Randomized Pilot Crossover Study Comparing Virtual Reality (VR) and Non-VR Distraction for Decreasing Preoperative/Procedural Anxiety as a Function of the Modified Yale Preoperative Anxiety Scale (mYPAS)
Phase: NA
Conditions: Preoperative Anxiety
Sponsor: University of Texas Southwestern Medical Center

STUDY PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
Official title: Randomized Pilot Crossover Study Comparing Virtual 
Reality (VR) and Non-VR Distraction (other Child Life guided activities) 
for Decreasing Preoperative/Procedural Anxiety as a Function of the 
modified Yale Preoperative Anxiety Scale (mYPAS) 
 
 
NCT number: NCT05094141 
IRB Approved Document date: 06-12-2024 

 
STU2020-0607, Rebstock, FormA-Protocol, Mod_7, 06-12-24 (4) 
 
 
 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center. 
Do not disclose or use except as authorized in writing by the study sponsor. 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016, 12/2018 
 
 
STU-2020-0607 
Randomized Pilot Crossover Study Comparing Virtual Reality (VR) and Non-VR Distraction (other Child 
Life guided activities) for Decreasing Preoperative/Procedural Anxiety as a Function of the modified Yale 
Preoperative Anxiety Scale (mYPAS) 
 
 
Principal Investigator: 
 
Sarah Rebstock M.D 
Children’s Medical Center, 
1935 Medical District Dr, Dallas, Tx sarah.rebstock@utsouthwestern.edu 
 
 
 
 
 
Biostatistician: 
Paul Nakonezny, PhD 
Peter O’Donnell Jr. School of Public Health 
University of Texas Southwestern Medical Center 
 
 
Study Drug/Treatment: 
mYPAS scoring while playing VR device versus non-VR distraction for 
Port access 
 
 
Funding Source: 
The University of Texas Southwestern Medical Center, Department of 
Anesthesiology and Pain Medicine 
 
 
Initial version: 
Version 5.0, 26Apr2022 
 
 
UT Southwestern Medical Center (UTSW) 
Harold C. Simmons Comprehensive Cancer Center 
Attn: Clinical Research Office 
5323 Harry Hines Blvd. MC 9179 
Dallas, Texas 75390-9179 

 
STU2020-0607, Rebstock, FormA-Protocol, Mod_7, 06-12-24 (4) 
 
 
 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center. 
Do not disclose or use except as authorized in writing by the study sponsor. 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016, 12/2018 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
Amendment/Version # Version 6.0, 29May2024 
 
STU-2020-0607 
Randomized Pilot Within Groups Comparison of VR and Non-VR Distraction to Decrease 
Preoperative/Procedural Anxiety as a Function of the modified Yale Preoperative Anxiety Scale (mYPAS) 
 
 
Principal Investigator (PI) Name: Sarah Rebstock, MD 
 
 
 
PI Signature:  
 
 
Date: 

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STU-2020-0607 
Randomized Pilot Crossover Study Comparing Virtual Reality (VR) and Non-VR Distraction for Decreasing 
Preoperative/Procedural Anxiety as a Function of the modified Yale Preoperative Anxiety Scale (mYPAS) 
 
STU2020-0607, Rebstock, FormA-Protocol, Mod_7, 06-12-24 (4) 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................................. 1 
STUDY SCHEMA ............................................................................................................................ 2 
STUDY SUMMARY ......................................................................................................................... 3 
1.0 
BACKGROUND AND RATIONALE ........................................................................ 4 
1.1 
Disease Background ........................................................................................................ 4 
1.2 
Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities .................. 4 
1.3 
Other Agents .................................................................................................................... 4 
1.4 
Rationale .......................................................................................................................... 4 
2.0 
STUDY OBJECTIVES.............................................................................................. 5 
2.1 
Primary Objectives ........................................................................................................... 5 
2.2 
Secondary Objectives ...................................................................................................... 6 
2.3 
Endpoints ......................................................................................................................... 6 
3.0 
SUBJECT ELIGIBILITY ........................................................................................... 6 
3.1 
Inclusion Criteria ............................................................................................. 6 
3.2 
Exclusion Criteria ............................................................................................ 6 
4.0 
STUDY PROCEDURES ......................................................................................................... 6 
4.1 
Screening/Baseline Procedures ..................................................................... 6 
4.2 
Procedures During Treatment ........................................................................ 7 
4.3 
Follow-up Procedures ..................................................................................... 8 
4.4 
Removal of Subjects from Study .................................................................... 9 
5.0 
SAFETY MONITORING ......................................................................................................... 9 
5.1 
Definition of an Adverse Event ....................................................................... 9 

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Randomized Pilot Crossover Study Comparing Virtual Reality (VR) and Non-VR Distraction for Decreasing 
Preoperative/Procedural Anxiety as a Function of the modified Yale Preoperative Anxiety Scale (mYPAS) 
 
STU2020-0607, Rebstock, FormA-Protocol, Mod_7, 06-12-24 (4) 
 
 
 
 
 
