A Phase II Feasibility Trial Using Immersive Virtual Reality (VR) at the Time of Clinical Evaluation to Improve Psychological Distress and Anxiety in Primary Brain Tumor (PBT) Patients
Phase: PHASE2
Conditions: Anxiety
Sponsor: National Cancer Institute (NCI)

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Abbreviated Title: PhII VR Brain Tumors 
NIH Protocol Number: 20C0065
Version Date:    04/25/2024
NCT Number: NCT04301089 
Title: A Phase II Feasibility Trial Using Immersive Virtual Reality (VR) at the Time of Clinical 
Evaluation to Improve Psychological Distress and Anxiety in Primary Brain Tumor (PBT) 
Patients 
NCI Principal Investigator:
Amanda King, PhD, APNP-BC, OPCORe/CCR/NCI 
9030 Old Georgetown Road, 82/B03A 
Bethesda, MD 20892
Tel: 240-535-7958
Email: amanda.king2@nih.gov  
Device:    
Device Name:
Pico G2 4K Headset with 
Applied VR software
IDE Number:
none 
Sponsor:
none
Manufacturer:
Pico, Applied VR
Supplier:
Applied VR 

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PRÉCIS 
Background

Psychological distress is a common concern for patient across the cancer trajectory, 
which has been associated with worse clinical outcomes in terms of quality of life, 
adherence to treatment regimens, satisfaction with care, and poorer survival in past 
research.  

Virtual reality (VR) has the potential to alleviate some of the negative aspects of illness 
by allowing individuals to “escape” from their lives and experience more positive 
thoughts and emotions, which can be accomplished using cardiac coherence breathing 
techniques and distraction (both of which can improve psychological symptoms).  

Past VR research has shown promising improvements in anxiety, pain, distress and 
distraction through use of immersive VR interventions, though there is scant evidence in 
PBT populations, particularly in the time period surrounding their neuroimaging and 
clinical appointments when distress and anxiety can be highest.  

Recent evidence has demonstrated that the COVID-19 pandemic and associated 
mitigation procedures introduce additional stress for cancer patients, with higher levels of 
anxiety, depression, loneliness, and financial toxicity being reported during this time.

The purpose of this phase II clinical trial is to determine the feasibility of implementing 
an immersive VR relaxation intervention in a PBT population and to assess the efficacy 
of the intervention to improve psychological distress and anxiety at the time of clinical 
evaluation.  VR is an innovative delivery approach to teach our patients validated 
breathing and mindfulness techniques that can improve their psychological symptoms 
and their ability to self-manage these symptoms.  
Objective:

To describe the feasibility of implementing a VR intervention in a PBT population, 
including eligibility, accrual, compliance, adverse device effects, study completion, and 
participant satisfaction with the intervention
Eligibility

PBT patients enrolled on the Natural History Study (NHS) trial in the Neuro-Oncology 
Branch (NOB) (all tumor types and grades eligible) 

Patients can be newly diagnosed, receiving active treatment, or on surveillance

Adults ( 18 years of age) who are English-speaking and able to self-report symptoms

Active corticosteroid therapy is permissible

Exclude patients without tissue diagnosis, recent cranial surgery ( 2 weeks), scalp 
wound healing issues, epilepsy, or seizures within the last 6 weeks

Participants have reported  1 on distress item from MDASI-BT prior to past clinic 
appointment 

Exclude patients who have a hypersensitivity to motion, severe nausea, or visual field 
deficits that might interfere with VR experience

Exclude patients with a current diagnosis of generalized anxiety disorder (GAD), post-
traumatic stress disorder (PTSD), claustrophobia, or panic disorder

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
Those with visual deficits that might interfere with the VR experience, including 
hemianopsia, diplopia, and agnosia, based on their most recent clinical assessment
Design

This is a phase II feasibility clinical trial with a single arm experimental design.  The VR 
intervention and all patient-reported outcome measures (PROs) will be done remotely 
using telehealth.

Study will include collection of self-reported PROs for distress, anxiety, mood 
disturbance, symptom burden/interference, quality of life, cognitive function, loneliness, 
and financial toxicity, as well as optional salivary stress biomarkers.  These measures will 
be collected at baseline and immediately after a brief VR relaxation intervention to 
determine acute effects on distress, anxiety, and biological stress measures.  Repeat post-
intervention assessments will be done approximately 1 week and 1 month following the 
initial intervention to determine sub-acute effects on distress and anxiety, as well as 
impact on other symptoms.  A semi-structured qualitative interview will also be 
conducted 1 month after the initial intervention to assess participant satisfaction with the 
intervention and how the pandemic has affected their psychological symptoms.

Descriptive statistics, T-tests, Wilcoxon rank sum tests, and multiple logistic regression 
models will be used to evaluate the feasibility of the VR intervention.  Linear mixed 
models and effect size calculations will be used to evaluate the acute and sub-acute 
effects of the VR intervention on self-reported PROs.  Pearson or Spearman correlations 
will be used to evaluate the relationship between the biological stress measures and self-
reported PROs.

 A total of 120 PBT patients will participate in this study.

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TABLE OF CONTENTS 
PRÉCIS............................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................4
STATEMENT OF COMPLIANCE ................................................................................................6
1
INTRODUCTION ...................................................................................................................7
1.1
Study Objectives ...............................................................................................................7
1.2
Background and Rationale................................................................................................8
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................13
2.1
Eligibility Criteria ...........................................................................................................13
2.2
Screening Evaluation ......................................................................................................14
2.3
Participant Registration And Status Update Procedures.................................................14
2.4
Baseline Evaluation.........................................................................................................15
3
STUDY IMPLEMENTATION .............................................................................................15
3.1
Study Design...................................................................................................................15
3.2
Device Administration ....................................................................................................15
3.3
Questionnaires.................................................................................................................17
3.4
Study Calendar................................................................................................................20
3.5
Cost and Compensation ..................................................................................................22
3.6
Criteria for Removal from Protocol Therapy and Off Study Criteria.............................22
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................23
5
CORRELATIVE STUDIES FOR RESEARCH ...................................................................23
5.1
Biospecimen Collection ..................................................................................................23
5.2
Sample Storage, Tracking and Disposition.....................................................................24
6
DATA COLLECTION AND EVALUATION .....................................................................25
6.1
Data Collection ...............................................................................................................25
6.2
Data Sharing Plans..........................................................................................................26
6.3
Toxicity Criteria..............................................................................................................26
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN...27
7.1
Definitions.......................................................................................................................27
7.2
OHSRP Office of Compliance and Training / IRB Reporting........................................27
7.3
NCI Clinical Director Reporting.....................................................................................27
7.4
Institutional Biosafety Committee (IBC) Reporting Criteria..........................................27

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7.5
NIH Required Data and Safety Monitoring Plan............................................................27
8
MANUFACTURER SAFETY REPORTING.......................................................................28
8.1
Safety Reporting Criteria to the Device Collaborator.....................................................28
9
STATISTICAL CONSIDERATIONS ..................................................................................28
9.1
Statistical Hypothesis......................................................................................................28
9.2
Sample Size Determination.............................................................................................28
9.3
Populations for Analyses ................................................................................................29
10
COLLABORATIVE AGREEMENTS..................................................................................31
10.1
Agreement Type..............................................................................................................31
11
HUMAN SUBJECTS PROTECTIONS................................................................................31
11.1
Rationale For Subject Selection......................................................................................31
11.2
Participation of Children.................................................................................................31
11.3
Participation of Subjects Unable to Give Consent..........................................................31
11.4
Risk/Benefit Assessment.................................................................................................31
11.5
Consent Process and Documentation..............................................................................32
12
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................34
12.1
Study Discontinuation and Closure.................................................................................34
12.2
Quality Assurance and Quality Control..........................................................................34
12.3
Conflict of Interest Policy...............................................................................................35
12.4
Confidentiality and Privacy ............................................................................................35
13
DEVICE INFORMATION....................................................................................................36
13.1
Pico G2 4K VR Headset with Applied VR Software .....................................................36
14
REFERENCES ......................................................................................................................38
15
APPENDICES .......................................................................................................................44
15.1
Study Protocol Flow Diagram.........................................................................................44
15.2
Salivary Biospecimen Collection Information Sheet......................................................45
15.3
Study Instruments ...........................................................................................................48

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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Council on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 

