the past several years and
sophisticated motion tracking helps to minimize discomfort among participants. Modern studies utilizing
VR have found high satisfaction with devices among participants. Participation in the study may alleviate
pain among individuals who have previously relied on opioids, subsequently decreasing both
opioid-induced side effects and providing pain relief. Sustained pain relief may allow individuals to return
to work faster, improve physical mobility, and enhance biopsychosocial health. We believe the short- and
long-term anticipated benefits outweigh minimal short-term risks. Furthermore, risks of cybersickness
and discomfort will be assessed following 1 week of usage and will be monitored closely.
To minimize the risk of breaches in confidentiality associated with survey collection, study staff will be
assigned unique passwords and usernames to access secure servers. Additionally, identifiable
information for participants will be obfuscated using unique ID numbers and a linking list will be held in a
secure location.
8
STUDY OBJECTIVES AND ENDPOINTS
Aims/Objectives
ENDPOINTS
JUSTIFICATION FOR ENDPOINTS
PRIMARY AIM
Primary Endpoint: Assess the
impact of skill-based VR on pain
Intensity or Interference
compared to sham VR.
•
Assess effect of EaseVRx
vs. Sham VR on group
The primary endpoint in this
study is a significant change in
pain intensity or pain inference
at the end of the 8-week
treatment period among
individuals in the two
skills-based VR arms compared
The Brief Pain Inventory (BPI)
survey is a validated instrument
with excellent content validity,
construct validity, and reliability
in participants with chronic
pain.
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score change from
baseline to end of
treatment on pain
intensity
•
Assess effect of EaseVRx
vs. Sham VR on group
score change from
baseline to end of
treatment on pain
interference
to those in the two Sham VR
arms.
The outcome measure used to
quantify this endpoint is the BPI
survey.
Interference and intensity are
tested separately, and therefore,
two (2) multiplicity adjusted
statistics are produced. Study
success will be declared if
statistical significance is
demonstrated on at least one of
the endpoints.
The primary endpoint will pool
the two EaseVRx stratum
(EaseVRx) together and the two
Sham stratum (Sham VR)
together.
The outcome measure is
administered before the 8-week
intervention, during and
immediately upon completion
of the 8-week intervention via
the Curebase dashboard.
Widely used and therefore may
be expected by some reviewers.
SECONDARY AIMS
Secondary Aim #1: Assess effect
of EaseVRx vs. Sham VR by
comparing:
•
Percentage of participants
with a ≥30% change in pain
intensity measured with
the BPI from pre-treatment
to end-of-treatment (8
weeks) for each group
•
Percentage of participants
with a ≥30% change in pain
interference measured with
the BPI (as represented by
a single composite score
derived from 7 pain
interference questions)
from pre-treatment to
The first secondary endpoint is
the group level comparison of
the percentage of participants in
each arm that experience a
clinically significant change in
pain intensity or pain
interference respectively.
The outcome measure used to
quantify this endpoint is the BPI
survey.
Clinical significance for this
endpoint is defined as a 30%
change from baseline.
Interference and Intensity are
tested separately, and therefore,
two (2) multiplicity adjusted
statistics are produced. Study
success will be declared if
statistical significance is
The BPI survey is a validated
instrument with excellent
content validity, construct
validity, and reliability in
participants with chronic pain.
The study is powered to
accomplish secondary endpoints
which require statistical power
beyond what is required for the
primary endpoint alone.
Therefore, the trial may
demonstrate a difference
between groups that is small
and not necessarily meaningful.
The secondary endpoint using
this responder definition will
accompany the primary results
to help interpret the primary
results.
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end-of-treatment (8 weeks)
for each group
demonstrated on at least one of
the endpoints.
The outcome measure is
administered before the
intervention, during and
immediately upon completion
of the 8-week intervention via
the Curebase dashboard.
See the Statistical Analysis Plan
for additional details.
Secondary Aim #2: Assess the
effect of EaseVRx vs. Sham VR
by comparing:
•
Change in Oswestry
Disability Index (ODI-2.1b),
PROMIS Sleep Disturbance,
PROMIS Depression and
PROMIS Anxiety from
pre-treatment to
end-of-treatment (8 weeks)
for each group
The secondary endpoints are
clinically significant changes in
Oswestry Disability Index
(ODI-2.1b) results, PROMIS
Sleep Disturbance scores,
PROMIS Depression scores and
PROMIS Anxiety scores from
pre-treatment to
end-of-treatment (8 weeks) for
each group.
Outcome measures used for this
endpoint include the BPI survey,
Oswestry Disability Index
(ODI-2.1b) results, PROMIS
Sleep Disturbance scores,
PROMIS Depression scores and
PROMIS Anxiety scores.
The outcome measures are
administered before the
intervention and immediately
upon completion of the 8-week
intervention via the Curebase
dashboard.
The ODI, and PROMIS Sleep
Disturbance, Depression and
Anxiety surveys are all validated
instruments with excellent
content validity, construct
validity, and reliability in
participants with chronic pain.
Secondary Aim #3: Assess effect
of EaseVRx vs. Sham VR by
comparing participant
satisfaction at end-of-treatment
(8 weeks) for each group.
The third secondary endpoint
compares participant
satisfaction at the end of
treatment across the EaseVRx
and Sham groups.
The outcome measure used to
quantify this endpoint is a
custom survey developed by the
AVR research team to assess
participant satisfaction.
This outcome will be collected
immediately upon completion
The AVR participant Satisfaction
survey was developed internally
by the Research team to assess
satisfaction with the EaseVRx
and Sham treatments.
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of the 8-week intervention via
the Curebase dashboard.
EXPLORATORY AIMS
Exploratory Aim #1: Assess the
impact of skill-based VR in
follow-up pain adjusting for
baseline pain. This endpoint is
included to primary sensitivity
around the primary endpoint.
Continuous group difference in
follow-up scores adjusted for
baseline.
Interference and Intensity are
tested separately, and therefore,
two (2) multiplicity adjusted
statistics are produced.
The outcome measure used to
quantify this endpoint is the BPI
survey.
Included to enable
understanding potential
limitations in the primary
endpoint.
The variables are inclusion
criterion, and therefore
regression to the mean could be
important.
Deals with floor and ceiling
effects of the change score.