5.2 
Data and Safety Monitoring Plan .................................................................... 9 
6.0 
TREATMENT INFORMATION ................................................................................. 9 
6.1 
Potential Risks of VR distraction ...................................................................................... 9 
7.0 
STATISTICAL CONSIDERATIONS .................................................................................... 10 
7.1 
Study Design/Study Endpoints ........................................................................................ 10 
7.2 
Sample Size and Accrual ................................................................................................. 10 
7.3 
Data Analyses Plans ........................................................................................................ 10 
7.4 
Interim Analysis Plan ....................................................................................................... 11 
8.0 
STUDY MANAGEMENT ...................................................................................................... 13 
8.1 
Conflict of Interest ............................................................................................................ 13 
8.2 
Institutional Review Board (IRB) Approval and Consent ............................................... 14 
8.3 
Registration/Randomization Procedures ....................................................................... 15 
8.4 
Data Management and Monitoring/Auditing .................................................................. 16 
8.5 
Adherence to the Protocol ............................................................................................. 17 
8.6 
Amendments to the Protocol ......................................................................................... 18 
8.7 
Record Retention ........................................................................................................... 19 
8.8 
Obligations of Investigators ........................................................................................... 19 
9.0 
REFERENCES ................................................................................................................... 19 
10.0 
APPENDICES .................................................................................................................... 20 
10.1 
Subject Demographics ................................................................................................... 20 
10.2 
Parent VR Group Questionnaire ..................................................................................... 20 
10.3 
Parent Control Group Questionnaire ............................................................................. 20 
10.4 
Study datasheet ............................................................................................................. 21 

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Randomized Pilot Crossover Study Comparing Virtual Reality (VR) and Non-VR Distraction for Decreasing 
Preoperative/Procedural Anxiety as a Function of the modified Yale Preoperative Anxiety Scale (mYPAS) 
 
STU2020-0607, Rebstock, FormA-Protocol, Mod_7, 06-12-24 (4) 
 
 
 
 
 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
CCBD 
Center for Cancer and Blood Disorders 
CHST 
Children’s Health System Texas 
CMC 
Children’s Medical Center as an entity of Children’s Health System Texas 
DOT 
Disease Oriented Team 
DSMC 
Data Safety Monitoring Committee 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IQR 
Inter-quartile range 
IRB 
Institutional Review Board 
IV (or iv) 
Intravenously 
LAR 
Legally Authorized Representative 
mYPAS 
modified Yale Preoperative Anxiety Scale 
Non-VR 
Child Life Guided distraction not including Virtual Reality 
SAE 
Serious Adverse Event 
SCCC 
Simmons Comprehensive Cancer Center 
SOC 
Standard of Care 
UPIRSO 
Unanticipated Problems Involving Risk to Subjects or Others 
UTSW 
University of Texas Southwestern Medical School 
VR 
Virtual Reality 

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Randomized Pilot Crossover Study Comparing Virtual Reality (VR) and Non-VR Distraction for Decreasing 
Preoperative/Procedural Anxiety as a Function of the modified Yale Preoperative Anxiety Scale (mYPAS) 
 
STU2020-0607, Rebstock, FormA-Protocol, Mod_7, 06-12-24 (4) 
 
 
 
 
 
 
STUDY SUMMARY 
Title 
Randomized Pilot Crossover Study Comparing Virtual Reality (VR) and 
Non-VR Distraction for Decreasing Preoperative/Procedural Anxiety as a 
Function of the modified Yale Preoperative Anxiety Scale (mYPAS) 
Short Title 
VR-mYPAS study 
Protocol Number 
STU-2020-0607 
Phase 
Pilot 
Methodology 
Cross Over Design 
Study Duration 
Up to two years 
Study Center(s) 
Single-center – Children’s medical center, Dallas, Texas 
Objectives 
To use the modified Yale Preoperative Anxiety Scale (mYPAS) to 
evaluate children prior to and during Port access, to look for a decrease 
preoperative anxiety during distraction in pediatric oncology patients 
undergoing port access. 
Number of Subjects 
77 patients 
Diagnosis and Main 
Inclusion Criteria 
CCBD patients requiring port access twice within a year 
Study Product(s), Dose, 
Route, Regimen 
mYPAS scoring while playing VR device versus non-VR distraction for 
Port access 
Duration of administration 
~ 15 minutes maximum (observation and completion of questionnaires 
after 10-minute familiarization with distraction method, during port 
access) 
Reference therapy 
N/A 
Statistical Methodology 
Cross over study will be performed. Subjects will be randomized (1 to 1 
randomization via Proc Plan in SAS 9.4) at their initial encounter to either 
VR or Non-VR. During their second visit patients will be given the 
alternative mode of care (i.e. patients who initially received VR distraction 
will be given Non-VR distraction, and patients who initially received Non- 
VR distraction will receive VR distraction) 

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STU-2020-0607 
Randomized Pilot Crossover Study Comparing Virtual Reality (VR) and Non-VR Distraction for Decreasing 
Preoperative/Procedural Anxiety as a Function of the modified Yale Preoperative Anxiety Scale (mYPAS) 
 
STU2020-0607, Rebstock, FormA-Protocol, Mod_7, 06-12-24 (4) 
 
 
 
 
 
 
1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Disease Background 
Pre-operative anxiety is common in children, with 50-70% of children 
experiencing it on 
the day of procedure (1). Children undergoing cancer treatment need multiple 
procedures throughout their course of treatment. Preprocedural anxiety can be 
particularly high in this group as the disruption to daily life, physical appearance, 
and the nature of therapy to include procedures, is aggressive to preserve health 
and life. 
 