United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 
812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB 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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1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective
To describe the feasibility of implementing a VR intervention in a PBT population, including 
eligibility, accrual, compliance, adverse device effects, study completion, and participant 
satisfaction with the intervention
1.1.2
Secondary Objectives
1.1.2.1. To assess the effects of a VR intervention on self-reported acute and subacute distress 
(as measured by the NCCN Distress Thermometer [DT]) and anxiety (as measured by 
the State Anxiety Inventory [STAI-6]) in PBT patients 
1.1.2.2. To determine if the effects VR has on distress and anxiety are more pronounced in those 
with high distress (based on DT cut-off score of  5) compared to those with low 
distress (based on DT scores of 0-4) 
1.1.2.3. To determine if the effects VR has on distress and anxiety are more pronounced in those 
individuals not on systemic corticosteroids (CS) compared to those who are on active 
CS therapy.
1.1.3
Exploratory Objectives
1.1.3.1
To explore the correlations between biological stress measures (as measured by 
salivary cortisol, salivary dehydroepiandrosterone-sulfate [DHEA-S], salivary 
-amylase [sAA], and heart rate [HR]) and self-reported outcome measures
1.1.3.2
 To explore the effects of a VR intervention on self-reported patient outcome 
measures collected on the Natural History Study (NHS), including mood 
disturbance (as measured by PROMIS®-Anxiety & PROMIS®-Depression Short 
Forms), symptom burden and interference (as measured by the MD Anderson 
Symptom Inventory Brain Tumor [MDASI-BT]), health-related quality of life 
(HRQOL) (as measured by the EQ-5D) and cognitive function as measured by 
the Neuro-QoL
1.1.3.3
To explore the impact of loneliness (as measured by the UCLA Loneliness 
Scale) and financial toxicity (as measured by the Comprehensive Score for 
Financial Toxicity) on distress (as measured by the DT) and anxiety (as 
measured by the STAI-6) during the COVID-19 pandemic
1.1.3.4
To determine the proportion of patients with adjustment disorder (AjD) (as 
measured by the ADNM-20) in a PBT population to assess potential utility of 
VR for improving AjD-related symptoms

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1.2
BACKGROUND AND RATIONALE 
1.2.1
Distress and Anxiety in the PBT Population
Psychological distress in cancer patients has been defined by the National Comprehensive 
Cancer Network (NCCN) as a multifactorial unpleasant emotional experience of a psychological, 
social, and/or spiritual nature that can interfere with the ability to effectively cope with the 
cancer diagnosis, its physical symptoms, treatment-related toxicities, and diagnostic imaging (1-
3).  Distress is a common concern for patients across the cancer trajectory, beginning at the time 
of diagnosis and extending into the post-treatment and survivorship phase.  Past cross-sectional 
studies have reported approximately 30–45% of cancer patients in North America experience 
significant levels of distress (4, 5), and in the advanced cancer population the prevalence may be 
as high as 60% (6, 7).  Significant levels of distress have been associated with worse clinical 
outcomes for oncology patients, in terms of worse quality of life, poor adherence to treatment 
regimens, lower satisfaction with care, and poorer survival (3).  In recent years, distress has been 
designated the “6th vital sign” by various accrediting bodies, both in the United States and 
worldwide, in order to increase the frequency of distress screenings for cancer patients across the 
disease trajectory (minimally at the time of initial diagnosis, before, during and after treatment, 
and at the transition to end-of-life care) (1, 8).  In doing so, the goal is to identify individuals 
with significant distress who would most benefit from interventions or referrals to manage their 
symptoms or concerns.
Distress, anxiety, and other psychological disorders may be more prevalent in PBT patients, 
compared to both the general population and those with non-CNS tumors (9, 10).  Once 
diagnosed, the overall prognosis for PBT patients remains poor, and they often have a difficult 
clinical course that is complicated and unpredictable due to significant morbidity from both 
tumor-related and psychological symptoms (11-13).  In addition to the distress and anxiety 
patients experience related to cancer progression, symptom burden, and therapeutic toxicities, the 
experience of these symptoms can also be related to diagnostic imaging and clinical evaluation.  
The term “scanxiety” describes the distress related to often-debilitating anxiety cancer patients 
can experience in the period surrounding their diagnostic imaging studies and leading up to their 
clinic appointments (14).  While there are some PBT patients who are claustrophobic and 
experience severe anxiety during MRI imaging, we hypothesize that the distress reported by 
approximately 20–30% of our patients is more often related to the uncertainty of their disease 
and what the diagnostic scans will reveal.  Past research has shown that PBT patients experience 
significant uncertainty surrounding their illness and that alterations in mood (e.g. anxiety and 
depression) may be modifiers of the relationship between uncertainty and overall symptom 
burden (15).  Therefore, we propose that by mitigating clinically significant distress in PBT 
patients, improvements in their psychological and physical health are likely to follow.
1.2.2
Psychosocial Impact of the COVID-19 Pandemic 
It is well-established that oncology patients are at increased risk for experiencing higher 
psychological distress compared to the general population (16, 17), as cancer is a life-threatening 
disease that can adversely impact all aspects of their life.  The COVID-19 pandemic and 
associated mitigation procedures, including social distancing, lockdowns, travel bans, and 
changes to work practices, have imposed additional stress on these individuals, as well as the 
general population (18, 19).  There is emerging evidence across the globe that fear of contracting 

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COVID-19, the negative impact of social distancing and other mitigation procedures, and 
economic uncertainty are associated with higher levels of distress, anxiety, and depression within 
the general population (20-24), though less is known about the psychosocial impact of the 
pandemic for cancer patients.  
Recent work that has focused on psychological symptoms in adult oncology patients during the 
pandemic (18, 25) have reported that over 30% of patients are experiencing high levels of stress, 
anxiety, and depression, as well as higher levels of loneliness and financial toxicity in those with 
severe psychological symptoms.  While this data is primarily from breast and hematologic cancer 
populations, we hypothesize that a similar impact on psychological symptoms exists for PBT 
patients during the pandemic.  We are interested in exploring loneliness and financial toxicity 
with distress and anxiety symptoms in our patients so that we may better understand how the 
pandemic has adversely impacted their psychological well-being.
1.2.3
Adjustment Disorder as Relevant Clinical Diagnosis
Adjustment disorder (AjD) is one of the most common mental disorders in clinical practice, 
accounting for up to 30% of all cases in psychiatric samples (26, 27), though its prevalence in 
oncology populations is unclear.  AjD can be defined as a maladaptive reaction to an identifiable 
psychosocial stressor (or multiple stressors) with 2 explicitly defined core symptom groups, 
namely 1) a preoccupation (including excessive worry, recurrent and distressing thoughts about 
the stressor, or constant rumination about its implications), and 2) a failure to adapt that 
significantly interferes with everyday functioning (e.g. difficulty concentrating or sleep 
disturbances) (28).  The emotional and behavioral symptoms in AjD include the otherwise 
normative reactions that manifest more intensely than usually expected when individuals are 
confronted with a specific stressor and are associated with significant social, occupational, and/or 
academic performance-related impairments (29).  These symptoms are suggested to emerge 
within 1 month of the onset of the stressor(s) and tend to resolve within 6 months, unless the 
stressor persists for a longer duration.  Given that AjD is associated with serious illness as a 
predisposing stressor, it seems prudent to investigate this diagnostic concept in oncology 
populations.  For the purposes of this study, we will use a validated screening instrument to 
assess the prevalence those at high-risk for AjD in PBT patients.  By doing so, we aim to assess 
the potential need for interventions that could improve AjD-related psychological symptoms, 
such as distress and anxiety, which could not only improve their quality of life and tolerance of 
therapies, but also potentially increase survival.
1.2.4
Use of Virtual Reality in Oncology Populations
Virtual reality (VR) is defined as a computer-generated simulation, such as a set of images and 
sounds that represent a real place or situation, that allows users to explore and interact with a 
virtual environment in a way that makes them feel actually present in that world (30-32).  As 
such, VR has the potential to alleviate some of the negative aspects of illness by providing 
multisensory information and allowing individuals to “escape” to pleasant locations and more 
positive thoughts and emotions (33).  VR systems can be classified into 2 types: immersive and 
non-immersive.  Immersive VR can be characterized by full immersion in a virtual environment 
through use of a head-mounted display, which is able to provide distraction by presenting the 
user with a view of a computer-generated world, thus allowing them to lose awareness of time 
and the real world (34).  In contrast, the non-immersive type of VR is often experienced with a 

