Preventing Post-Vaccination Presyncope and Syncope in Adolescents Using Simple, Clinic-based Interventions
Phase: NA
Conditions: Syncope, Vasovagal
Sponsor: Duke University

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 Preventing Post-Vaccination Presyncope and Syncope in Adolescents Using Simple, 
Clinic-based Interventions 
 
Short Title: Presyncope/Syncope Prevention Study (PS2) 
 
 
 
Centers for Disease Control and Prevention  
Clinical Immunization Safety Assessment (CISA) Project  
 
 
Lead Site Principal Investigator: Emmanuel B. Walter, MD, MPH 
 
Centers for Disease Control and Prevention (CDC) Principal Investigator:  
Theresa Harrington, MD, MPH&TM 
 
CDC Sub-principal Investigator: Karen Broder, MD 
 
 
 
 
NCT # (NCT04772755) 
 
Version Number: 2.0 
March 4, 2021 
 
 
 

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STATEMENT OF COMPLIANCE 
• 
This trial will be conducted in compliance with the protocol, the International 
Conference on Harmonization (ICH) Guideline E6-Good Clinical Practice (GCP), 
and the applicable guidelines and regulatory requirements from the United States 
(US) Code of Federal Regulations (CFR), 45 CFR Part 46. 
• 
All study personnel with subject contact have completed Human Subjects 
Protection Training. 
 
 
 

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TABLE OF CONTENTS 
 
PROTOCOL SUMMARY .............................................................................................................................................. 5 
1 BACKGROUND ......................................................................................................................................................... 8 
1.1 BACKGROUND ......................................................................................................................................................................... 8 
1.2 SUMMARY .............................................................................................................................................................................. 12 
2 STUDY OBJECTIVES ............................................................................................................................................ 13 
2.1 PRIMARY OBJECTIVE (PO): ............................................................................................................................................... 13 
2.2 SECONDARY OBJECTIVES (SO):......................................................................................................................................... 13 
2.3 EXPLORATORY OBJECTIVES (EO): .................................................................................................................................... 13 
3 STUDY OUTCOME MEASURES AS RELATED TO OBJECTIVES ............................................................... 14 
3.1 PRIMARY OUTCOME MEASURES (POM): ........................................................................................................................ 14 
3.2 SECONDARY OUTCOME MEASURES (SOM): ................................................................................................................... 14 
3.3 EXPLORATORY OUTCOME MEASURES (EOM): .............................................................................................................. 14 
4 DEFINING PRESYNCOPE AND SYNCOPE ...................................................................................................... 15 
4.1 PRESYNCOPE ......................................................................................................................................................................... 15 
4.2 SYNCOPE ................................................................................................................................................................................ 16 
5 STUDY DESIGN...................................................................................................................................................... 17 
6 STUDY ENROLLMENT AND WITHDRAWAL................................................................................................ 18 
6.1 SUBJECT INCLUSION CRITERIA .......................................................................................................................................... 18 
6.2 SUBJECT EXCLUSION CRITERIA .......................................................................................................................................... 18 
6.3 RECRUITMENT ...................................................................................................................................................................... 18 
6.4 REASONS FOR AND HANDLING OF WITHDRAWALS ........................................................................................................ 19 
6.5 TERMINATION OF STUDY .................................................................................................................................................... 19 
7 STUDY SCHEDULE, PROCEDURES, & EVALUATIONS ............................................................................... 19 
7.1 SCHEDULE OF EVENTS ........................................................................................................................................................ 19 
7.2 PARENT/GUARDIAN(S) PERMISSION PROCESS (INFORMED CONSENT).................................................................... 20 
7.3 OVERVIEW OF STUDY ASSESSMENTS ................................................................................................................................ 21 
7.4 DEMOGRAPHIC INFORMATION, MEDICAL HISTORY ....................................................................................................... 22 
7.5 PHYSICAL MEASURES .......................................................................................................................................................... 22 
7.6 NEEDLE RELATED FEAR ..................................................................................................................................................... 22 
7.7 ANXIETY ................................................................................................................................................................................ 23 
7.7.1 Risk Mitigation Procedure .................................................................................................................................. 23 
7.8 RANDOMIZATION ................................................................................................................................................................. 23 
7.8.1 Blinding ...................................................................................................................................................................... 23 
7.9 STUDY INTERVENTIONS ...................................................................................................................................................... 23 
7.9.1 Buzzy® and Electronic Game Intervention ................................................................................................. 23 
7.9.2 Control Group .......................................................................................................................................................... 24 
7.10 IMMUNIZATIONS ADMINISTERED DURING VISIT ......................................................................................................... 24 
7.11 POST VACCINATION PAIN ASSESSMENT ........................................................................................................................ 24 
7.12 PRESYNCOPE AND SYNCOPE ............................................................................................................................................ 24 
7.13 ACCEPTABILITY ................................................................................................................................................................. 25 
7.14 UNSOLICITED SAES .......................................................................................................................................................... 25 
8 STATISTICAL CONSIDERATIONS .................................................................................................................... 25 
8.1 SAMPLE SIZE AND POWER ESTIMATION .......................................................................................................................... 26 