Does not require the pre- and
post-values to be linearly
related.
Exploratory Aim #2: Assess the
impact of skill-based VR based
on clinical importance changes
in a responder framework. This
endpoint is included to provide
sensitivity around the secondary
endpoint.
Clinically Important Difference
(CID) in Interference/Severity
Brief Pain Interference Scale
(score range 0-10); CID = 2
Brief Severity Item (score range
0-10); CID = 2
Interference and Intensity are
tested separately, and therefore,
two (2) multiplicity adjusted
statistics are produced.
Commonly CID thresholds are
commonly used to answer the
question of whether statistically
significant differences in groups
are driven by
meaningful improvements for
individuals.
Both 30% change and CID
thresholds are used in
responder analyses. By including
both, the research team will
answer the question of whether
the study would have obtained
a different result using one
versus the other.
See the Statistical Analysis Plan
for additional details.
Exploratory Aim #3: Assess the
impact of skill-based VR on
changes in healthcare utilization
and outcomes throughout an
8-week intervention and
follow-up period.
Pain-related healthcare
utilization will be assessed in a
subset of participants for whom
access to complete insurance
claims files are available. All
claims for medical care
associated with CLBP will be
included and includes claims for
the following types of services:
While the EaseVRx intervention
targets pain and pain
interference, it should follow
that pain-related medical
resource use should be reduced
with clinical improvement.
Healthcare resource use is
difficult to track and assign to a
particular diagnosis. Linking the
participants to their own claim
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•
Number and type of
imaging and diagnostic
procedures
•
Number and type of health
care practitioner visits
including specialty care
•
Number of chiropractic and
physical therapy visits
•
Number and type of
emergency room visits
•
Number and type of
surgeries
•
Number, type, and duration
of hospitalizations
•
Frequency of 30-, 60-, 90-
day readmissions
•
Complications that can be
assigned to the pain or
pain-related interventions
records to allow for assessment
of changes over time.
Exploratory Aim #4: Assess
effect of EaseVRx vs. Sham VR
by comparing change in
participant’s Global Impression
of Change (PGIC), Concerns
About Pain (CAP-6); and
behavioral skills from
pre-treatment to
end-of-treatment for each
group.
The exploratory endpoints are
clinically significant changes in
PGIC, CAP and behavioral skills
from pre-treatment to
end-of-treatment (8 weeks) for
each group.
Outcome measures for this
endpoint include the PGIC,
CAP-6 and a behavioral skills
survey developed by the AVR
team.
The CAP-6 survey is a validated
instrument with excellent
content validity, construct
validity, and reliability. The
behavioral skills survey has not
been validated but has been
found informative for internal
use.
Exploratory Aim #5: Assess
effect of EaseVRx vs. Sham VR
by comparing participant Global
Impression of Change (PGIC)
and system usability (as
measured with the System
Usability Scale; SUS) at
end-of-treatment for each
group.
The exploratory endpoint
compares PGIC and SUS at the
end of treatment across the
EaseVRx and Sham groups.
The outcome measure used to
quantify this endpoint is the
PGIC and SUS survey.
The PGIC and SUS surveys are
validated instruments with
excellent content validity,
construct validity, and reliability.
Exploratory Aim #6: Assess
effect of EaseVRx vs. Sham VR
by comparing change in all
objectives from pre-treatment
to end-of-treatment, 4 weeks
See descriptions above
See descriptions above
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post treatment, 8 weeks post
treatment, 12 weeks post
treatment, 6 months post
treatment, 12 months post
treatment, 18 months post
treatment and 24 months post
treatment in the EaseVRx-8w
and EaseVRx-8w plus extended
on-demand groups.
9
STUDY DESIGN
9.1
OVERALL DESIGN
This RCT will enroll approximately 1000 participants with a self-reported diagnosis of chronic lower back
pain (defined as moderate to severe pain lasting longer than three months) to test the efficacy of
skills-based VR (EaseVRx) on long term pain management as an adjunct to traditional medical therapy.
Enrolled participants will be randomized 1:1:1:1 and assigned to one of four treatment arms:
•
56-day skills-based VR program (EaseVRx-8w)
•
56-day skills-based VR program followed by an extended 56-day on-demand period
(EaseVRx-8w plus extended on-demand)
•
56-day control (Sham VR-8w)
•
56-day control followed by an extended 56-day on-demand period (Sham VR-8w extended
on-demand)
The primary outcome will be assessed using the BPI: an eight-item scale assessing pain intensity and
pain interference on general activity, mood, walking ability, normal work, relations with other people,
sleep, and enjoyment of life. Each participant’s BPI score will be assessed immediately before the
intervention, during the intervention, immediately following the intervention, and at 4-, 8-, 12-weeks,
and 6-, 12-, 18-, and 24-months post intervention (see Schedule of Activities in Section 5.2).
Secondary outcomes include the Oswestry Disability Index score (ODI v2.1b), PROMIS Sleep
Disturbance, PROMIS Depression, and PROMIS Anxiety that will be evaluated before the intervention,
immediately following the intervention (Day 56 in all arms), 4-weeks post-treatment, 8-weeks
post-treatment, 12-weeks post-treatment, 6 months post-treatment, 12 months post-treatment, 18
months post-treatment, and 24 months post-treatment. participant Satisfaction will be evaluated at Day
56.
Additionally, participants will be administered the following surveys as tertiary and exploratory
outcomes at the specified timepoints:
•
Participant’s Global Impression of Change Scale (PGIC): Day 56, 4-weeks post-treatment,
8-weeks post-treatment, 12-weeks post-treatment, 6 months post-treatment, 12 months
post-treatment, 18 months post-treatment, and 24 months post-treatment
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•
Concerns About Pain (CAP-6) Scale: Baseline, Day 56, 4-weeks post-treatment, 8-weeks
post-treatment, 12-weeks post-treatment, 6 months post-treatment, 12 months
post-treatment, 18 months post-treatment, and 24 months post-treatment
•
Systems Usability Scale (SUS): Day 56
•
Behavioral Skills Use: Baseline, Day 56, 4-weeks post-treatment, 8-weeks post-treatment,
12-weeks post-treatment, 6 months post-treatment, 12 months post-treatment, 18 months
post-treatment, and 24 months post-treatment
•
Product Enhancement recommendations: Day 56 for the EaseVRx-8w and EaseVRx-8w plus
extended on-demand groups, and at 8-weeks post-treatment for the EaseVRx-8w plus
extended on-demand group
•
Treatment Compliance: End of treatment for the EaseVRx and Sham VR groups and 8-weeks
post treatment for the EaseVRx plus on demand Library and Sham VR plus on demand
Library groups.