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computer screen or other non-wearable media platform where the user can still remain connected 
to the external world while being able to explore the virtual one.  
Past empiric research has found VR technology to be efficacious in improving a variety of 
patient symptoms across both adult and pediatric populations, including distraction during 
stressful medical procedures (35), improved pain control during burn dressing changes (36, 37), 
and improved anxiety and depressive symptoms (38-40).  However, there are few studies that 
have examined the effects of a VR intervention on adverse symptoms in oncology populations, 
which is somewhat surprising given the high prevalence of cancer and its associated symptom 
burden.  A systematic review of the literature focused on use of VR in adult and pediatric 
oncology populations revealed some promising effects of VR on distress (41-45), pain (33, 46, 
47), anxiety (33, 42-44, 46, 48), depression (43, 49), and distraction (41, 44, 48, 50), though 
sample sizes were small and included very few PBT patients in the study populations.  There 
also was significant heterogeneity in the instruments used to operationalize the outcome 
measures in these studies, so comparing findings across different cancer populations was 
difficult.  Additionally, the study designs relied solely on self-reported outcome measures to 
assess the efficacy of the VR intervention to improve symptoms, with no inclusion of biomarkers 
or any correlative biology to better elucidate mechanisms of effects.  Ultimately, further 
investigation is needed to determine the feasibility and efficacy of using VR technology to 
improve adverse physical and psychological symptoms in PBT patients, which have to date been 
largely understudied in this context.  
1.2.5
Stress Physiological Pathways and Biomarkers of Interest
Little is known about the biological pathways involved with symptomatic improvement from VR 
use, but it is hypothesized that VR can improve distress and other psychological symptoms 
through a combination of distraction and promotion of relaxation states.  Both of these 
approaches could help blunt or decrease the severity of the physiological stress response, which 
involves the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenal-medullary 
(SAM) system (51) (Figure 1).  Activation of these neuroendocrine systems is essentially an 
adaptive mechanism that enables the human body to maintain physiological stability in response 
to stress (52-55).  While measurement of biomarkers has historically be performed with serum 
samples in clinical research, many stress hormones and enzymes that once required blood 
samples now have validated salivary assays available (53).  Utilizing salivary biomarkers 
provides a sound, cost-effective, and relatively simple approach to measuring neuroendocrine 
analytes, and is currently the “gold standard” in biomedical stress research.  

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Figure 1 The HPA Axis and Stress Response System
For this study, we will focus on salivary cortisol, DHEA, sAA, and HR, which together represent 
activity of the neuroendocrine stress regulatory systems.  In response to stress, cortisol and 
DHEA are released from the adrenal glands in response to upstream hormonal signaling from the 
hypothalamus and pituitary gland (51).  Release of cortisol, a glucocorticoid, shunts metabolic 
activity away from regulatory processes towards those that function primarily in immediate 
survival and homeostasis (51).  In contrast, DHEA, a glucocorticoid antagonist, can counter the 
effects of systemic glucocorticoid exposure and is thought to serve as an anxiolytic and 
protective factor against stress (56).  Salivary -amylase, an enzyme secreted by the parotid 
gland, and HR have been shown to increase in response to both physical and psychological 
stressors as a part of the SAM system response (53, 54).  By measuring these stress biomarkers 
and correlating their activity with self-report psychological measures, we hope to gain a more 
holistic picture about the efficacy of stress reducing interventions for PBT patients and what 
biological mechanisms are involved.  

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2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1. Inclusion Criteria
2.1.1.1
Primary brain tumor (PBT) patients enrolled on the Natural History Study 
(NHS) trial (16C0151) in the Neuro-Oncology Branch (NOB) who have an 
upcoming scan and clinical appointment
2.1.1.2
Participants can be newly diagnosed, receiving active treatment, or on 
surveillance 
2.1.1.3
Concurrent enrollment in other NOB trials is permissible
2.1.1.4
Adults ( 18 years of age) who are English-speaking 
2.1.1.5
Participants must be able to reliably self-report symptoms, based on clinician 
assessment 
2.1.1.6
Participants have reported  1 on distress item from MDASI-BT prior to a 
previous clinic appointment
2.1.1.7
Active corticosteroid therapy is permissible
2.1.1.8
Ability of subject to understand and the willingness to sign a written informed 
consent document
2.1.2
Exclusion Criteria
2.1.2.1
Participants who do not have a tissue diagnosis (no past surgery or biopsy to 
confirm diagnosis)
2.1.2.2
Cranial surgery  2 weeks prior to initiation of study intervention
2.1.2.3
Scalp wound healing issues that might interfere with comfortable VR headset 
use
2.1.2.4
Those who have epilepsy or have had a seizure in the last 6 weeks
2.1.2.5
Participants with a current diagnosis of generalized anxiety disorder (GAD), 
post-traumatic stress disorder (PTSD), claustrophobia, or panic disorder
2.1.2.6
Participants who have a hypersensitivity to motion or severe nausea, which 
could make the VR experience uncomfortable 
2.1.2.7
Those with visual deficits that might interfere with the VR experience, including 
hemianopsia, diplopia, and agnosia, based on their most recent clinical 
assessment 
2.1.3
Recruitment Strategies
Participants will be recruited from the Natural History Study as outlined in Section 2.2.1 
This protocol may be abstracted into a plain language announcement posted on NIH websites 
and on NIH social media platforms.

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2.2
SCREENING EVALUATION
2.2.1
Screening Activities Performed Prior to Obtaining Informed Consent
Research staff from the Neuro-Oncology Branch (NOB) will screen participants for study 
inclusion by targeting those who have reported distress scores 1 on the MDASI-BT 
questionnaire within the previous 12 months.  Those with past distress will be contacted by 
phone or email to assess eligibility, introduce the VR trial, and determine their interest in 
participating in the trial.  Patients who meet eligibility criteria and are interested in participating 
will be consented to the study and the date of their upcoming neuro-oncology scan appointment 
(either with NOB or outside neuro-oncology providers) will be documented.  The VR 
intervention will be aligned with this upcoming scan appointment.
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 

Email, written, in person or telephone communications with prospective subjects that are 
enrolled in the NIH16C0151 Natural History Protocol.

Review of existing medical records to include H&P, laboratory studies, MDASI-BT, 
etc.  

Phone call or email to introduce the VR study and determine their interest in participating
2.2.2
Screening Activities Performed After a Consent for Screening Has Been Signed
No additional screening activities are required.
2.3
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
2.3.1
Intervention Assignment 
Cohorts
Number
Name
Description
1
Group 1
Primary brain tumor patients 
Arm
Number
Name
Description
1
Experimental 
intervention
Experimental VR intervention, completion of 
questionnaires, and (optional) biological sample 
submission  

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Arm Assignment
Participants will be assigned to Cohort 1 and directly assigned to Arm 1.  
2.4
BASELINE EVALUATION
All baseline evaluation procedures should be done prior to the VR intervention.  All baseline 
PROs measures will be administered using the Scribe electronic interface.

NCCN Distress Thermometer (DT)

State-Trait Anxiety Inventory (STAI-6) 

UCLA Loneliness Scale

Comprehensive Score for Financial Toxicity (COST)

Adjustment Disorder Instrument (ADNM-20) 

Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse 
Events (PRO-CTCAE)

Correlative stress biomarkers (salivary hormones) – Kits will be sent to participants with 
instructions in section 15.2 included.
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
This protocol is a single arm experimental design and will target PBT patients currently enrolled 
on the Natural History Study.  The VR intervention and all assessments will be done remotely 
using telehealth.  Following consent, the timing of the VR intervention will be aligned with the 
participant’s upcoming neuro-oncology scan appointment (either with NOB or outside neuro-
oncology providers).  Once consented, the participant will be asked if they would like to 
participate in the correlative biomarkers portion of the protocol, and if interested they will be 
provided with saliva sampling materials.  Prior to their appointment, NOB research staff will 
provide participants with a VR headset and saliva sampling materials (optional) and send 
baseline questionnaires for participants to complete prior to the VR intervention.  The 
intervention will include a 5-minute relaxation scenario delivered via an immersive, head-
mounted VR device.  Repeat assessments of PROs and salivary biomarkers will be done 
immediately following the intervention, as well as repeat PROs 1 week and 1 month later in 
order to assess acute and subacute effects on symptoms and stress hormones.  Additionally, a 
semi-structured qualitative phone interview will be done  1 month following the VR intervention.  
3.2
DEVICE ADMINISTRATION
The VR headset to be utilized in this study, called the Pico G2 4K was designed by Pico.  The 
AppliedVRTM company designed the AppliedVRTM software for therapeutic use in clinical 
populations.  
3.2.1
VR Intervention
Research staff will introduce participants to the VR headsets demonstrating how to put it on and 
adjust the fit, how to navigate the main virtual interface and select different scenarios, and proper 