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8.2 ANALYSIS PLAN .................................................................................................................................................................... 26 
8.2.1 Study Populations .................................................................................................................................................. 26 
8.2.2 Descriptive Statistics ............................................................................................................................................ 26 
8.2.3 Primary Objective (PO 1): ................................................................................................................................... 27 
8.2.4 Secondary and Exploratory Objectives .......................................................................................................... 27 
8.3 DATA MANAGEMENT .......................................................................................................................................................... 28 
8.3.1 Research Electronic Data Capture (REDCap) ............................................................................................. 28 
8.4 ROLE OF THE CDC INVESTIGATORS IN THE PROJECT .................................................................................................... 29 
9 HUMAN SUBJECTS ............................................................................................................................................... 29 
9.1 HUMAN SUBJECTS INVOLVEMENT, CHARACTERISTICS, AND DESIGN .......................................................................... 29 
9.2 SOURCES OF MATERIAL ...................................................................................................................................................... 30 
9.3 POTENTIAL RISKS AND BENEFITS ..................................................................................................................................... 30 
9.4 ADEQUACY OF PROTECTION AGAINST RISKS .................................................................................................................. 30 
9.4.1 Protections against Risk ...................................................................................................................................... 30 
9.4.2 ClinicalTrials.gov Requirements ...................................................................................................................... 31 
9.5 HUMAN SUBJECTS ................................................................................................................................................................ 31 
9.5.1 Vulnerable Subjects Research ........................................................................................................................... 31 
10 REFERENCES ....................................................................................................................................................... 32 
 
 

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PROTOCOL SUMMARY 
 
Title:  
Preventing Post-Vaccination Presyncope and Syncope in Adolescents 
Using Simple, Clinic-based Interventions 
Population: 
Up to 340 adolescents, 10 through 14 years of age, who will receive at 
least one intramuscularly administered vaccine  
Clinical Sites: 
One: Duke University  
Study Duration: 
18 months 
Participant 
Duration: 
Up to 2 hours 
Description of 
Study Procedures: 
This is a randomized controlled trial.  During the study, adolescents 
scheduled to receive at least one intramuscular (IM) vaccine will receive 
either a combined intervention (vibration and cool pack device plus an 
electronic game) versus usual care to evaluate the efficacy and 
acceptability of the intervention in preventing post-vaccination 
presyncope and syncope.  Efficacy will be assessed per participant 
written self-report to standardized survey questions regarding 
presyncope symptoms and the occurrence of presyncope/syncope in 
addition to changes in participant’s self-report of pre- versus post- 
vaccination state anxiety, and post-vaccination pain. Acceptability will be 
assessed according to the participant’s self-report. 
Objectives: 
Primary Objectives (PO): 
PO 1: To assess if simultaneous use of a vibration and cool pack device 
(Buzzy®) (reduces injection site pain) and an electronic game (simple 
active distraction intervention) before and during IM vaccination reduces 
risk for presyncope or syncope after vaccination in adolescents. 
 
Secondary Objectives (SO): 
SO 1: To compare with control (usual care) the change in state anxiety 
score in adolescents before and after vaccination, when Buzzy® and the 
electronic game intervention are used. 
 