9.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
The use of the two active control groups (Sham VR-8w, Sham VR-8w extended on-demand arms) in this
randomized control trial will minimize biases related to the novelty of the hardware and immersion.
9.3
JUSTIFICATION FOR DOSE
Based on previous research by AppliedVR and other researchers in the virtual reality therapeutic space,
individuals have experienced success in pain management by using VR at least once daily, for 10-15
minutes, and as needed for breakthrough flares of pain. For those with significant career and
family-related responsibility, AppliedVR recommends using the device once daily at night before bed.
9.4
END OF STUDY DEFINITION
The study will be considered complete at the time that the last participant performs the last survey.
Participants are expected to remain in the study for 24 months after undergoing their respective
treatment period (8 or 16 weeks). Participants who complete their 24-month follow-up survey (see
Schedule of Activities, Section 5.2.) will be considered to have completed study participation.
10
SELECTION OF STUDY POPULATION
10.1
INCLUSION CRITERIA
In order to be eligible to participate in this study, an individual must meet all of the following criteria:
1.
Male and female participants aged 18-85.
2.
Self-reported diagnosis of chronic lower back pain.
3.
Pain duration of at least three months.
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4.
Average pain intensity score of ≥ 4 and average pain interference score of ≥ 4 on the 0-10
BPI Pain Scale for the past month at screening.
5.
Fluency in English.
6.
Willing and able to comply with all study procedures including all required restrictions for
the duration of study participation.
7.
Able to give voluntary, written informed consent to participate and have signed an Informed
Consent Form specific to this study.
8.
Access to Wi-Fi for the duration of their study participation (24 months).
9.
Access to a smartphone or computer for the duration of the study.
10. Availability of a physical mailing address that is not a PO box address for receipt of the
device.
11. Completed the Baseline Survey plus at least two of the five sets of participant surveys that
are administered during the 10-day pretreatment assessment period.
12. Able to provide photo ID.
10.2
EXCLUSION CRITERIA
An individual who meets any of the following criteria will be excluded from participation in this study: 
1.
Unable to understand the goals of the study due to cognitive difficulty.
2.
Any medical condition that may prevent the use of virtual reality (e.g., current, or prior
diagnosis of epilepsy, seizure disorder, hypersensitivity to flashing light or motion, migraines,
any medical condition predisposing participant to nausea or dizziness, dementia, absence of
stereoscopic vision or severe hearing impairment).
3.
Injury to eyes, face, or neck that prevents comfortable use of VR.
4.
Index back pain is linked to a cancer-related diagnosis.
5.
Possible suicidal ideation as indicated by the 9th item of the participant Health
Questionnaire-9 (PHQ-9).
6.
Previous participation in the 2020 AVR EaseVRx pivotal study.
7.
Receiving worker’s compensation and/or involved in any active litigation related to an injury.
8.
Current or recent participation (i.e., within the last 2 months) in any other research study
involving a drug, device, vaccine, or other interventional treatment product; or plans to
participate in another research study over the next 24 months.
10.3
PARTICIPANT RECRUITMENT AND SCREENING
Participants will be recruited for this decentralized virtual trial via two methods.
Method 1: participants diagnosed with chronic lower back pain will be recruited from physician referrals
through the Sponsor’s relationships with physicians who treat chronic lower back pain in adult
populations within the United States. Physicians seeing participants who appear to be a good fit for the
study will refer the participants to the study by providing them with a pamphlet that provides a link to
the study website, where they will have an opportunity to learn more about the study. Participants will
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then be directed to Curebase where they will be asked to create a user account. After the creation of
such an account, participants will be able to take a brief Eligibility Survey. If eligible to participate,
participants will be asked to go through the consenting process. During the next 10 days, participants will
be required to complete their baseline survey and at least 2 out of 5 brief surveys to become eligible for
randomization.
Method 2: AppliedVR will also use direct email marketing and social media advertising to make potential
participants aware of the study. The email and social media advertisements will provide a link to the
study website, where they will have an opportunity to learn more about the study. Potential participants
will be redirected to Curebase to sign an e-consent form and take the Eligibility Survey.
The total number of participants that were pre-screened (prior to consent), screened (post consent), and
screen failed, including the reasons for screen failure, will be captured automatically in
Curebase. Research staff will be able to report on this as needed.
10.4
INFORMED CONSENT
After passing the screener survey, prospective participants will be directed to review and sign an
electronic HIPAA, California Bill of Rights (if a participant is located in California, and an IRB-approved
consent (eConsent) form prior to enrolling in the study. The eConsent form will explain the nature and
scope of the study, the procedures to be performed as part of the study, the potential risks, and benefits
of participation, expected duration of participation, possible treatment alternatives, and an overview of
his/her rights as a study participant in lay terms. Participants will have the opportunity to discuss the
study with their family or surrogates or think about it before agreeing to participate. Participants will be
informed that participation is voluntary and will be assured that they may withdraw from the study at
any time and for any reason, without repercussion. The HIPAA, California Bill of Rights, and eConsent
process will be via the study dashboard (hosted by Curebase, Inc.).
After viewing the eConsent materials, participants will have an opportunity to email or call the research
team with any questions they may have and will be given as much time as needed to receive answers
before making a final decision regarding study participation. Participants will receive a telephone
number, email, and will have access to contact support staff as needed.
When the individual is ready to confirm their willingness to participate, an electronic signature will be
collected to complete the eConsent formalities. The participant will receive a copy of the fully signed
HIPAA, California Bill of Rights, and eConsent forms via email to retain for their records, and a digital
copy will be retained within the Curebase system as part of the study records.
10.5
SCREEN FAILURES
A screen failure is a participant who consents but does not receive any of the study interventions due to
withdrawing consent, being withdrawn from the study, or not meeting eligibility requirements for
treatment.