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use of the handheld remote.  Additionally, NOB research staff will go over any questions 
participants have about use of the headset in a virtual meeting prior to administering the 
intervention.  Once all baseline questionnaires have been completed and participants feel 
comfortable with use of the VR headset, they will complete the VR intervention under the 
supervision of research staff.
The VR intervention will take place in a telehealth meeting on an NIH approved platform with 
NOB research staff with the participant sitting in a comfortable chair.  Participants will select a 
VR scenario from the pre-loaded options on the VR headset (each around 5 minutes in duration), 
which fall into one of the following categories:
3.2.1.1
Dynamic breathing
Experiences that teach breath awareness and slow, diaphragmatic breathing in 
order to induce relaxation and increase HR variability to manage stress  
3.2.1.2
Guided relaxation
Experiences that provide meditative environments to practice mindfulness, 
relaxation, and attention to streams of thought
3.2.1.3
Instant escape
Experiences that are specifically designed to provide immersive, multi-sensory 
distraction from unpleasant symptoms 
3.2.1.4
Interactive games
Fun distraction activities designed to redirect attention away from unpleasant 
symptoms or thoughts
*** These games will be available for participants to enjoy on the VR headsets 
while using them at home, but not for the initial VR intervention.
For the purposes of standardizing duration of the initial VR experience in clinic across 
individuals, participants will not be allowed to change scenarios once they have begun, which 
will keep the duration to approximately 5 minutes.  Research staff will remain in the virtual 
meeting with the participants during the VR intervention in order to monitor for any issues or 
adverse device effects related to the intervention and also to address any questions that arise.
Immediately following completion of the intervention, participants will repeat the DT, STAI-6, 
and PRO-CTCAE questionnaires using the Scribe interface. 
3.2.2
Post-Intervention VR Use and Measurements
Following completion of the initial VR intervention, participants will continue use of the VR 
headsets at their discretion.  Participants will have the opportunity to share their thoughts about 
the VR headset and study experience during a semi-structured qualitative phone interview  1 
month following the remote VR intervention.  Participants will also be asked the Was It Worth It 
(WIWI) questions immediately post-intervention as well as at the 1 month post-VR timepoint to 
ascertain their satisfaction with initial VR use as well as their experience throughout the 
participation period.  All post-intervention PROs measurements will be done electronically 
through Scribe.  If for technical or physical reasons the participant is unable to complete their 
questionnaires electronically, the questionnaires may be read to them by research staff and their 

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responses documented within Scribe.  Research staff will follow-up with participants weekly to 
help assist with any issues or questions about the VR headsets and will ask about any adverse 
effects participants experience while using the headset.
Following completion of the study, participants will be allowed to keep the VR headsets 
indefinitely.  Other members of the household are allowed to use the VR headsets and we will 
encourage participants to let us know if that occurs.
3.3
QUESTIONNAIRES 
3.3.1
National Comprehensive Cancer Network (NCCN) Distress Thermometer (DT)
The NCCN Distress Thermometer (DT) will be used to operationalize distress in this study.  This 
instrument was first developed in 1997 based on release of the NCCN distress management 
guidelines, which consisted of a global distress screener (the Distress Thermometer), an 
accompanying 40-item problem list, and treatment recommendations for psychosocial issues (57-
59).  The DT is a one-item, 11-point Likert scale that is represented on a visual graphic of a 
thermometer   that ranges from 0 (no distress) to 10 (extreme distress), with patients reporting 
their level of distress over the preceding week (including the day of assessment).  Individuals 
who report high levels of distress can be given the accompanying problem list that identifies 
commonly reported problems related to the cancer experience.   The DT has been validated using 
receiver operating characteristic (ROC) curve analyses in numerous oncology populations and 
has demonstrated validity and reliability against other validated legacy instruments (57, 60-62), 
including the Hospital Anxiety and Depression Scale (HADS), the Brief Symptom Inventory 
(BSI), and the Behavioral Health Status (BHS) Scale.
There has been a lack of uniformity in reporting clinically significant cut-off scores for 
moderate-severe distress on the DT, with cut-off scores ranging from 3 to 6.  When the DT was 
initially validated, a cut-off score of 5 was used to identify patients experiencing significant 
distress, as this as the midpoint of the 11-point Likert Scale (59).  In much of the DT research 
that utilizes mixed oncology patient samples, cut-off scores indicating distress varied by culture, 
setting, demographics, and cancer type, but most studies support a DT cut-off score of either 4 or 
5 (58, 60, 63).   For the purposes of this study, we will implement a cut-off score for moderate-
severe (and clinically significant) distress of  5, mirroring that of the MDASI-BT instrument 
(63-65).
3.3.2
State-Trait Anxiety Inventory, 6-Item Short-Form (STAI-6)
The State-Trait Anxiety Inventory 6-item Short-Form (STAI-6) will be used to operationalize 
anxiety .  The Spielberger State-Trait Anxiety Inventory (STAI), initially developed in 1970 
(Form X) and revised in 1983 (Form Y), is one of the most commonly used measurement tools 
for anxiety in applied psychology research, with demonstrated reliability and validity across 
numerous sample populations (66-69).  Despite its popularity and sound psychometrics in past 
research, the legacy instrument is rather lengthy, consisting of 40 items total with 2 subscales: 
state anxiety, known as the S-scale (how anxious one feels in that moment) and trait anxiety, 
known as the T-scale (how anxious one generally feels).  For the purposes of this study, we are 
more interested in state anxiety and how a VR intervention might be effective at reducing this 
kind of transient anxiety.  A shortened 6-item version of the original S-scale of the STAI was 
initially validated by Marteau and Bekker (66) in 1992 in a sample of pregnant women, student 

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nurses and medical students, finding that the 6-item version (known as STAI-6) produced 
acceptable reliability ( = 0.82) compared to that of the full 20-item version ( = 0.91) with 
similar sensitivity to detect change in anxiety levels.  Since then, other 6-item short-forms of the 
S-scale for STAI have been developed and validated (67-69), all of which demonstrate highly 
correlated scores with the 20-item STAI and similar internal consistency reliabilities.  For this 
study, we will be utilizing the STAI-6 S-scale developed by Marteau and Bekker, given it was 
validated in outpatient participants and tends to perform best from a psychometric standpoint 
compared to other short versions of the instrument.
3.3.3
UCLA Loneliness Scale
The UCLA Loneliness Scale will be used to operationalize loneliness and social isolation.  This 
instrument is the widely used in the literature and has well-established psychometrics in a variety 
of clinical populations (70, 71) (including oncology) (72), with internal consistency reported at 
0.95 (73).  It utilizes a 20-item scale that is designed to measure one’s subjective feelings of 
loneliness (10 items) as well as feelings of social isolation (10 items), with participants rating 
each item on a Likert scale from 1 (Never) to 4 (Often).  Scoring for this instrument is fairly 
straightforward and involves summing the responses for the 20 items (including reverse scoring 
of a few questions), with higher scores indicating higher levels of loneliness and social isolation 
(71).  While short-forms of this instrument have been developed, they do not perform as well 
from a reliability standpoint, therefore we will be utilizing the full 20-item version of the UCLA 
Loneliness Scale for the purposes of this trial.
3.3.4
Comprehensive Score for Financial Toxicity (COST)
The Comprehensive Score for Financial Toxicity (COST) instrument will be used to 
operationalize financial toxicity.  Financial toxicity has been defined as “the distress patients can 
experience related to the high costs of cancer treatment and subsequent economic challenges 
(such as loss of income)” (74).  This is a recently developed instrument that was initially 
validated in 155 patients with advanced cancer using item analysis and exploratory factor 
analysis, which demonstrated good content and face validity as well as internal consistency 
(Cronbach’s alpha of 0.9) (75).  The COST is an 11-item instrument using a 5-point Likert scale 
ranging from 0 (Not at All) to 4 (Very Much) asking patients about the financial impact that their 
disease and treatment has had on their lives.  Scores for individual items are summed (with a few 
questions reverse scored) and higher scores on the COST indicate higher levels of distress related 
to financial toxicity (75).  
3.3.5
Adjustment Disorder New Module 20-Item 
The Adjustment Disorder New Module 20-item instrument (ADNM-20) will be used to screen 
for AjD in this study population.  The ADNM-20 questionnaire is a theory-driven instrument that 
measures AjD as a stress response disorder, according to the new diagnostic concept of the 
International Classification of Diseases, 11th edition (ICD-11) (28).  The first iteration of the 
ADNM, developed by Einsle, Kollner (76), was a 29-item self-report measure that was validated 
in adult cardiac and psychosomatic outpatients.  In this study, the most frequently reported 
stressor reported by individuals was their own physical illness, followed by financial difficulties, 
illness of a significant other, and work difficulties or unemployment.  Due to newer diagnostic 
criteria for AjD according to the ICD-11, the ADNM instrument was revised to 20-items using 

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confirmatory factor analysis (77), and it has demonstrated validity and sound psychometrics in 
past studies (28, 78, 79).  
The contemporary ADNM-20 consists of 2 parts: a stressor list and an item list (80).  The 
stressor list captures a broad range of acute (e.g. divorce, moving) and chronic (e.g. serious 
illness, family or work conflicts) stressors that have occurred over the last two years (76, 77, 80).   
The item list measures the symptoms in response to the most distressing event identified by the 
participant.  Individuals indicate on a 4-point Likert scale, ranging from 1 (never) to 4 (often), 
how often they have experienced different symptoms of an adjustment disorder in the past 2 
weeks.  The ADNM-20 has 6 subscales: preoccupation (4 items), failure to adapt (4 items), 
avoidance (4 items), depressive mood (3 items), anxiety (2 items), and impulse disturbance (3 
items) (80).  Preoccupation and failure to adapt are considered the core symptoms and the 
remaining subscales are considered accessory symptoms.  Based on cluster analysis and ROC-
analysis, a cut-off total score of 47.5 on the ADNM-20 is clinically predictive of the presence of 
AjD (test sensitivity 87%, specificity 74%, positive predictive value 57%, negative predictive 
value 93%) (80).  
Identifying individuals who are at high risk for AjD can be based on the presence/severity of 
core AjD symptoms, as well as their total ADNM-20 score, with the following criteria:

1 item rated  3 and at least 2 items rated  2 in both core symptom clusters 
(preoccupation and failure to adapt) AND a rating of  3 on the impairment question 

(Item 20: “All in all, the situation causes serious impairment in my social life or 
occupational life, my leisure activities, or other important areas of functioning.”)