1.2 
Study Agent(s)/Therapy(ies) Background and Associated Known 
Toxicities 
The mYPAS observational scale will be used to assess VR and non-VR 
distraction for decreasing preoperative/procedural anxiety in pediatric oncology 
patients undergoing port access. It is an observational scale that consists of five 
domains (activity, emotional expressivity, state of arousal, vocalization and use of 
parents) and has shown good to excellent inter-observer reliability (2). It can be 
applied to children two years and older although it was validated for use in the 5- 
12 age group (2). 
 
VR technology can be used as a distractor to decrease preoperative/procedural 
anxiety in pediatric oncology patients undergoing port access. Side effects of VR 
technology are minimal but include motion sickness and nausea. 
 
1.3 
Other Agents 
Child Life guided activities for pre- and intraprocedural distraction for anxiety 
management. 
 
1.4 
Rationale 
The purpose of the research study is to evaluate the use of VR as a distractor to 
decrease preoperative/procedural anxiety in pediatric oncology patients 
undergoing port access. In a study looking at the use of VR for needle-related 
procedural pain and distress in children and adolescents in a pediatric oncology 
unit, while the quantitative data did not show reduction of pain and distress in the 
VR group, results from observational pain scores showed a decrease, and the 
interviews indicated that using VR could be a positive experience (3). In a study 
of pediatric burn patients, another population that requires repeated procedures, 
the patients randomized to the VR group had significantly lower pain and anxiety 
scores as well as achieved faster healing rates (4). 
 
Most of the studies on VR used pain assessment scales like faces pain scale, 
visual analogue scale and FLACC focusing on its effect on pain rather than 
anxiety (3-6). There have been few studies examining the use of VR as a tool to 
decrease preoperative/procedural anxiety and even fewer studies utilizing the 

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Randomized Pilot Crossover Study Comparing Virtual Reality (VR) and Non-VR Distraction for Decreasing 
Preoperative/Procedural Anxiety as a Function of the modified Yale Preoperative Anxiety Scale (mYPAS) 
 
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mYPAS to assess the effect of VR on preoperative anxiety in children. The 
mYPAS is now considered the gold standard in assessing preoperative anxiety in 
children (1,2) 
 
VR can be a safe, non-pharmacologic way, of decreasing preoperative anxiety 
with minimal side effects, improving quality of care, patient experience and 
satisfaction. CHST currently uses the Kind VR device in house as a method of 
procedural distraction in various locations. Kind VR is a research-based 
company that has partnered with several research hospitals in the United States 
and Canada. Areas of research where the kind VR device has been used 
includes vaso-occlusive crisis in children with sickle cell disease, pediatric cancer 
patients needing port access procedures, Emergency Room patients needing IV 
placement or laceration repair and in children needing surgical procedures to 
help with preoperative stress.7 A study of Virtual reality on children with sickle cell 
disease vaso-occlusive crisis concluded that The Kind VR Aqua software was 
able to provide distraction through total immersion.8 Another study using Kind VR 
was able to demonstrate the safety of VR interventions in children and 
adolescents with cancer undergoing port access procedure.5 CHST and this 
research group are not partnering entities with the Kind VR, and the Kind VR 
device is not being studied. The effect of virtual reality (VR) on preprocedural 
anxiety as measured by questionnaires and the observations of the modified 
Yale Preoperative Anxiety Scale (mYPAS) is being studied. 
 
If VR proves clinically useful in decreasing pre-op anxiety, patients may 
potentially allow clinicians to treat them for any number of ailments using 
interactive VR in lieu of, or at decreased requirement for, medicinal anxiolysis or 
anesthesia. Avoiding and minimizing sedation can potentially decrease length of 
post anesthesia recovery room stay. In addition, physical therapy is a big part of 
rehabilitation for pediatric pain patients. By distracting patients from pain and 
anxiety, VR can help patients improve function and range of motion during 
physical therapy, decreasing days away from school and promoting return to 
normal activities faster. Looking at post anesthesia recovery room length of stay 
with and without VR and range of motion/outcome of physical therapy with and 
without VR are areas of potential further studies. 
 
 
2.0 
STUDY OBJECTIVES 
 
2.1 
Primary Objectives 
2.1.1 
To utilize the modified Yale Preoperative Anxiety Scale (mYPAS), a 
validated preoperative/procedural anxiety score, to decrease 
preoperative anxiety via distraction in pediatric oncology patients 
(primary outcome). 

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Randomized Pilot Crossover Study Comparing Virtual Reality (VR) and Non-VR Distraction for Decreasing 
Preoperative/Procedural Anxiety as a Function of the modified Yale Preoperative Anxiety Scale (mYPAS) 
 
STU2020-0607, Rebstock, FormA-Protocol, Mod_7, 06-12-24 (4) 
 
 
 
 
 
 
2.2 
Secondary Objectives 
2.2.1 
Parents or legally authorized representative (LAR) subjective report 
decreased anxiety with the use of VR (secondary outcome). 
 
2.3 
Endpoints 
2.3.1 
We expect to see statistically significant changes in the 
preoperative anxiety scores using the mYPAS when the VR group 
is compared to the non-VR group. 
2.3.2 
We expect parents or the legally authorized representative (LAR) 
to subjectively report decreased anxiety with the use of VR. 
 
 
3.0 
SUBJECT ELIGIBILITY 
Eligibility waivers are not permitted. Subjects must meet all the inclusion and 
exclusion criteria to be registered to the study. Study treatment may not begin 
until a subject is registered. 
 
3.1 
Inclusion Criteria 
3.1.1 
Any patient of the Children’s Medical Center CCBD 
3.1.2 
5-18 years of age 
3.1.3 
Patient requiring their port accessed twice or more within a 
year 
3.1.4 
Ability to understand and the willingness to sign a written informed 
consent. 
 