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If a participant signs the eConsent form but is found ineligible for inclusion in the study prior to or during
the initiation of the study intervention, the participant will not be advanced any further in this clinical
investigation and will be listed as a screen failure. The participant will be notified and the participant’s
signed eConsent form and updated inclusion/exclusion criteria details will be retained by the research
team.
A minimal set of screen failure information is required to ensure transparent reporting of screen failure
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements
and to respond to queries from regulatory authorities. Minimal information includes demography, screen
failure details, eligibility criteria, and any serious adverse event (SAE).
To collect data related to CONSORT requirements, a Screening and Enrollment Log will be maintained. A
research team member will review automated data from the eligibility survey on the Curebase
dashboard.
11
STUDY PROCEDURES
11.1
BASELINE SURVEY
After signing the eConsent form, participants will automatically be directed to complete a set of Baseline
survey assessments that will include the following:
•
Brief Pain Inventory - intensity/interference
•
Oswestry Disability Index
•
PROMIS Sleep Disturbance
•
PROMIS Depression
•
PROMIS Anxiety
•
Concerns About Pain (CAP-6) Scale
•
Behavioral Skills Use
Reminders will be sent approximately 1 hour and 24 hours after starting a survey to encourage the
completion of Baseline surveys.
Twenty-four hours after completing the Baseline survey assessments, participants will be contacted with
information about completing an optional incentivized set of surveys that include the following:
•
Pain Self-Efficacy Questionnaire (PSEQ-10)
•
Multidimensional Assessment of Interoceptive Awareness (Version 2)
•
Multidimensional Health Locus of Control
Reminders will be sent approximately 1 hour and 24 hours after starting a survey to encourage optional
survey completion.
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Participants who filled out the Baseline Survey assessments will be contacted via an automated Curebase
email/text to fill out at least 2 out of 5 pre-treatment BPI surveys over the next 9 days. Note: Completion
of these surveys is a pre-requisite for randomization.
11.2
ENROLLMENT & RANDOMIZATION
Curebase will automatically direct the participant to a survey to provide a shipping address before
participants complete the Baseline Survey assessments and two out of five sets of BPI surveys. Once the
second BPI survey is filled out, the participant will be randomized into an arm of the study in 1:1:1:1 via
Curebase and assigned a Participant ID number. The AppliedVR research team will arrange a device
shipment based on the randomization assignment, and Curebase will notify the participant of the
shipment tracking details.
11.3
PRE-TREATMENT DEVICE USE ONBOARDING
Participants in the EaseVRx and Sham VR conditions will receive a PICO G2 4K headset with either
EaseVRx or Sham content along with detailed instructions that will help them familiarize themselves with
the hardware and software components. Telephonic and email technical support from study staff will be
available to advise participants having trouble using the equipment. The participant will receive a
reminder email to confirm VR headset receipt within 48 hours after FedEx tracking number was sent.
11.4
TREATMENT PHASE (WEEKS 0-8) & EXTENDED USE PERIOD (WEEKS 9-16)
Weeks 1-8: All participants will be instructed to use VR once a day for these 8 weeks. Research staff will
monitor participants’ progress through twice weekly BPI surveys and provide guided technical support.
Device use can be monitored on a weekly basis for those participants who connect the device to Wi-Fi.
Weeks 9-16: For the 2 groups that are assigned to the arms with an extended 56-day on-demand period,
participants will have the option of accessing VR for an additional 8-week period at their discretion.
These groups will be instructed to use VR on an as-needed basis (i.e., there will be no set requirement
for daily use as with the initial 8-week treatment phase).
11.5
DAY 56
On Day 56, participants will complete their treatment phase and will be prompted to log onto the
Curebase portal and complete the following assessments:
•
Brief Pain Inventory - intensity/interference
•
Oswestry Disability Index
•
PROMIS Sleep Disturbance
•
PROMIS Depression
•
PROMIS Anxiety
•
Participant Satisfaction
•
Participant’s Global Impression of Change Scale (PGIC)
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•
Concerns About Pain (CAP-6) Scale
•
System Usability Scale (SUS)
•
Behavioral Skills Use
•
EaseVRx User Experience Questionnaire (and at week 16 in two arms with on demand Library)
Data Completion Reminders: Participants will be sent a reminder if they have not submitted data
approximately 1 hour after starting a survey. Participants will also receive a reminder email or text
message if they do not submit data approximately 24 hours after starting a survey. Research staff will
make up to 3 call attempts to contact the participant to help get these surveys completed.
Twenty-four hours after completing the surveys listed above, participants will be contacted with
information about completing an optional incentivized set of surveys that include the following:
•
Pain Self-Efficacy Questionnaire (PSEQ-10)
•
Multidimensional Assessment of Interoceptive Awareness (Version 2)
•
Multidimensional Health Locus of Control
Reminders will be sent approximately 1 hour and 24 hours after starting a survey to encourage optional
survey completion.
11.6
POST-TREATMENT DATA COLLECTION
After Day 56, participants will be prompted to log onto the Curebase portal and complete the following
assessments at 4-weeks, 8-weeks, 12-weeks, 6-months, 12-months, 18-months, and 24-months
post-treatment:
•
Brief Pain Inventory - intensity/interference
•
Oswestry Disability Index
•
PROMIS Sleep Disturbance
•
PROMIS Depression
•
PROMIS Anxiety
•
participant’s Global Impression of Change Scale (PGIC)
•
Concerns About Pain (CAP-6) Scale
•
Behavioral Skills Use
Data Completion Reminders: Participants will be sent a reminder if they have not submitted data
approximately 1 hour after starting a survey. Participants will also receive a reminder email or text
message if they do not submit data approximately 24 hours after starting a survey. Research staff will
make up to 3 call attempts to contact the participant to help get these surveys completed.
Twenty-four hours after completing the surveys listed above, participants will be contacted with
information about completing an optional incentivized set of surveys that include the following:
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•
Pain Self-Efficacy Questionnaire (PSEQ-10)
•
Multidimensional Assessment of Interoceptive Awareness (Version 2)
•
Multidimensional Health Locus of Control
Reminders will be sent approximately 1 hour and 24 hours after starting a survey to encourage optional
survey completion.