A total score  48 on the ADNM-20 questionnaire
3.3.6
Patient-Reported Outcomes Common Terminology Criteria for Adverse Events 
(PRO-CTCAE)
PRO-CTCAE is a patient-reported outcome measurement system that was developed by the NIH 
in order to capture the symptomatic adverse events in patients on oncology clinical trials.  This 
instrument allows us to select, but not be limited to, the symptoms that are anticipated with use 
of the VR headset based on past clinical research and experience with the technology, including 
nausea, vomiting, dizziness, and headache, with the option to report other unanticipated 
symptoms as well. 
3.3.7
Virtual Reality Qualitative Interview Guide
A brief, 7-item semi-structured questionnaire developed by a trained qualitative NOB researcher 
will be used during a phone interview with participants approximately 1 month following the 
remote VR intervention.  The purpose of the interview is to allow the participants to share their 
experiences with VR and to provide feedback about their likes and dislikes of the experience, as 
well as about the headset itself.  Additionally, information regarding any side effects or adverse 
symptoms from using the VR headset will be discussed.  The interviewer may ask additional 
probe questions to obtain complete information regarding the participants’ VR experience.  
There is also a question related to their experience with having a brain tumor during the COVID-
19 pandemic and any psychological symptoms they are having during this time. The phone 

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interview will be recorded, and the content transcribed in preparation for qualitative thematic 
analysis. 
3.3.8
Was It Worth It (WIWI) Questionnaire
The WIWI is a brief questionnaire that is designed to measure a participant’s opinion of their 
participation in a phase 2 or 3 clinical trial.  Knowledge of whether participants thought the 
clinical trial experience was beneficial to them may provide insights for barriers to accrual, 
improvements in the intervention, and can inform future trial design.  WIWI questions are 
typically dichotomous (yes/no) and are tailored to be specific to the intervention involved in that 
particular clinical trial.  For the purposes of this study, there will be 4 yes/no questions that 
ascertain the participants’ satisfaction with the initial VR intervention as well their experience 
over the 1 month participation period, which will be collected electronically via Scribe.
3.3.9
Completion Time for Questionnaires
 The DT and STAI-6 instruments will be administered at 4 timepoints (baseline, immediately 
post-intervention, 1 week later, and 1 month later) and are estimated to take approximately 5 to 
10 minutes to complete, in addition to the questionnaires currently administered as part of the 
main Natural History Study (MDASI-BT, PROMIS®-Anxiety and PROMIS®-Depression Short-
Forms, Neuro-QoL, and EQ-5D).  The PRO-CTCAE questionnaire will be administered at 3 
timepoints (baseline, immediately post-intervention & 1 month later) and is estimated to take less 
than 5 minutes to complete.  The UCLA Loneliness Scale, COST, and ADNM-20 will be 
administered once at baseline and is estimated to take 10 to 15 minutes to complete.  The WIWI 
Questionnaire will be collected at 2 timepoints (immediately post-intervention and 1 month later) 
electronically via Scribe and will take approximately 5 minutes to complete.  The qualitative VR 
questionnaire administered during the phone interview is estimated to take 15 minutes to 
complete.
3.4
STUDY CALENDAR
Evaluation
Screening 
Measures
Study 
Entry & 
Baseline 
Measures 
Post-VR 
Measures   
(T1 = within 
1 hour)
Post-VR 
Measures
(T2 = 1 week 
later, +/- 3 
days)
Post-VR 
Measures 
(T3 = 1 
month later, 
+/- 7 days)
Informed consent
X
Patient-Reported Outcomes
NCCN Distress 
Thermometer (DT), section 
3.3.1
X
X
X
X
State-Trait Anxiety 
Inventory (STAI-6), section 
3.3.2 
X
X
X
X
UCLA Loneliness Scale, 
section 3.3.3  
X
Comprehensive Score for 
Financial Toxicity (COST), 
section 3.3.4 
X

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Evaluation
Screening 
Measures
Study 
Entry & 
Baseline 
Measures 
Post-VR 
Measures   
(T1 = within 
1 hour)
Post-VR 
Measures
(T2 = 1 week 
later, +/- 3 
days)
Post-VR 
Measures 
(T3 = 1 
month later, 
+/- 7 days)
Adjustment Disorder 
Instrument (ADNM-20), 
section 3.3.5 
X
PRO-CTCAE Section 3.3.6
X
X
X
Was It Worth It (WIWI) 
questionnaire Section 3.3.8 
X1
X1
Review PROs and forms 
collected on Natural History 
Study2
X
X
X
X
Qualitative Assessment
Semi-structured phone 
interview, section 3.3.7
X
Correlative Biomarkers and Device
Salivary hormones
Cortisol
DHEA-S
sAA
 X3
 X3
VR Instrument4
1 WIWI questionnaires will be administered electronically via Scribe.  
2 PROs (MDASI-BT, PROMIS®-Anxiety and PROMIS®-Depression Short-Forms, Neuro-QoL and EQ-5D) and 
clinical/demographic information will be collected as part of the Natural History Study.  
3 Salivary hormone collection kits will provided to participants for pre/post-intervention assessments.  This is an 
optional collection at the discretion of the participant and investigator.  If participants agree to the saliva sample 
collection, they will be asked standard screening questions for COVID symptoms by research staff within 72 hours 
of collecting their saliva. See Section 5.1.1 for instructions if the COVID screen is positive.
4 Instrument use will be as defined in Section 3.2.
3.5
COST AND COMPENSATION 
3.5.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center.  If some tests and procedures performed 
outside the NIH Clinical Center, participants may have to pay for these costs if they are not 
covered by insurance company.  Medicines that are not part of the study treatment will not be 
provided or paid for by the NIH Clinical Center.    
3.5.2
Compensation/Incentives
The cost estimate of the Pico G2 4K headsets sold unlocked with full content is approximately 
$400, however, the devices used in this study are locked and have a limited amount of pre-loaded 
software.  As a result, the value of the headsets utilized in this trial is likely considerably less, 
given the limited content and inability to upload additional software.  Therefore, the concern for 
attempted resale of the Pico G2 4K devices by participants is considerably mitigated.  

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AppliedVRTM has agreed to provide the headsets and uploaded relaxation software free of charge 
for the purposes of this trial, per Collaboration Agreement 45562-19, and participants will be 
allowed to keep the device (if they choose) after they have completed study participation.  
3.5.3
Reimbursement 
This study does not offer reimbursement for, or payment of, travel, lodging or meals. 
3.6
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from study, effort must be made to have all subjects complete a safety phone 
call approximately 30 days after the initial VR intervention. 
3.6.1
Criteria for removal from protocol therapy

Completion of protocol intervention

Participant requests to be withdrawn from study

Investigator discretion
3.6.2
Off-Study Criteria

Completed study follow-up period

Participant requests to be withdrawn from study

Participant lost to follow-up

Permanent loss of capacity to consent 

Adverse device effect warranting participant to be taken off study (i.e., seizure)

Death
3.6.3
Lost to Follow-Up
A participant will be considered lost to follow-up if he or she fails to participate in the 1 week 
and 1 month post-intervention data collection timepoints and is unable to be contacted by the 
study site staff. 

Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods).  These contact attempts should be documented in the participant’s 
medical record or study file. 

Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
4
CONCOMITANT MEDICATIONS/MEASURES
Non-Applicable.