3.2 
Exclusion Criteria 
3.2.1 
Subjects younger than 5 and older than 18 
3.2.2 
Patients requiring recovery in PICU or sites other than PACU 
3.2.3 
If parents or subject is not willing to participate 
3.2.4 
Subjects with severe developmental delays and subjects with 
developmental challenges preventing them from keeping the VR 
device on are also excluded 
3.2.5 
Patients who will not be in CCBD for port access at least twice 
within a year 
 
4.0 
STUDY PROCEDURES 
 
4.1 
Screening/Baseline Procedures 
Potential subjects will be identified from the CCBD schedule. Subjects are not 
patients of the study investigator, so a member of the study staff will request 
permission from the treating team to approach and include subjects in the study. 

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Randomized Pilot Crossover Study Comparing Virtual Reality (VR) and Non-VR Distraction for Decreasing 
Preoperative/Procedural Anxiety as a Function of the modified Yale Preoperative Anxiety Scale (mYPAS) 
 
STU2020-0607, Rebstock, FormA-Protocol, Mod_7, 06-12-24 (4) 
 
 
 
 
 
 
The legal authorization of parents to be approached will be verified by a member 
of the study team before approaching them in the preoperative holding area. 
 
The study will be explained to the subject (if old enough to participate in 
discussion) and the parents on a telephone call the night before the CCBD visit in 
order to determine interest in participation.. It will be explained that participation 
is completely voluntary and that whether they choose to participate or not will not 
affect their treatment in our facility. They will be given ample time to consider 
participation and ask any questions they may have with the study doctor and 
their treating physician. The next day, in clinic, it will be verified if they are still 
interested in participating, all questions will be answered by a member of the 
research team in the room virtually on the CHST telemedicine tablet platform. If 
they agree, written informed consent will be obtained and a copy of the signed 
consent form will be given to the subject’s LAR by their nurse or child life 
specialist. 
 
Children’s Medical Center has a large Hispanic population; therefore, the study 
will be discussed using a certified on-site Spanish translator, or virtual platform 
Spanish translator if this language barrier exists. A Spanish version of the parent 
questionnaires and the  consent form will be provided. 
 
4.2 
Procedures During Treatment 
Once it is confirmed that the subject qualifies and the parents (LARs) are willing 
to participate, the parents (LARs) will be given the demographics form to fill out 
and the subject will be randomized in the study system. Whether the patient 
participates in the Virtual Reality group or the Non-Virtual Reality group first will 
depend on a computerized randomization process independent of the study 
researchers. 
 
For the Non-virtual reality group, a member of the study team will evaluate the 
patient using the mYPAS prior to port access. Parents will be asked to fill out a 
questionnaire evaluating their child’s preoperative anxiety after port access is 
complete (see study schema). 
 
For the port access with virtual reality (VR) distraction, the patient will be able to 
play the VR game for 15 minutes prior to actual port access procedure start. 
During this first 5-15 minutes of being in their CCBD procedure/infusion room 
with the placement of the VR headset, a researcher will be doing the first 
mYPAS observation and scoring (Holding).  The patient will then continue to play 
the game through the port access procedure.  The point where the port access 
kit is opened by the nurse marks the start of the Port access portion of the 
mYPAS observation (Induction 1).  The end of the second mYPAS observation is 
when the Tegaderm dressing is applied to the port access needle.  
 
After port access is complete with VR, or control, the parents or LAR will then be 
asked to fill out a questionnaire assessing their child’s perioperative anxiety. 

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Randomized Pilot Crossover Study Comparing Virtual Reality (VR) and Non-VR Distraction for Decreasing 
Preoperative/Procedural Anxiety as a Function of the modified Yale Preoperative Anxiety Scale (mYPAS) 
 
STU2020-0607, Rebstock, FormA-Protocol, Mod_7, 06-12-24 (4) 
 
 
 
 
 
 
NOTE: For safety of the researchers and patients, all mYPAS patient 
observations on day of CCBD visit, as well as any further consent questions, will 
be performed through a virtual telemedicine platform with approved tablets run 
and vetted by telemedicine at Children’s Health System of Texas (CHST).  The 
process has already been approved and vetted by CHST telemedicine so that 
there is little to no risk of virtual PHI breach.  The observation of the patients will 
be done in real time with no recording of the encounter.  Tablets are currently in 
place from CHST, and nursing and Child Life are informed of process. 
 
4.3 
Follow-up Procedures 
We will examine the CCBD schedule for the second opportunity to include each 
subject and complete the study in the other study arm (VR-distraction or Non-VR 
distraction). Surveys and Assessments will be filled out twice: once without the 
use of VR (control group) and the second time with the use of VR (study group).

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Randomized Pilot Crossover Study Comparing Virtual Reality (VR) and Non-VR Distraction for Decreasing 
Preoperative/Procedural Anxiety as a Function of the modified Yale Preoperative Anxiety Scale (mYPAS) 
 
STU2020-0607, Rebstock, FormA-Protocol, Mod_7, 06-12-24 (4) 
 
 
 
 
 
Data collected will be compared and analyzed for statistically significant 
difference in anxiety scores with mYPAS. Parents’ questionnaires will also be 
scored and evaluated for subjective improvement in parental assessment of 
preoperative anxiety. 
 