11.7
HEALTHCARE UTILIZATION ANALYSIS
To assess resource use associated with CLBP, participants’ data will be run through a secure Datavant
matching process to be linked to their healthcare claims data if it is available in the Komodo data set. The
claims will provide descriptive characterizations of resource use and costs associated with CLBP. For
participant-level changes in resource use, and for comparisons between study arms, only the
participants with complete claims files will be assessed. Claims-matched data will capture all interactions
with the healthcare system that generate an insurance claim record, which includes such things as
physician visits, interventions such as steroid injections, surgery or physical therapy, emergent use of
services, medications, and diagnostic procedures. Claims adjudication often lags a few months, so the
most robust analyses of utilization will be performed about 6 months after the time point of interest
(check with Komodo on adjudication/timing implications). Health economic modeling will be performed
after 1 year to assess the cost and economic outcomes of the EaseVRx intervention.
The Komodo claims data provides a real-world source of utilization and cost parameters associated with
claims of CLBP.  As such, it can be used more broadly to either compare the study participants' resource
use and costs to the broader population of participants with CLBP, or a “synthetic arm” can be
constructed using available demographic data to match any of the study arms.
Additional details are detailed in a standalone Healthcare Utilization Analysis Plan.
12
STUDY INTERVENTION
12.1
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING
The primary endpoint of this study will be collected via Electronic Data Capture and securely transmitted
to the Database. Curebase will maintain the database and be responsible for all aspects of data
management.
Participants, study statisticians and investigators will be blinded to treatment group assignment until
after the last subject contributes their primary outcome at week 8
. Prior to the primary analysis, the
database will be officially locked and signed off by the Sponsor and key stakeholders. Study participants
will remain blinded to treatment group assignment until study completion.
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12.2
STUDY INTERVENTION COMPLIANCE
Compliance to the treatment protocol will be monitored using remote data uploads of survey logs if a
headset is connected to Wi-Fi by the participant. For participants who do not connect their headset to
Wi-Fi, compliance will be assessed post-intervention when the headset has been returned.
13
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL
13.1
DISCONTINUATION OF STUDY INTERVENTION
A small proportion of participants may find the headset uncomfortable, the VR experiences ineffective,
or find themselves not using the device and wish to withdraw. Participants who report moderate to
severe adverse events that prevent them from using the program will be discontinued. Discontinuation
from the use of the VR program or Sham VR will not automatically trigger discontinuation from the
study, and remaining study procedures should be completed as indicated by the study protocol. If a
clinically significant finding is identified (including, but not limited to changes from baseline) after
enrollment, the investigator or qualified designee will determine if any change in participant
management is needed. Any new clinically relevant finding will be recorded as an adverse event (AE).
13.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY
Participants are free to withdraw from participation in the study at any time and for any reason. A
member of the research team will ask the participant for the reason for their withdrawal and will record
all information regarding the participant discontinuation in their study records.
An investigator may also discontinue or withdraw a participant from the study for the following reasons:
•
If any serious to severe adverse event (AE) or other medical condition or situation occurs such
that continued participation in the study would not be in the best interest of the participant
-
Participants who experience an SAE due to an undisclosed condition that would have
prevented trial eligibility will be discontinued from the study and will be documented as
an eligibility deviation.
•
Disease progression which requires discontinuation of the study intervention
•
If the participant meets an exclusion criterion (either newly developed or not previously
recognized) that precludes further study participation
•
Any other problem deemed by the Investigator to be sufficient to cause discontinuation.
The reason for participant discontinuation from the study will be recorded.
13.3
LOST TO FOLLOW-UP
A participant will be considered lost to follow-up if he or she fails to complete two or more consecutive
surveys and is unable to be contacted by the study site staff. Before a participant is deemed lost to
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follow-up, the investigator or designee will make every effort to regain contact with the participant
(where possible, 3 telephone calls). If participants are not reached in these attempts, they will receive a
final email asking them to complete a discontinuation form. These contact attempts and any
discontinuation will be documented. Should the participant continue to be unreachable, he or she will
be considered to have withdrawn from the study with a primary reason of lost to follow-up.
13.4
EQUIPMENT RETURN
Participants will not be financially responsible for damage to, or loss of, equipment loaned to
participants by the research team during this study. However, if they are not able to return the headset
at the end of the VR treatment, regardless of its condition, then they will not be eligible to receive their
honorarium payment. Reminders will be sent via email and text at the end of VR treatment period
(8-weeks or 16-weeks), and a call will be made if the device still is not returned after multiple reminders
during a 14-day period. If the device is not returned, then the study team will document the reason for
the participant not returning the device from the phone call (e.g., lost).
14
STUDY ASSESSMENTS
14.1
EFFICACY ASSESSMENTS
Primary Outcome
The primary outcome for this study will be the BPI questionnaire. The BPI questionnaire is a validated
instrument with good content validity, construct validity, and reliability in participants with chronic pain.
The range of scores are from 0-10. The BPI contains a single item related to pain intensity and 7 items
related to pain interference. The BPI pain interference score is the mean of seven questions that assess
pain interference on general activity, mood, walking ability, normal work, relations with other people,
sleep, and enjoyment of life. The higher the score the greater the impact of chronic pain on the
participant.
Secondary Outcomes
Secondary outcomes include the Oswestry Disability Index score (ODI v2.1b), PROMIS Sleep Disturbance,
PROMIS Depression, PROMIS Anxiety, and participant Satisfaction that will be evaluated before the
intervention, immediately following the intervention (Day 56 in all arms), 4-weeks post-treatment,
8-weeks post-treatment, 12-weeks post-treatment, 6 months post-treatment, 12 months
post-treatment, 18 months post-treatment, and 24 months post-treatment. participant Satisfaction will
be evaluated on Day 56.
•
Oswestry Disability Index
-
The Oswestry Disability Index (also known as the Oswestry Low Back Pain Disability
Questionnaire) is a tool that researchers and disability evaluators use to measure a
participant's functional disability. The test is considered the ‘gold standard’ of low back
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functional outcome tools. The tool is well validated with excellent content validity,
construct validity and reliability.
•
PROMIS Scales Sleep Disturbance, Depression & Anxiety
-
For participants with chronic pain, sleep quality is often diminished, and participants
seek return to normal function. The PROMIS® short-form scales are widely- validated
instruments with excellent content validity, construct validity, and reliability in
participants with spinal disorders and other conditions marked by diminished mobility.