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5
CORRELATIVE STUDIES FOR RESEARCH
5.1
BIOSPECIMEN COLLECTION
5.1.1
Saliva Samples (optional, at discretion of investigator and participant)
If participants choose to participate in the saliva sample collection, they will be asked standard 
screening questions by research staff for any COVID symptoms that may have been experienced 
within the 72 hours prior to collecting their saliva.  If the screening is positive (e.g., reveals that a 
participant may have COVID, COVID symptoms or exposure), the sample will not be collected.
Passive drool saliva samples will be collected in a Cryovial 2mL passive drool collection tube 
(please note that tubes and media may be substituted based on availability with the permission of 
the PI or laboratory investigator) from participants at 2 different time points, according to the 
study calendar: at baseline and immediately following the initial VR intervention.  To avoid 
fluctuations attributed to circadian rhythms in some of the stress biomarkers (specifically 
salivary cortisol and sAA), the collection times for the salivary samples will be standardized 
across timepoints for each participant.  Additionally, levels of two of the analytes are flow-rate 
dependent (DHEA-S and sAA), meaning that concentrations of these molecules decrease as 
saliva flow increases.  Given the variability of saliva flow from person to person (or even for the 
same person at different times) the total time necessary to collect the desired volume of saliva 
will be recorded by participants when collecting at home.  With this information, assay results 
can later be multiplied by the flow rate (mL/min) to calculate a secretion rate that can be 
covaried in analyses (81).  
Adherence to a salivary hormone collection protocol will be important to ensure validity of 
specimens collected.  See Appendix 15.2 for the Salivary Biospecimen Collection Information 
Sheet that will be reviewed with participants and provided to them as a reference during the trial.  
Freezing samples as soon as possible at or below -20oC (temperature of a household freezer) is 
ideal to minimize sample degradation and to prevent bacterial growth.  If immediate freezing is 
not possible, participants can briefly refrigerate samples at +4oC (for up to 1 day) prior to 
freezing them.  Contact information for the lead study investigator is provided on the saliva 
collection form to address any participant questions that arise related to salivary biospecimen 
collection.  
Once collected, salivary samples will be sent to the Clinical Laboratory Services Core (CLSC) 
for the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), which will 
be responsible for aliquoting, storing, and processing the samples (Mary Walter, Director, 
Clinical Laboratory Services Core, https://www.niddk.nih.gov/research-funding/at-niddk/cores-
support-services/clinical-laboratory-core, Contact: mary.walter@nih.gov).  Salimetrics enzyme-
linked immunosorbent assay (ELISA) kits specific for each hormone/enzyme will be used by the 
CLSC to process saliva samples and provide final biological data to the research team.  

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Salivary 
hormone/enzyme
Optimal 
collection 
volume 
Type of collection 
tube 3
Considerations
Specimen 
storage and 
processing
Cortisol
75 L
Cryovial – 2 mL 
(passive drool)
Diurnal variation
NIDDK lab core 
DHEA-S
225 L
Cryovial – 2 mL
(passive drool)
Flow-rate dependent
NIDDK lab core 
sAA
25 L
Cryovial – 2 mL
(passive drool)
Diurnal variation, 
flow-rate dependent
NIDDK lab core 
Minimum total 
saliva volume 
325 L1
Recommended 
total saliva volume
625 L2
1  Reflects minimum saliva volume for each of the 2 collection timepoints
2  Salimetrics recommends adding an extra 300 L of collection volume when measuring multiple analytes from 
saliva samples in order to account for any sample handling losses and potential repeat analyses
3 Please note that tubes and media may be substituted based on availability with the permission of the PI or 
laboratory investigator.
5.2
SAMPLE STORAGE, TRACKING AND DISPOSITION

Samples will be ordered in CRIS. Should a CRIS screen not be available, the CRIS 
downtime procedures will be followed.  Samples will not be sent outside NIH without 
appropriate approvals and/or agreements, if required. All specimens obtained in the 
protocol are used as defined in the protocol.  Any specimens that are remaining at the 
completion of the protocol will be stored in the conditions described below.  The study 
will remain open so long as sample or data analysis continues.  Samples from consenting 
subjects will be stored until they are no longer of scientific value or if a subject 
withdraws consent for their continued use, at which time they will be destroyed. 

All salivary biospecimens processed and stored by the CLSC are tracked by a web-based 
system called Biological Specimen Inventory (BSI), which maintains a full audit trail.  
Detailed records are maintained on the status, location, and nature of the sample.  These 
data are backed up every night on a server, which is at a different location.  

The CLSC has been compliant with government regulations and NIH policy since June 
2009.  The CLSC maintains a detailed Standard Operating Procedure manual so that the 
samples can be maintained in the biorepository indefinitely, irrespective of the tenure of 
the technician.  

All freezers are locked and maintained in locked rooms in the CLSC.  Freezer 
temperatures are continuously monitored electronically by Rees Scientific and a detailed 
phone tree has been established if there are any temperature deviations.  Additionally, 
multiple lab personnel are emailed and with any temperature deviations.  There are 2 
empty freezers at all times set at -80oC to serve as backup freezers if there is a main 
freezer failure.  Freezers are also connected to emergency power in the event of a power 
failure, and the freezer rooms are located in multiple sites.

All salivary biospecimens will be labelled using Thermal transfer, high-definition self-
laminating polyester labels that are abrasion and smudge resistant, and also stable in a 
100oC water bath to liquid nitrogen.  These labels have a unique identifier and contain a 
2-dimensional barcode with electronic record documentation.  There is no personal 

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identifying information on the label, however the unique identifier is linked to the 
database which contains the clinical or research data about the participant.

If the participant withdraws consent, the participants data will be excluded from future 
distributions, but data that have already been distributed for approved research use will 
not be able to be retrieved.

The PI will record any loss or unanticipated destruction of samples as a deviation. 
Reporting will be per the requirements of section 7.2.
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system Labmatrix and ensuring data accuracy, consistency and timeliness.  Research 
staff in the CLSC will use the Biological Specimen Inventory (BSI) system for tracking and 
processing salivary biospecimens.  The principal investigator, associate investigators/research 
nurses and/or a contracted data manager will assist with the data management efforts.  Primary 
and final analyzed data will have identifiers so that research data can be attributed to an 
individual human subject participant.
All adverse device effects, including clinically significant abnormal findings on laboratory 
evaluations, regardless of severity, will be followed until return to baseline or stabilization of 
event. 
Document adverse device effects from the first study intervention, Study Day 1, through 30.
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1. 
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
What data will be shared?
I will share human data generated in this research for future research as follows 
_x__ Coded, linked data in an NIH-funded or approved public repository.
_x__ Coded, linked data in another public repository.
_x__ Coded, linked data in BTRIS (automatic for activities in the Clinical Center)
_x__ Identified or coded, linked  data with approved outside collaborators under appropriate 
agreements.

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How and where will the data be shared? 
Data will be shared through 
_x__ An NIH-funded or approved public repository. Insert name or 
names:___clinicaltrials.gov______________.
___ Another public repository. Insert name or names: ____________________________.
_x__ BTRIS (automatic for activities in the Clinical Center)
_x__ Approved outside collaborators under appropriate individual agreements.
_x__ Publication and/or public presentations.
When will the data be shared? 
_x__ Before publication.
_x__ At the time of publication or shortly thereafter.
6.2.2
Genomic Data Sharing Plan
Non-Applicable.
6.3
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
participant while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).  
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.2.1
Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 

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7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
7.3
NCI CLINICAL DIRECTOR REPORTING 
Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary.
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease.  
To report these deaths, please send an email describing the circumstances of the death  
NCICCRQA@mail.nih.gov within one business day of learning of the death.
7.4
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) REPORTING CRITERIA
Non-Applicable.
7.5
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.5.1
Principal Investigator/Research Team 
The clinical research team will meet on a regular basis weekly to discuss participants enrolled on 
the trial. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator.  Events meeting requirements for expedited reporting as described in 
section 7.2.1 will be submitted within the appropriate timelines.  
The principal investigator will review adverse device effect and response data on each 
participant to ensure safety and data accuracy.  The principal investigator will personally conduct 
or supervise the investigation and provide appropriate delegation of responsibilities to other 
members of the research staff. 
8
MANUFACTURER SAFETY REPORTING
8.1
SAFETY REPORTING CRITERIA TO THE DEVICE COLLABORATOR
Reporting will be per the collaborative agreement. 

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9
STATISTICAL CONSIDERATIONS  
9.1
STATISTICAL HYPOTHESIS
9.1.1
Primary Endpoint: 
To describe the feasibility of implementing a VR intervention in a PBT population, including 
eligibility, accrual, compliance, adverse events, study completion, and participant satisfaction 
with the intervention
9.1.2
Secondary Endpoints: 
9.1.2.1. To assess the effects of a VR intervention on self-reported acute and subacute distress 
(as measured by the NCCN Distress Thermometer [DT]) and anxiety (as measured by 
the State Anxiety Inventory [STAI-6]) in PBT patients 
9.1.2.2. To determine if the effects VR has on distress and anxiety are more pronounced in high 
distress (based on DT cut-off score of  5) compared to low distress (based on DT 
scores of 0–4) individuals
9.1.2.3. To determine if the effects VR has on distress and anxiety are more pronounced in those 
individuals not on systemic corticosteroids (CS) compared to those who are on active 
CS therapy.
9.2
SAMPLE SIZE DETERMINATION
The primary objective of this study is to determine the feasibility of implementing a VR 
intervention that aims to reduce psychological distress and anxiety in primary brain tumor 
patients.  This study will be considered successful if the following feasibility conditions are met: 
80% of approached eligible patients agreed to participate, 70% compliance with the VR headset 
use, no grade 3 or higher intervention-related adverse device effects during the remote VR 
intervention, and 70% of required data points are completed.  Assuming that about 80% of 
patients approached for the study are eligible, with a target of 100 patients in the final study 
sample, we would be reasonably certain (95% confident) that our estimate of the proportion of 
eligible patients would lie within 7.8% of the true proportion of eligible patients.  In other words, 
a two-sided 95% confidence interval around an expected proportion of 80% of eligible patients 
will have a width of +/- 7.8%.  To account for 10% attrition of participants during the trial, we 
will plan to recruit a total of 120 patients for this study.  
In order to ensure adequate representation of low/high distress individuals and those on/off CS 
therapy to address the secondary objectives of this study, we will utilize the following enrollment 
strategies: 

For distress levels, we will aim to enroll approximately 20% of the sample with high 
distress (N=24) and approximately 80% with low distress (N=96).