All the study forms and questionnaires will be identified with the unique study ID 
number assigned in the study system with no other identifying data. There are no 
additional procedures outside the standard of care participants would normally 
receive. There will be no additional costs to subjects for participating in this 
study. 
 
4.4 
Removal of Subjects from Study 
Subjects can be taken off the study treatment and/or study at any time at their 
own request or if deemed necessary by the study team due to distress. 
 
5.0 
SAFETY MONIITORING 
 
5.1 
Definition of an Adverse Event 
Any issues experienced while being observed by the research team should be 
recorded as a potential adverse event for evaluation by the PI as to the 
seriousness, relatedness, and expectedness in relation to the study. 
 
It is expected that a patient may experience some discomfort or motion sickness 
while using VR. 
 
5.2 
Data and Safety Monitoring Plan 
The researchers will be monitoring should a patient encounter any issues, 
particularly any discomfort or motion sickness while using the VR device. If so, 
the VR device will be removed, and the subject will be eliminated from the study. 
 
The study staff will record all concerns experienced by enrolled subjects, the total 
number of side effects experienced by all enrolled subjects, and the number of 
subjects eliminated from the study due to side effects. 
 
□ Reporting requirement: The principal investigator will oversee the subject 
safety and data records and report all pertinent information to the IRB, as 
necessary. 
 
6.0 
TREATMENT INFORMATION 
 
6.1 
Potential Risks of VR distraction 
While this study is considered low risk, patient discomfort and motion sickness 
are potential risks. Should a patient experience any discomfort or motion 

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Randomized Pilot Crossover Study Comparing Virtual Reality (VR) and Non-VR Distraction for Decreasing 
Preoperative/Procedural Anxiety as a Function of the modified Yale Preoperative Anxiety Scale (mYPAS) 
 
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sickness, VR device will be removed, and the subject will be excluded from 
study. Disposable VR covers will be used, and device will be sanitized between 
patients to minimize risk of infection. 
 
There is a risk of the loss of confidentiality, but measures will be taken to 
minimize this risk, such as only the named study staff will be handling the study 
forms and all the subjects will be assigned unique study numbers. The only 
document that could identify a patient is the informed consent that would be 
linked to a study participant by a study number.  These informed consents will 
be kept in a locked cabinet in the locked office of the principal investigator.  No 
other identifiers will be collected as a part of the research data that links a  
study number to the patient PHI. 
 
For the safety of the researchers and patients, all mYPAS patient observations 
on day of CCBD visit, as well as any further consent questions, will be 
performed through a virtual telemedicine platform with approved tablets run and 
vetted by telemedicine at Children’s Health System of Texas (CHST).  The 
process has already been approved and vetted by CHST telemedicine so that 
there is little to no risk of virtual PHI breach. 
 
7.0 
STATISTICAL CONSIDERATIONS 
 
7.1 
Design/Study Endpoints 
To assess the effect of the VR on children’s Modified Yale Preoperative Anxiety 
Scale (mYPAS), a cross over study will be performed. Subjects will be 
randomized (1 to 1 randomization via Proc Plan in SAS 9.4) at their initial 
encounter to either VR or Non-VR. During their second visit patients will be given 
the alternative mode of care (i.e. patients who initially received VR distraction will 
be given Non-VR distraction, and patients who initially received Non-VR 
distraction will receive VR distraction) 
 
7.2 
Sample Size and Accrual 
To fully power our study, we will recruit 77 patients to detect a difference of 3.5 in 
the mYPAS score; assuming a standard deviation of 10, a 10% reduction in 
patient participation due to attrition, and a power of 0.8. If attrition exceeds 10% 
additional post hoc power analysis will be performed. 
 
7.3 
Data Analyses 
Categorical outcomes will be presented as frequency and percentages and 
compared using chi-square and/or Fisher’s exact test. Continuous outcomes will 
be summarized by median and inter-quartile range (IQR) OR mean and standard 
deviation (depending on the data’s distribution). Depending on the data’s 
distribution a paired t-test or Wilcoxon-sign rank test will be performed to assess 
the difference between VR distraction and Non-VR distraction. For this crossover 
design a mixed model will also be implemented, which accounts for 

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treatment/intervention (VR vs. non-VR), sequence, and period as fixed effects.  
Patients will be nested within sequence. 
 
7.4.  Interim Analysis Plan 
 
Interim Analysis for Efficacy and Safety 
This two-sided symmetrical group sequential design, which is based upon the 
existing sample size specified in the protocol (N=77), has two planned stages: 1 
interim stage at information fraction 0.67 (n=52) and a final stage (N=77).  We 
will implement the two-sided O’Brien-Fleming methodology to monitor the clinical 
trial for early stopping because of efficacy or “safety” (exacerbated anxiety).  The 
latter is not anticipated, but will be evaluated.  We used the procedures of PROC 
SEQDESIGN in SAS to create the group sequential design by computing 
boundary values for the stages (based on the O’Brien-Fleming methodology).  
The boundary values are derived in such a way that the overall Type I (0.05) and 
Type II (0.20) error probability levels will be maintained in this design.  With early 
stopping to reject the null hypothesis, the lower rejection boundary is constructed 
by connecting the lower critical values (on the Z scale) for the stages.  Similarly, 
the upper rejection boundary is constructed by connecting the upper critical 
values (on the Z scale) for the stages.  See Table 1 and Figure 1 (boundary 
plot). 
 