The sleep disturbance scale assesses perceptions of sleep quality, including perceived
difficulties and concerns with getting to sleep or staying asleep, as well as perceptions of
the adequacy of and satisfaction with sleep. The depression scale assesses the pure
domain of depression in individuals aged 18 and older. The anxiety scale assesses the
pure domain of anxiety in individuals aged 18 and older. All PROMIS® measures use a
7-day recall period reflecting the previous week’s health status.
•
Virtual Reality Sickness Questionnaire
-
The Virtual Reality Sickness Questionnaire was developed for use as a motion sickness
measurement index specialized for virtual reality environments. The 12 items measure
such symptoms as dizziness and nausea with four response options (None to Severe).
•
Participant Satisfaction (adverse effects and recommendations)
-
A custom survey was created to assess satisfaction with our VR program. Topics include
device usability, enjoyment or difficulties, and likelihood to continue treatment.
Tertiary / Exploratory Outcomes
•
Participant’s Global Impression of Change Scale (PGIC)
-
This single item questionnaire is validated for use in studies to compare participant
satisfaction between different treatment assignments.
•
Concerns About Pain (CAP-6) Scale
-
This six-item scale represents the first item response theory-based item bank of pain
catastrophizing. The measure is intended for clinicians interested in improving outcomes
of participants with chronic pain and for researchers who study impact of and treatment
interventions aimed at reducing pain catastrophizing.
•
Systems Usability Scale (SUS)
-
The System Usability Scale (SUS) provides a reliable tool for measuring the usability of
our VR program. It consists of a 10-item questionnaire with five response options
(Strongly disagree to Strongly agree).
•
Behavioral Skills Use
-
One major goal of the skills-based VR intervention (EaseVRx) is to facilitate the
development of behavioral coping strategies in chronic pain sufferers that can be utilized
outside of the VR headset. The research team has constructed a survey to assess the
development of these skills. Specifically, participants will be asked whether they can
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manage their pain outside of the VR headset using deep breathing, releasing unhelpful
thoughts, redirecting attention, and self-compassion coping behaviors.
•
EaseVRx User Experience Questionnaire
-
This is a questionnaire constructed to better understand the user experience, usefulness,
and participant satisfaction with the VR therapeutic program and some of its features. It
is a 19-multiple-choice-item questionnaire with 6 optional open-ended questions. This
questionnaire will only be presented to participants in the skills based EaseVRx
conditions.
•
Pain Self-Efficacy Questionnaire (PSEQ-10)
-
The Pain Self-Efficacy Questionnaire (PSEQ-10) is a validated instrument used to assess
participants’ confidence in their ability to carry out their daily activities. The 10-item
questionnaire asks participants to rate their confidence from 0 to 6 corresponding to not
at all confident to completely confident.
•
Multidimensional Assessment of Interoceptive Awareness (Version 2)
-
The Multidimensional Assessment of Interoceptive Awareness (MAIA-II) will be used to
evaluate how interoceptive awareness relates to the other study’s outcome measures by
assessing participants’ bodily sensation awareness. It consists of a 37-item questionnaire
with 6 response options (never to always) for 8 state traits (e.g., noticing, body listening).
•
Multidimensional Health Locus of Control (MHLC-C)
-
The Multidimensional Health Locus of Control (MHLC-C) will be used to help characterize
participants, their health-related behaviors, and response to treatment. It is an 18-item
scale evaluating health locus of control with four subscales: internal, doctors, chance,
and other people.
•
Discontinuation of Treatment Questionnaire
-
The Discontinuation of Treatment Questionnaire will only be used if a moderate adverse
event occurs. This will give the participants the option to discontinue from the study and
may pinpoint cause of discomfort, if any.
14.2
OTHER ASSESSMENTS
•
Treatment Compliance:
-
Data related to the frequency and length of time using the intervention will be stored on
the virtual reality headset for the entire 8-week or 16-week period (depending upon the
participant’s arm in the study. The data will be sent back to the research team via
connection to the participant’s phone using mobile data, or when the headset is
returned.
•
Perceived Treatment assignment Question:
-
At the end of treatment for all groups, the research team will evaluate how expectations
relate to our program’s outcomes by assessing participants’ beliefs about their group
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assignments. The research team will also ask participants to report which VR program
condition they believed they participated in.
•
Benefits Screening:
-
At 12 months participants will be asked if they are currently receiving or have previously
received/petitioned for disability or worker’s compensation benefits. This will allow the
research team to account for possible motivating factors for participants to report
increased pain or have increased healthcare utilization during the course of the study.
14.3
HEALTHCARE UTILIZATION ASSESSMENTS
Pain-related healthcare utilization will be assessed in a subset of participants for whom access to
complete insurance claims files are available. All claims for medical care associated with CLBP will be
included and includes claims for the following types of services:
•
Number and type of imaging and diagnostic procedures
•
Number and type of health care practitioner visits including specialty care
•
Number of chiropractic and physical therapy visits
•
Number and type of emergency room visits
•
Number and type of surgeries,
•
Number, type, and duration of hospitalizations
•
Frequency of 30-, 60-, 90- day readmissions
•
Complications that can be assigned to the pain or pain-related interventions
Clinical outcomes and health care utilization data captured will include billed and paid claim amounts
and can be used to in modeling to demonstrate the economic value of the product.
15
PROTOCOL DEVIATIONS
Conformance to the protocol is essential to the quality and integrity of the clinical study. A protocol
deviation is any noncompliance with the clinical trial protocol. The noncompliance may be either on the
part of the participant, the investigator, or the research team.
It is the responsibility of the study investigators to use continuous vigilance to identify and report
deviations within five working days of identification of the protocol deviation, or within ten working days
of the scheduled protocol-required activity. Protocol deviations must be sent to the reviewing IRB per
their policies. The study investigators are responsible for knowing and adhering to the reviewing IRB
requirements.
16
SAFETY REPORTING
Participants will be carefully monitored during the study for possible adverse events (AEs) from the time
they start treatment or sham to the time of study completion. All medical events and conditions prior to
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this time point are to be captured as medical history. Any observed AE will be fully investigated by the
Investigator and classified in line with the definitions below.