For corticosteroid use, we will aim to enroll approximately 20% of the sample on active 
CS therapy (N=24) and approximately 80% who are not on CS therapy (N=96).

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9.3
POPULATIONS FOR ANALYSES
9.3.1
Analysis of the Primary Endpoints
To evaluate the feasibility of the VR intervention, we will use descriptive statistics to summarize 
information, including rates of recruitment and retention.  We will calculate total scores, subscale 
scores, and/or t-scores (if applicable) for the DT, STAI-6, PROMIS®-Depression and Anxiety 
Short Forms, Neuro-QoL, MDASI-BT, EQ-5D, and PRO-CTCAEs questionnaires, completed 
at varying timepoints (baseline, immediately post-intervention, 1-week post-intervention, and 1-
month post-intervention).  The quantity of missing data, variability of the data over time, and 
trends over time will be especially important to report to assess the feasibility of this 
intervention.  This data will be summarized by time point quantitatively and graphically.  
Patients who drop out will also be compared to those who continue, based on their demographic 
characteristics (such as gender, age) and on other baseline assessments using t-tests or Wilcoxon 
rank sum tests.  A multiple logistic regression model will be constructed to identify variables 
independently associated with dropping out.  This information will help determine the 
characteristics of patients who are recruited into the study and those who are retained in the 
study.  This will help guide future recruitment efforts and identify types of patients who may 
require special attention to minimize attrition. 
We will also use descriptive statistics to report how patients rate their responses on various 
measures.  For the NCCN Distress thermometer, we will report the proportion of patients who 
scored  5 on DT that indicate moderate-severe distress. We will report subscale scores for the 
MDASI-BT and the proportion of patients with 5 or greater (moderate to severe) and 7 or greater 
(severe) ratings on the 0-10 numeric rating scale of each symptom items.  T-scores from the 
PROMIS®-Anxiety and Depression Short-Forms and Neuro-QoL instrument will also be 
reported.  
Additionally, we will report participant satisfaction with the VR experience using descriptive 
statistics for responses from the WIWI questionnaire, as well as through qualitative thematic 
analysis from participant responses from the semi-structured phone interview.
9.3.2
Analysis of Secondary Endpoints
To determine the effect of a VR intervention on self-reported acute and subacute distress, we will 
fit a linear mixed model with patients as random effect and time as fixed effect using scores from 
the DT as the dependent variable.  To quantify the acute VR effect, we will calculate effect size 
difference between baseline scores and immediate post-use of VR scores.  To quantify the 
subacute VR effect at home, we will calculate effect size differences in distress scores between 
baseline and week 1.  Likewise, we will calculate effect size differences in distress ratings 
between baseline and week 4.  A similar approach will be taken to analyze effects of the 
intervention on acute and subacute anxiety, using the STAI-6 as the dependent variable in a 
linear mixed model.  Similar effect size calculations will be made comparing anxiety scores 
between the baseline and immediate post-intervention, week 1, and week 4 timepoints.  
To determine if the effect VR has on distress and anxiety is more pronounced in high distress 
(based on DT cut-off score of  5) compared to low distress (based on DT scores of 0–4) 
individuals, we will calculate difference scores in distress between baseline and immediate post 
use of VR.  We will then perform an independent t-test on the distress difference scores using 

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two groups based on their baseline DT scores ( 5 vs. < 5).  We hypothesize that the changes in 
distress scores will be greater in the high baseline distress group, compared to the low baseline 
distress group.  We will repeat the analyses using the same groups, but with changes in anxiety 
as the dependent variable. 
To determine if the effect VR has on distress and anxiety is more pronounced in those who are 
not on systemic corticosteroids (CS) (compared to those on active CS therapy), we will calculate 
difference scores in distress and anxiety between baseline and immediate post use of VR.  We 
will then perform an independent t-test on the distress difference scores using two groups based 
on whether or not they are on steroids.  We hypothesize that changes in distress and anxiety will 
be greater in those who are not on active CS therapy, compared to those who are currently taking 
CS, due to alterations in adrenal function, behavior, and mood associated with CS use. 
9.3.3
Analysis of Exploratory Endpoints
To evaluate the relationship between the biological stress measures (salivary cortisol, DHEA-S, 
sAA, and HR) and self-reported distress, anxiety, mood disturbance, symptom burden, cognitive 
function, and quality of life, we will calculate either Pearson or Spearman correlations 
(whichever is appropriate) at each available timepoint (baseline, immediate post-VR 
intervention).  For these exploratory analyses, we will take note of the magnitude of the 
relationships between the biological stress measures and self-report measures.  
We will perform linear mixed models and effect size calculations to explore the effects of VR on 
symptom burden and interference, mood disturbance, HRQOL, and cognitive function using raw 
and subscale scores from the MDASI-BT and EQ-5D, and using t-scores from the PROMIS®-
Anxiety and Depression Short-Forms and Neuro-QoL instrument.  We will also evaluate the 
relationships between loneliness and financial toxicity on distress and anxiety by calculating 
either Pearson or Spearman correlations.
To evaluate the proportion of patients with AjD, we will use descriptive statistics to report 
participant scores on the ADNM-20 questionnaire.  Individuals that meet at least one of the 
following criteria will be reported as at high risk for AjD:

1 item rated  3 and at least 2 items rated  2 in preoccupation and failure to adapt core 
symptom clusters AND a rating of  3 on the impairment question 

A total sum score  48 for all items on the ADNM-20
9.3.4
Planned Interim Analyses
Non-Applicable.
10 COLLABORATIVE AGREEMENTS
10.1 AGREEMENT TYPE
Pico G2 4K headsets have been provided by Applied VRTM under a Collaboration Agreement 
45562-19.

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11 HUMAN SUBJECTS PROTECTIONS 
11.1 RATIONALE FOR SUBJECT SELECTION
Adult patients will be invited to enroll onto this trial if they are already enrolled on the Natural 
History Protocol (NIH 16C0151) and meet the eligibility criteria outlined in Section 2.1.  No 
gender, racial or ethnic groups will be excluded from participation in this trial.  Only English-
speaking individuals will be invited to enroll in this trial, given that the PROs questionnaires 
utilized in this study have not been validated in other languages.  
11.2 PARTICIPATION OF CHILDREN
This protocol will not include those less than 18 years old since the patients will be only 
recruited from the Natural History Protocol (NIH 16C0151), and the patient population for that 
study is  18.
11.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired.  In such cases, subjects would be removed from the study. 
11.4 RISK/BENEFIT ASSESSMENT
11.4.1 Known Potential Risks
Though infrequent, side effects of VR headset use reported by the manufacturers include motion 
sickness, dizziness, eyestrain, headaches, or other visual abnormalities, as well as a small number 
of individuals (up to 0.025%) reporting seizures.  For seizure risk mitigation, individuals with 
epilepsy or seizures within the last 6 weeks will be excluded from the trial.  In addition, the 
relaxation scenarios on the VR headsets will not include any flashing lights that might trigger 
seizure activity in participants.  Any participant that experiences a seizure while using the VR 
headset will be instructed to discontinue use immediately and notify NOB research staff, at 
which point the adverse event will be reported and they will come off study. 
While there is scant past research using similar VR headset devices for symptomatic 
improvement in PBT patients, literature in solid tumor patients was reviewed and revealed very 
few side effects reported by participants in experimental studies using VR (33, 41, 47, 82), none 
of which were serious or life-threatening.  Should participants experience any unpleasant or 
serious side effects while using the Pico G2 4K device used in this study, they will be instructed 
to discontinue use and notify NOB research staff immediately.  Additionally, we will be 
collecting PRO-CTCAEs information related to any adverse effects related to use of the headset 
for each participant at 3 of the 4 timepoints in this study, which will be helpful for monitoring for 
and reducing risks associated with the VR headset. 
An additional potential risk relates to the physical safety of the participant while using the VR 
device, which the device manufacturer provides recommendations for.  All study participants 
will be instructed to use the Pico G2 4K headset while in a seated position in a safe environment 
in order to mitigate risk for injury, given that individuals will lose awareness of the real world 
and their body position in it while immersed in the virtual relaxation environments.  These 