We will then use the procedures of PROC SEQTEST in SAS to compare the 
obtained test statistic with these boundary values (at each stage) to evaluate the 
trial for stopping.  For this two-sided symmetrical group sequential design, a 
standardized Z test statistic will be computed by standardizing the estimate of 
the effect in Preoperative Anxiety, and a negative Z test statistic indicates a 
beneficial effect. Thus, at the interim stage, if the standardized Z test statistic is 
less than or equal to the corresponding lower alpha boundary value, the null 
hypothesis is rejected for efficacy and the trial will be considered for stopping.  
Conversely, while not anticipated, if the standardized Z test statistic is greater 
than or equal to the corresponding upper alpha boundary value, the null 
hypothesis is rejected for a “harmful/safety” effect (exacerbated anxiety) and the 
trial will be considered for stopping.  Otherwise, the process continues to the 
next stage.  At the final stage (stage 2), the null hypothesis is rejected for 
efficacy if the Z statistic is less than or equal to the corresponding lower alpha 
boundary value of -2.004, and the null hypothesis is rejected for a 
“harmful/safety” effect if the Z statistic is greater than or equal to the 
corresponding upper alpha boundary value of 2.004.  Otherwise, the null 
hypothesis is not rejected.  When the trial is stopped at either the interim stage 
or at the final stage, the SEQTEST procedure can also be used to derive 
parameter estimates, confidence limits for the parameter, and p-values for 
hypothesis testing. 
  
 

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Figure 1.   
Boundary Plot, which corresponds to the information in Table 1. 
 
Note.  Fixed Sample Design Critical Values (α=0.05 two-sided):  ±1.96.   
Note.  Two planned stages:  1 interim stage at information fraction 0.67 (n=52) 
and a final stage (N=77). 
 
Table 1.  
Nominal Critical Values and Alpha Levels for a two-sided symmetrical group sequential 
design, with 2 stages, for  Efficacy and Safety (O’Brien-Fleming, α=0.05 two-sided, β=0.20) 
 
 
Stage 
 
 
Sample Size (N) 
 
Nominal Critical 
Value 
(Z-value scale) 
 
Nominal Alpha Level 
Lower                   Upper 
 
Nominal Alpha 
Level 
(two-sided) 
1 
52 
±2.431 
0.00737             0.00737 
0.01474 
Final 
77 
±2.004 
0.02280             0.02280 
        0.04560 
Note.  Fixed Sample Design Critical Values (α=0.05 two-sided):  ±1.96. 
 
Interim Analysis for Futility 
Futility analyses are planned to be conducted to coincide in timing with the 
tentatively scheduled interim analysis for efficacy and “safety” at each stage of 

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information.  The stochastic curtailment method is adopted based on conditional 
power (Lan et al, 1982). The informal criterion for determination of futility is that 
at the interim stage, if the conditional power (defined as the probability of 
rejecting the null hypothesis of no effect once some data are available at each 
stage) is low (e.g., <20%), then a conclusion could be reached that it would be 
futile to continue the trial.  At this juncture, the research team will evaluate all 
study information to consider stopping the study for futility. The evaluation will be 
conducted in a blinded manner.  
 
Evaluation of futility using conditional power allows flexibility in that it can be 
calculated and assessed at any time during the study without inflation of the 
Type I error probability and that the threshold does not necessarily have to be 
pre-specified.  This approach to assessing futility holds appeal because it allows 
other information to be taken into consideration such as recruitment and safety 
data and conditional power at other alternative effect sizes (Freidlin B and Korn 
EL, 2002).  We will use the procedures of PROC SEQTEST in SAS to compute 
conditional power at each stage of the group sequential trial. 
 
8.0 
STUDY MANAGEMENT 
 
8.1 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, 
etc.) must have the conflict reviewed by the UTSW COI Committee and IRB 
according to UTSW Policy on Conflicts of Interest. All investigators will follow the 
University conflict of interest policy. 

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8.2 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations. The IRB must approve the 
consent form and protocol. 
 
In obtaining verbal or written informed consent and documentation, the 
investigator should comply with the applicable regulatory requirement(s) and 
should adhere to Good Clinical Practice (GCP) and to ethical principles that 
have their origin in the Declaration of Helsinki. 
 
Potential subjects will be identified from the CCBD schedule. Subjects are not 
patients of the study investigator, so a member of the study staff will request 
permission from the treating team to approach and include subjects in the study. 
The legal authorization of parents to be approached will be verified by a member 
of the study team before approaching them. The study will be explained to the 
subject (if old enough to participate in discussion) and the parents the night 
before their CCBD visit by a named member of the study team designated to 
perform the task of obtaining informed consent. It will be explained that 
participation is completely voluntary and that whether they choose to participate 
or not will not affect their treatment in our facility. They will be given ample time 
to consider participation and ask any questions they may have with the study 
team members and their treating physician. 
 
Once verbal consent from the LARs and verbal assent from study participant (if 
old enough to participate in the discussion) is obtained over the phone the 
night prior to the CCBD visit (see study schema), the researcher will prepare 
for the following day’s mYPAS observation. 
 
On the next day’s CCBD visit, when the patient is placed in their CCBD holding 
room prior to port access, it will be verified that they are still interested in 
participating. If the LAR or patient has any additional questions, the researcher 
will be in the room virtually on the CHST telemedicine tablet platform to answer 
any further questions. Then, written informed consent will be obtained and a 
copy of the signed consent form will be given to the subject’s LAR by their 
nurse or the child life specialist.  
 