All adverse events that occur during this study will be recorded on the adverse event eCRFs and must
include the following information at minimum:
•
Event Description
•
Date of Onset
•
Date of Resolution
•
Severity
•
Seriousness
•
Relationship to Study Device/Procedure
•
Outcome
Adverse events will be recorded and classified by the research team, including a medical doctor on staff,
using the specific signs, symptoms, or medical diagnosis if no signs or symptoms can be identified.
Significant new information and updates should continue to be captured in the participant’s records and
in the EDC as they become available and the adverse event should be followed until it is resolved or no
further improvement is expected, or the participant is lost to follow-up. The Investigator will record all
AEs regardless of whether they are anticipated or unanticipated and regardless of classification,
seriousness, intensity, outcome, or causality.
16.1
DEFINITIONS
Adverse Event (AE): any untoward medical occurrence, disease, injury, or untoward clinical signs
(including abnormal laboratory findings, surgical complications, etc.), whether related or unrelated to
the investigational device or its use.
Adverse Device Effect (ADE): An adverse device effect (ADE) is any adverse event related to the use of an
investigational device.
Serious Adverse Event (SAE): A Serious Adverse Event is an adverse event which:
1.
Led to a death
2.
Resulted in life threatening illness or injury
NOTE: the term ‘life-threatening’ refers to an event in which the participant was at a risk of
death at the time of the event; it does not refer to an event which hypothetically might have
caused death if it were more severe.
3.
Resulted in in-participant hospitalization or prolonged hospitalization
NOTE: Planned hospitalization for any pre-existing condition, or a procedure required by the
Clinical Investigation Plan, without a serious deterioration in health, is not considered a
serious adverse event.
4.
Resulted in a persistent or significant incapacity or substantial disruption of the ability to
conduct normal life functions
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5.
Resulted in participant disability or permanent damage or required intervention to prevent
permanent impairment/damage
6.
Led to a congenital abnormality or birth defect
Unanticipated Adverse Device Effect (UADE) – An Unanticipated Adverse Device Effect is:
•
Any serious adverse effect on health or safety or any life-threatening problem or death caused
by, or associated with, a device, if that effect, problem, or death is not identified in nature,
severity, or degree of incidence in this protocol; or
•
Any other unanticipated serious problem associated with a device that relates to the rights,
safety, or welfare of the participants.
16.2
ASSESSMENT OF SEVERITY
The Investigator will assess the severity of the adverse event and classify it according to the following
definitions:
Severity
Description
Mild
Symptoms are tolerable, involve no more than mild discomfort and subside
shortly after removing the headset; no medical attention is required. Participants
report a desire to continue using the headset.
Moderate
Symptoms last for a subjective significant period after removing the headset and
may require minimal medical attention (e.g., to reduce severe headache).
Participants may or may not report a desire to discontinue the study
intervention.
Severe
Symptoms have enough of an impact to prevent further use of the headset or
involve a limitation in ability to function (e.g., participant can’t walk); medical
attention is required/hospitalization possible. Participants report a desire to
discontinue the study intervention.
These definitions are for descriptive purposes only and are independent of the judgment of whether an
event is classified as serious or non-serious.
16.3
ASSESSMENT OF RELATIONSHIP
The relationship between the use of the medical device and the occurrence of each adverse event shall
be assessed and categorized. During causality assessment, clinical judgment shall be used, and the
Clinical Protocol shall be consulted, as all the foreseeable adverse events and the potential risks are
listed and assessed there. The presence of confounding factors, such as concomitant
medication/treatment, the natural history of the underlying disease, other concurrent illness or risk
factors shall also be considered.
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The term "device-related," as it pertains to adverse events, means that the event was or may have been
attributable to a device, or that a device was or may have been a factor in an event, including those
occurring as a result of malfunction, poor manufacture, inadequate labeling, or improper design.
The Investigator will assess the potential relationship of the AE to the use of the investigational device
and classify the causality of the event according to the following definitions.
•
Related: An adverse event that has a strong causal relationship. An adverse event that follows a
strong temporal relationship to the use of the device, follows a known response pattern, and
cannot reasonably be explained by known characteristics of the participant’s clinical state or
other therapies.
•
Probably Related: An adverse event that potentially has a causal relationship. The adverse event
has a reasonable temporal relationship to the use of the device and alternative etiology is less
likely compared to the potential relationship to the use of the device or the procedure.
•
Possibly Related: An adverse event that potentially has a causal relationship. The adverse event
has a reasonable temporal relationship to the use of the device, but alternative etiology is
equally likely compared to the potential relationship to the use of the device or the procedure.
•
Not Related: An adverse event without any apparent causal relationship. The adverse event is
due to the underlying disease state or is due to concomitant medication or therapy not related
to the use of the device.
•
Unknown Relationship: If the adverse event cannot be determined to have a causal relationship,
it will be classified as unknown.
16.4
ADVERSE EVENT REPORTING
The collection of AEs will begin as soon as the participant first puts on the VR headset for this study. All
AEs that occur through completion of the final follow-up visit, whether or not thought to be device
related, should be recorded in detail and followed to resolution.
The description of the AE will include the date and time of onset, severity, relationship to the use of the
device, the results of any diagnostic procedures or laboratory tests, if any treatment was required, and
the outcome of the event. The AVR research team will follow each participant who experiences an AE
until the event resolves, resolves with sequelae, or no further improvement is expected. In the unusual
circumstance that an AE has not resolved by the time the participant completes the study, an
explanation will be entered in the study database.
Note: Any condition at baseline that is recorded as a preexisting condition is not an AE unless it worsens
in intensity or duration.
16.5
SERIOUS ADVERSE EVENT REPORTING
The Sponsor is responsible for the classification and reporting of adverse events and ongoing safety
evaluation of the clinical investigation in line with US regulatory requirements.
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It is the responsibility of the Investigator to report all SAEs and UADEs according to FDA regulations and
IRB requirements. A copy of the IRB report should be forwarded to the TMF.