SO 2: To compare with control (usual care) injection-site pain after 
vaccination in adolescents, when Buzzy® and the electronic game 
intervention are used. 
 
SO 3: To assess acceptability of Buzzy® and the electronic game 
intervention among adolescents. 
 
Exploratory Objectives (EO): 

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EO 1:  To assess if using Buzzy® and an electronic game before and 
during IM vaccination reduces risk for presyncope or syncope after 
vaccination using alternate case definitions for presyncope. 
 
EO 2: To assess for factors associated with post-vaccination presyncope 
in adolescents in the control and intervention groups. 
Outcome Measures: Primary Outcome Measures (POM):  
POM 1: Proportion of adolescents with presyncope or syncope after 
vaccination in the intervention and usual care groups. 
 
Secondary Outcome Measures (SOM): 
SOM 1.1:  Categorical change (positive, negative, no change) in pre- and 
post- vaccination state anxiety. 
 
SOM 1.2: Numeric change (mean and 95% confidence interval (CI)) in 
pre- minus post- vaccination state anxiety. 
 
SOM 2.1: Mean injection-site pain scores on the Wong-Baker Faces 
Pain Scale© at ≤ 1 minute following vaccination. 
 
SOM 2.2: Proportion of adolescents reporting an injection site pain score 
≥ 2, on the Wong-Baker Faces Pain Scale©, ≤ 1 minute following 
vaccination. 
 
SOM 2.3: Proportion of adolescents reporting an injection site pain score 
≥ 4, on the Wong-Baker Faces Pain Scale©, ≤ 1 minute following 
vaccination. 
 
SOM 2.4: Mean injection-site pain scores on the Wong-Baker Faces 
Pain Scale© at (approximately) 10 minutes following vaccination. 
 
SOM 2.5: Proportion of adolescents reporting an injection site pain score 
≥ 2, on the Wong-Baker Faces Pain Scale©, at (approximately) 10 
minutes following vaccination. 
 
SOM 2.6: Proportion of adolescents reporting an injection site pain score 
≥ 4, on the Wong-Baker Faces Pain Scale©, at (approximately) 10 
minutes following vaccination. 
 
SOM 3: Proportion of adolescents reporting positive and negative 
perceptions about their vaccination experience will be determined for 
each survey item. 
 
Exploratory Outcome Measures (EOM): 

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EOM 1: Proportion of adolescents with presyncope or syncope after 
vaccination in the intervention and usual care groups using the alternate 
case definitions for presyncope. 
 
EOM 2: Descriptive results of factors associated with post-vaccination 
presyncope and syncope using the primary and alternate case definitions 
for presyncope. 
Estimated Time to 
Complete 
Enrollment: 
13 months 

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1 BACKGROUND  
1.1 Background 
 
Vasovagal Syncope 
Syncope is a sudden and transient loss of consciousness and postural tone that typically 
lasts from several seconds to a minute, followed by spontaneous recovery. Syncope is 
caused by a sudden decrease or brief cessation of cerebral blood flow.1 Although 
uncommon, syncope can occur following immunization and result in serious injury.2   
 
Vasovagal (neurocardiogenic) syncope is the most common form of syncope.3 
Characterized by the development of arterial vasodilation in the setting of relative or 
absolute bradycardia, the mechanism by which vasovagal factors lead to syncope are 
not well understood. In some cases, syncope may be triggered in the central nervous 
system. In other cases, activity at the level of baroreceptors may lead to an increase in 
vagal tone and sympathetic withdrawal, leading to bradycardia, hypotension, and 
decreased cerebral blood flow. Multiple factors have been identified as possible triggers 
for syncope including: fear, anxiety, pain, hunger, overcrowding, illness, fatigue, 
injections, venipuncture, the sight of blood, and maintaining a still upright posture for a 
prolonged period. Alcohol, drugs and exposure to cold or heat can also precipitate 
syncope. Typically, vasovagal syncope is preceded by prodromal symptoms, known as 
presyncope, which may involve nausea, dizziness, visual changes (e.g., spots, 
dimming), feelings of apprehension, pallor, yawning, diaphoresis, and feelings of 
warmth.3 
 