Children’s Medical Center has a large Hispanic population; therefore, the study 
will be discussed using a certified on-site Spanish translator, if a language 
barrier exists. Fully translated Spanish versions of the parent questionnaires 
and the study consent form will be provided. 
 
The study PI will keep a list of study subjects on a firewalled Children’s Medical 
Center (Dallas Campus) computer which links study number with the study 
subject. This study subject list will be kept in a password protected file 
accessible only to the faculty mentor and the PI for the duration of the study. To 
protect PHI, this list will be deleted at the end of the study. 

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8.3 
Registration/Randomization Procedures 
All subjects must be registered with the CMC Anesthesiology Research Office 
before enrollment to study. Prior to registration, eligibility criteria must be 
confirmed with the Study Coordinator. 

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New subjects will receive a number beginning with 1-001 upon study consent 
such that the first subject consented is numbered 1-001, the second subject 
consented receives the number 1-002, etc. 
 
Upon confirmation of eligibility and enrollment as per the afore-mentioned 
instructions, the subject will be assigned a secondary number in the order of 
enrollment. For example, subject 1-001 will become 1-001-01 upon enrollment. If 
subject 1-002 screen fails, and subject 1-003 is the next subject enrolled, subject 
1-003 will become 1-003-02 and so-on. 
 
Each newly consented subject should be numbered using the schema provided 
above. Upon registration, the registrar will assign the additional 
registration/randomization code according to the numbering schema outlined 
above, which should then be entered as the patient study id in Velos upon 
updating the status to enrolled. 
 
To assess the effect of the VR on children’s Modified Yale Preoperative Anxiety 
Scale (mYPAS), a cross over study will be performed. Subjects will be 
randomized (1 to 1 randomization via Proc Plan in SAS 9.4) at their initial 
encounter to either VR or Non-VR. During their second visit patients will be given 
the alternative mode of care (i.e. patients who initially received VR distraction will 
be given Non-VR distraction, and patients who initially received Non-VR 
distraction will receive VR distraction). 
 
8.4 
Data Management and Monitoring/Auditing 
Only the subjects assigned unique study number will be used on study 
questionnaires, staff mYPAS assessments, and exclusion log. The only link to 
participants identity will be the electronic subject enrollment log, which will 
include only the name, date of port access appointments, medical record 
number, and unique study ID #. 
 
A password-protected computer file will be created, and all study data will be 
saved on a Children’s Medical Center computer, in the secure research file, kept 
behind the Children’s Health firewalled system. The secure research file will be 
limited access, only members of the study team will be given password access 
for the purpose of data analysis. 
 
At the conclusion of study enrollment, the data from the questionnaires and 
assessment forms will be transferred into the secure study REDCap database, 
and the paper forms will be properly discarded according to HIPPA standards at 
Children’s Health System. In addition, the electronic enrollment and exclusion log 
will also be properly discarded. No paper documents or link to study participants 
identities will be retained. 

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REDCap is the UTSW SCCC institutional choice for the electronic data capture 
of case report forms for SCCC Investigator Initiated Trials. REDCap will be used 
for electronic case report forms in accordance with Simmons Comprehensive 
Cancer Center requirements, as appropriate for the project. All the study data will 
be stored within the UTSW RedCap system, which is stored behind the secure 
UTSW firewall. 
 
The UTSW Simmons Comprehensive Cancer Center (SCCC) Data Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and 
patient safety for all UTSW SCCC clinical trials. As part of that responsibility, the 
DSMC reviews all local serious adverse events and UPIRSOs in real time as 
they are reported and reviews adverse events on a quarterly basis. The quality 
assurance activity for the Clinical Research Office provides for periodic auditing 
of clinical research documents to ensure data integrity and regulatory 
compliance. A copy of the DSMC plan is available upon request. 
 
The SCCC DSMC meets quarterly and conducts annual comprehensive reviews 
of ongoing clinical trials, for which it serves as the DSMC of record. The QAC 
works as part of the DSMC to conduct regular audits based on the level of risk. 
Audit findings are reviewed at the next available DSMC meeting. In this way, 
frequency of DSMC monitoring is dependent upon the level of risk. Risk level is 
determined by the DSMC Chairman and a number of factors such as the phase 
of the study; the type of investigational agent, device or intervention being 
studied; and monitoring required to ensure the safety of study subjects based on 
the associated risks of the study. Protocol-specific DSMC plans must be 
consistent with these principles. 
 
8.5 
Adherence to the Protocol 
Except for an emergency situation, in which proper care for the protection, safety, 
and well-being of the study subject requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol. 
 
8.5.1 
Exceptions (also called single-subject exceptions or single-subject 
waivers): include any departure from IRB-approved research that is 
not due to an emergency and is: 
• intentional on part of the investigator; or 
• in the investigator’s control; or 
• not intended as a systemic change (e.g., single-subject 
exceptions to eligibility [inclusion/exclusion] criteria) 
□ Reporting requirement: Exceptions are non-emergency 
deviations that require prospective IRB approval before being 
implemented. Call the IRB if your request is urgent. If IRB 
approval is not obtained beforehand, this constitutes a major 
deviation. 

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8.5.2 
Emergency Deviations: include any departure from IRB-approved 
research that is necessary to: 
• Avoid immediate apparent harm, or 
• Protect the life or physical well-being of subjects or others 
□ Reporting requirement: Emergency deviations must be 
promptly reported to the IRB within 5 working days of 
occurrence. 
 