16.6
DETERMINATION AND REPORTING OF UNANTICIPATED ADVERSE DEVICE EFFECTS
The Sponsor shall review all reported SAEs to evaluate whether they meet the criteria for an
Unanticipated Adverse Device Effect (UADE). For adverse events that are determined to be UADEs, the
Sponsor will submit an expedited safety report to the FDA’s Center for Devices and Radiological Health
(CDRH).  The expedited safety report will be submitted to the FDA as soon as possible and, in no event,
later than ten (10) business days after the Sponsor first receives notice of the UADE. A copy of this safety
report will be provided to the reviewing IRB and all participating study Investigators.
If, following receipt and investigation of follow-up information regarding an adverse event that was
previously determined not to be a UADE, the Sponsor determines that the event does meet the
requirements for expedited reporting, the Sponsor will submit a report as soon as possible, but in no
event later than ten (10) business days after this is determined.
To determine whether an UADE presents an unreasonable risk to study participants, the Sponsor will:
•
Immediately investigate and evaluate the adverse effect (21 CFR § 812.46(b)(1));
•
If the event presents, an unreasonable risk to participants, shall terminate the investigation, or
parts of the investigation presenting that risk as soon as possible, and no later than 5 business
days after the Sponsor makes the “unreasonable risk” determination, and no later than 15
business days after the Sponsor receives notice of the UADE;
•
Resume the study, if appropriate, when permitted by the IRB and FDA;
•
Notify FDA of event and any action taken by the Sponsor as a result of this UADE.
16.7
DEVICE DEFICIENCY REPORTING PROCEDURES
Device deficiencies will be documented and reported to AppliedVR by the technical support staff if a
complaint is received from a participant. If possible, the device(s) should be returned to the Sponsor for
analysis. Instructions for returning the device(s) will be provided to the participants by the technical
support team.
Device deficiencies are not adverse events. However, an adverse event that results from a device
deficiency, would be recorded as an adverse event on the appropriate CRF.
Investigators will be expected to report the following information for each device deficiency:
•
Date deficiency discovered
•
Type of deficiency (e.g., malfunction, use error, inadequate labeling)
•
Description of the deficiency
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STATISTICAL CONSIDERATIONS
All statistical considerations are detailed in a standalone Statistical Analysis Plan.
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REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS
18.1
STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable
cause. Written notification, documenting the reason for study suspension or termination, will be
provided by the suspending, or terminating party to study participants, investigators, and sponsors. If the
study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study
participants and the IRB and will provide the reason(s) for the termination or suspension. Study
participants will be contacted, as applicable, and be informed of changes to the study visit schedule.
Circumstances that may warrant termination or suspension include, but are not limited to:
•
Determination of unexpected, significant, or unacceptable risk to participants
•
Demonstration of efficacy that would warrant stopping
•
Insufficient compliance to protocol requirements
•
Data that are not sufficiently complete and/or evaluable
•
Determination that the primary endpoint has been met
•
Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are addressed and
satisfy the Sponsor or IRB.
18.2
CONFIDENTIALITY AND PRIVACY
Participant privacy is strictly held in trust by the participating investigators, their staff, and their
interventions. Therefore, the study protocol, documentation, data, and all other information generated
will be held in strict confidence. No information concerning the study, or the data will be released to any
unauthorized third party without the prior written approval of the Sponsor.
Representatives of the IRB may inspect all documents and records required to be maintained by the
investigator for the participants in this study.
Data in the study is collected in two ways: in real-time and at infrequent intervals throughout the study.
Real-time data, including survey data delivered via mobile device or computer, will be stored on secure
servers hosted by Curebase and will contain only a unique identifier for each participant. Virtual reality
adherence data will also be tracked in real-time and hosted on secure servers by AppliedVR, and a
separate unique ID will be assigned to each participant. Data collected at infrequent intervals throughout
the study, such as entry, weekly, and exit questionnaires will be stored on secure servers with unique IDs
for each participant. Each dataset will utilize different unique IDs and a list linking each unique ID to each
participant will be stored internally on the secured network. The linking list allows a researcher with
access to the secured files to merge all data using statistical software while maintaining data
confidentiality.
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Healthcare utilization data for a subset of the study participants will be accessed in collaboration with
Komodo Health. We will use the Datavant service, which generates a one-way cryptographic hash to
ensure that tokenization cannot be reversed, in a process certified by leading HIPAA experts. Security
controls ensure that no one (including the Datavant and Komodo teams) can get access to participants’
protected health information (PHI) or study data without permission. Tokens act as keys that can be used
to link the same individual’s data without sharing identifying information.
18.3
PUBLICATION AND DATA SHARING POLICY
This study will be conducted in accordance with the following publication and data sharing policies and
regulations:
This trial will be registered at ClinicalTrials.gov in compliance with 42 CFR Part 11, and results
information from this trial will be submitted to the ClinicalTrials.gov database at the conclusion of the
study. In the event that the study is terminated early, the posting of these results will be completed
within 30 days of completion of data analysis. In addition, every attempt will be made to publish results
in peer-reviewed journals.
18.4
CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the pharmaceutical
industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design,
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore,
persons who have a perceived conflict of interest will be required to have such conflicts managed in a
way that is appropriate to their participation in the design and conduct of this trial. The study leadership,
in conjunction with the IRB, has established policies and procedures for all study group members to
disclose all conflicts of interest and will establish a mechanism for the management of all reported
dualities of interest.
18.5
STUDY RECORDS RETENTION
The Sponsor will maintain accurate, complete, and current records relating to this clinical investigation.
Upon study completion, the study files will be maintained in a known location for a maximum of a
two-year period after the device’s marketing approval is issued by FDA in accordance with US regulatory
requirements.
The Sponsor will maintain records in accordance with 21 CFR 812, Subpart G, to include:
•
Current and past versions of the IRB-approved clinical protocol and amendments
•
IRB-approved consent materials and participant recruitment advertisements
•
IRB correspondence (including submissions and approval notifications) including safety and
protocol deviation reports, and annual or interim reports
•
Signed Investigator Agreements and financial disclosure forms for participating Investigators
•
Curriculum vitae for all Investigators
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•
Certificates of required training for Investigators, including human subject protection and Good
Clinical Practice
•
Instructions for handling the investigational device and other study-related materials
•
Device tracking logs
•
Signed consent records
•
eCRF and Source Documents
•
Screening and Enrollment Log
•
Final clinical study report
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19
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