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instructions will be reviewed with participants at study entry and reinforced throughout the 
duration of the study by research staff.   
11.4.2 Known Potential Benefits
While VR has been used in clinical populations for the last 2 decades, there is little data in 
oncology populations, thus its potential benefits for symptomatic improvement in PBT patients is 
relatively unknown.  However, a systematic review of literature of VR interventions in primarily 
solid tumor patients revealed promising improvements in patient anxiety (42, 48, 83), pain or 
physical discomfort (43, 45, 83, 84), and distress (44, 45, 84), with near universal reporting that 
it was an effective distraction tool that promoted relaxation.  For the purposes of this study, 
immediate potential benefits for PBT participants include improvements in psychological 
symptoms they experience at the time of clinical evaluation (i.e. distress and anxiety), as 
described in the protocol background sections.  Longer-term potential benefits include 
improvements in overall symptom burden and quality of life, greater ability to tolerate oncologic 
therapies, increased ability to self-manage their psychological symptoms, and improved overall 
survival.  
11.4.3 Assessment of Potential Risks and Benefits
The potential benefits to subjects that participate in this study include improvements in their 
psychological health (particularly psychological distress and anxiety), which may or may not 
have a favorable impact on symptoms and/or survival.  The potential risks for patients 
participating in this study are related to use of the VR Pico G2 4K headset, both in terms side 
effects experienced and physical safety while using the device.  
11.5 CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant for review prior to consenting.  A designated study investigator will carefully explain 
the procedures and tests involved in this study, and the associated risks, discomforts and benefits.  
In order to minimize potential coercion, as much time as is needed to review the document will 
be given, including an opportunity to discuss it with friends, family members and/or other 
advisors, and to ask questions of any designated study investigator.  A signed informed consent 
document will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
policy, including HRPP Policy 303) per discretion of the designated study investigator and with 
the agreement of the participant/consent designee(s).  Whether in person or remote, the privacy 
of the subject will be maintained.  Consenting investigators (and participant/consent designee, 
when in person) will be located in a private area (e.g., clinic consult room).  When consent is 
conducted remotely, the participant/consent designee will be informed of the private nature of 
the discussion and will be encouraged to relocate to a more private setting if needed.  A 
templated PowerPoint, covering all aspects of the consent form, may be utilized by consenting 
investigators during remote consents for ease of viewing and to aid participant understanding.
Note: When required, witness signature will be obtained similarly as described for the 
investigator and participant as described below.

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Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic) signature on the electronic document.  When required, witness signature will be 
obtained similarly as described for the investigator and participant. 
Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent at 
the NIH Clinical Center, this study will use the following to obtain the required signatures:

Adobe platform (which is not 21 CFR Part 11 compliant); or,  

iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the same 
screen may be used when in the same location but is not required.  
Both the investigator and the participant will sign the document using a finger, stylus or mouse. 
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process 
for additional information (e.g., verification of participant identity when obtaining consent 
remotely) 
found 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
12 REGULATORY AND OPERATIONAL CONSIDERATIONS 
12.1 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 and 
investigators.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) 
will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and 
will provide the reason(s) for the termination or suspension.  Study participants will be 
contacted, as applicable, and be informed of changes to study visit schedule.
 Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

Demonstration of efficacy that would warrant stopping   

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

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, IRB and as applicable Food and Drug Administration (FDA).

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12.2 QUALITY ASSURANCE AND QUALITY CONTROL
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management 
plan will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated.  Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Council on 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities.
12.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical or device 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 National 
Cancer Institute 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.
12.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators 
and their staff. This confidentiality is extended to cover testing of biological samples and genetic 
tests in addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party 
without prior written approval of the appropriate parties. 
All research activities will be conducted in as private a setting as possible.
The study monitor, representatives of the Institutional Review Board (IRB), and/or regulatory 
agencies may inspect all documents and records required to be maintained by the investigator, 
including but not limited to, medical records (office, clinic, or hospital) and pharmacy records 
for the participants in this study. The clinical study site will permit access to such records.
The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB or Institutional policies.

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Study participant research data, which is for purposes of statistical and scientific reporting, will 
be transmitted to and stored at NCI CCR.  This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems 
used by the clinical site and by NCI CCR research staff will be secured and password protected. 
At the end of the study, all study databases will be archived at the NIH Clinical Center.
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants.
13 DEVICE INFORMATION  
There will be no IDE obtained for the use the PICO G2 4K headset with Applied VR software 
used in this study based on FDA’s guidance, Policy for Device Software Functions and Mobile 
Medical Applications. The FDA has indicated in the guidance that they will apply regulatory 
oversight only to those software functions that are medical devices and whose functionality 
could pose a risk to a participant’s safety if the device were to not function as intended. This 
device is similar to the non-exhaustive list of devices provided in Appendix B of the guidance. It 
is designed to manage psychiatric symptoms and its malfunction will not cause the participant 
additional harm.
The Applied VR software was designed by Applied VR company for therapeutic use in clinical 
populations, which aims to improve adverse symptomatology and promote relaxation in 
participants.  
13.1 PICO G2 4K VR HEADSET WITH APPLIED VR SOFTWARE
Pico G2 4K is a lightweight stand-alone VR headset that comes with an orientation-tracked 
controller and does not require a smartphone or a PC to run.  The headset provides the user with 
a premium viewing experience that features a 4K LCD 3840 X 2160 5.5-inch display with blue 
ray reduction, a refresh rate of 75 hertz, and 615 pixels per inch (PPI).  The headset features a 
Qualcomm Snapdragon 835 central processing unit (CPU) with 4G high-speed LPDDR4-1866 
RAM to run virtual content and a battery that allows 3 hours of continuous use.  
The following use instructions and health and safety information is provided by the manufacturer 
and will be reviewed with participants prior to use.   A trained study staff member will be present 
in the telehealth meeting during initial use of the headset to ensure participant safety and monitor 
for any adverse symptoms or events.
Participants using the VR headset may experience side effects common to users of VR and those 
who view 3D video, including motion sickness, dizziness, eye strain, headaches, and other visual 

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abnormalities.  If an individual experiences any of these symptoms, they will be asked to stop 
using the device and to notify NOB research staff immediately.
A small number of participants (up to 0.025%) may experience seizures or severe symptoms 
(e.g. disorientation, nausea, or drowsiness) upon viewing the VR scenarios.  Seizures from 
flashing lights are more common in children and epileptic individuals (who are excluded from 
use in this trial).  Importantly, flashing lights are not present in the VR experiences built into the 
Pico G2 4K headset.  If any seizure activity occurs while a participant is using the headset, the 
intervention will be discontinued, clinical staff will be notified, the adverse event will be 
reported, and the participant will come off study.
Some individuals may find the VR headset uncomfortable to wear or may feel it to be confining.  
Research staff will assist participants with adjusting the fit of the headset during the initial use..  
Comfort and fit information related to the VR headset will be collected from participants by 
NOB research staff during a qualitative interview.
To date, individuals with claustrophobia have not reported discomfort using this VR headset, as 
this type of therapy is often utilized for treatment of that condition.  Nevertheless, those 
previously diagnosed with claustrophobia will be excluded for the purposes of this clinical trial.
The VR headset does not support focus adjustment, so participants should continue use of 
glasses/contacts if they have poor eyesight.
Refer to Pico G2 4K User Manual for additional information.
13.1.1 Source/Acquisition and Accountability 
Applied VR Company will supply Pico G2 4K headsets  with Applied VR Software under Tech 
Transfer Agreement Collaboration Agreement 45562-19.

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15 APPENDICES
15.1 STUDY PROTOCOL FLOW DIAGRAM

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15.2 SALIVARY BIOSPECIMEN COLLECTION INFORMATION SHEET
 Optional

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15.3 STUDY INSTRUMENTS
The following study instruments, forms and questionnaires are maintained and provided 
separately from the protocol document include the following:

National Comprehensive Cancer Network (NCCN) Distress Thermometer (DT)

State-Trait Anxiety Inventory, 6-Item Short-Form (STAI-6)

UCLA Loneliness Scale

Comprehensive Score for Financial Toxicity (COST)

Adjustment Disorder New Module 20-Item

Virtual Reality Qualitative Interview Guide, including Was It Worth It (WIWI)

SootheVR QuickStart Guide

SootheVR Care and Cleaning Information
The following study instruments are provided in the protocol and are cross-referenced:

Study Protocol Flow Diagram Section 15.1

Salivary Biospecimen Collection Information Sheet 15.2