8.5.3 
Major Deviations (also called violations): include any departure 
from IRB-approved research that: 
• Harmed or placed subject(s) or others at risk of harm (i.e., did or 
has the potential to negatively affect the safety, rights, or welfare 
of subjects or others), or 
• Affect data quality (e.g., the completeness, accuracy, reliability, 
or validity of the data) or the science of the research (e.g., the 
primary outcome/endpoint of the study) 
□ Reporting requirement: Major deviations must be promptly 
reported to the IRB within 5 working days of PI awareness. 
 
8.5.4 Minor Deviations: include any departure from IRB-approved 
research that: 
• 
Did not harm or place subject(s) or others at risk of harm (i.e., did 
not or did not have the potential to negatively affect the safety, 
rights, or welfare of subjects or others), or 
• 
Did not affect data quality (e.g., the completeness, accuracy, 
reliability, or validity of the data) or the science of the research 
(e.g., the primary outcome/endpoint of the study) 
□ Reporting requirement: Minor deviations should be tracked 
and summarized in the progress report at the next IRB 
continuing review. 
 
8.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be 
originated and documented by the Principal Investigator. A summary of changes 
document outlining proposed changes as well as rationale for changes, when 
appropriate, is highly recommended. When an amendment to the protocol 
substantially alters the study design or the potential risk to the patient, a revised 
consent form might be required. 
 
The written amendment, and if required the amended consent form, must be sent 
to the IRB for approval prior to implementation. 

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8.7 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or 
queries, source documents, Sponsor-Investigator correspondence, monitoring 
logs/letters, and regulatory documents (e.g., protocol and amendments, IRB 
correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. 
 
Government agency regulations and directives require that the study investigator 
retain all study documentation pertaining to the conduct of a clinical trial. In the 
case of a study with a drug seeking regulatory approval and marketing, these 
documents shall be retained for at least two years after the last approval of 
marketing application in an International Conference on Harmonization (ICH) 
region. In all other cases, study documents should be kept on file until three 
years after the completion and final study report of this investigational study. 
 
8.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki. The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients. The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study 
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations 
and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for 
assuring that all the required data will be collected and entered onto the Case 
Report Forms. Periodically, monitoring visits may be conducted and the Principal 
Investigator will provide access to his/her original records to permit verification of 
proper entry of data. At the completion of the study, all case report forms will be 
reviewed by the Principal Investigator and will require his/her final signature to 
verify the accuracy of the data. 
9.0 
REFERENCES 
1. 
Eijlers R, Dierckx B, Staals LM, et al. Virtual reality exposure before 
elective day care surgery to reduce anxiety and pain in children: A 
randomised controlled trial. Eur J Anaesthesiol. 2019;36(10):728-737. 
2. 
Kain ZN, Mayes LC, Cicchetti DV, Bagnall AL, Finley JD, Hofstadter MB. 
The Yale Preoperative Anxiety Scale: how does it compare with a "gold 
standard"? Anesth Analg. 1997;85(4):783-788. 
3. 
Nilsson S, Finnstrom B, Kokinsky E, Enskar K. The use of Virtual Reality 
for needle-related procedural pain and distress in children and 

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adolescents in a paediatric oncology unit. Eur J Oncol Nurs. 
2009;13(2):102-109. 
4. 
Brown NJ, Kimble RM, Rodger S, Ware RS, Cuttle L. Play and heal: 
randomized controlled trial of Ditto intervention efficacy on improving re- 
epithelialization in pediatric burns. Burns. 2014;40(2):204-213. 
5. 
Birnie KA, Kulandaivelu Y, Jibb L, et al. Usability Testing of an Interactive 
Virtual Reality Distraction Intervention to Reduce Procedural Pain in 
Children and Adolescents With Cancer [Formula: see text]. J Pediatr 
Oncol Nurs. 2018;35(6):406-416. 
6. 
Dunn A, Patterson J, Biega CF, et al. A Novel Clinician-Orchestrated 
Virtual Reality Platform for Distraction During Pediatric Intravenous 
Procedures in Children With Hemophilia: Randomized Controlled Trial. 
JMIR Serious Games. 2019;7(1):e10902. 
7. 
KindVR. https://www.kindvr.com/. Accessed 4/8/2020. 
8. 
Agrawal AK, Robertson S, Litwin L, et al. Virtual reality as complementary 
pain therapy in hospitalized patients with sickle cell disease. Pediatr 
Blood Cancer. 2019;66(2):e27525. 
9. 
O’Brien, P. C. and Fleming, T. R. (1979), “A Multiple Testing Procedure 
for Clinical Trials,” Biometrics, 35, 549–556 
10. 
Freidlin B, Korn EL. A comment on futility monitoring. Controlled Clinical 
Trials 2002; 23: 355-366. 
11. 
Lan KKG, Simon R, Halperin M. Stochastically curtailed tests in longterm 
clinical trials. Communications in Statistics – Sequential Analysis 1982; 1: 
207-219. 
 
10.0 
APPENDICES 
 
10.1 
Subject Demographics 
VR_mYPAS 
Demographics.docx 
 
10.2 
Parent VR Group Questionnaire 
VR_mYPAS Parent 
questionaire VR.doc 
 
10.3 
Parent Control Group Questionnaire 
VR_mYPAS Parent 
questionnaire_Cont 
 
 

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10.4 
Study Datasheet 
VR_mYPAS 
datasheet.xlsx