Following a syncopal event, individuals may complain of malaise, fatigue, weakness, 
nausea, and headache. Although vasovagal syncope is self-limited, there is a potential 
for harm if affected individuals fall. For example, a syncope-related fall resulting in 
cerebral injury and death has been reported after vaccination.4 Rarely, syncope can be 
followed by a brief tonic-clonic seizure.1 In addition to the potential for injury, syncopal 
episodes often prompt extensive diagnostic testing in the emergency department and 
can sometimes lead to hospitalization.  Moreover, syncopal episodes triggered by 
identifiable stimuli such as needle-exposure can potentiate risk for development of more 
severe reactions to similar stimuli over time (e.g., blood-injection-injury phobia).5  The 
median age of onset of blood-injury-injection phobia is 7-11 years.6 
 
Post-vaccination syncope 
The National Academy of Medicine (formerly Institute of Medicine) has concluded that 
evidence “convincingly supports a causal relationship between the injection of a vaccine 
and syncope” likely due to a vasovagal reaction.7 Although uncommon, with an estimated 
range of 1.3 - 5 per 1000 in the adolescent age group,8,9  syncope after vaccination can 
lead to serious injury. An analysis of cases reported to Vaccine Adverse Event Reporting 
System (VAERS) in the 1990s described cases of syncope following immunization.2 
Reported episodes (n=697) occurred most frequently among those 10 through 18 years 
of age (45%), in females (58%), and within 15 minutes after vaccination (89%). 
Complications included tonic or clonic movements (24%) and subsequent hospitalization 
(10%). Reported serious adverse events associated with post-vaccination syncope 
included concussion, skull fracture, intracranial bleeding, cerebral contusions, and a 
motor vehicle collision due to syncope while driving. 
 

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Following the introduction of new vaccines for adolescents (i.e., Tetanus, Diphtheria and 
Pertussis (Tdap), Meningococcal (MCV4), Human papillomavirus (HPV)) between 2005-
2007, the number of cases of post-vaccination syncope reported to VAERS increased, 
primarily among females 11-18 years of age.10 Post-vaccination syncope has also been 
described in military personnel.11 The rate of medical encounters for post-vaccination 
syncope was 9.7 per 100,000 immunization episodes.  The rate of syncope was higher 
among females, declined with increasing age, and increased with increasing number of 
injections per immunization episode. Injuries occurred in approximately 7% of 
encounters for post-vaccination syncope, including head wounds, contusions, 
concussions, facial and clavicle fractures, and intracranial and ocular injuries.11  
Additional work has also shown that patients who experience syncopal symptoms in 
association with injection procedures are much more likely to be diagnosed with needle-
phobia.6,12 Moreover, emerging theories regarding acquisition of needle phobia in 
children describe that negative physical experiences such as syncope symptoms and 
pain can serve as fear-conditioning events, which may contribute to the development of 
needle phobia.13  
 
Post-vaccination vasovagal syncope and associated injuries, as well as risk for recurrent 
symptoms and related interference in functioning, are a public health concern that 
should be addressed with evidence-based preventive interventions. Although post-
vaccination presyncope does not always lead to syncope, it is more common than 
syncope, and both are vasovagally-mediated,11,14 so presyncope is appropriate for use 
as a surrogate for syncope in prevention research. Presyncope has been used as a 
surrogate for syncope in syncope prevention studies in the blood donation literature. 
Also, CDC supported a previous post-vaccination syncope prevention study at Duke and 
Boston University using presyncope as a surrogate endpoint for syncope.15  
 
Predictors of Vasovagal Syncope   
The efficiency of primary prevention of vasovagal syncope could be improved if 
preventive interventions could be targeted at those at greatest risk. Unfortunately, 
predicting risk of syncope is difficult. In blood donors, for example, pre-donation blood 
pressure was not associated with risk of syncope and a pre-donation elevated pulse rate 
has inconsistently been associated with risk of syncope,16-18 and the best predictor, 
anxiety, demonstrated only a modest association.19 Due to the challenge of accurately 
predicting risk, any preventive intervention would likely have to be broadly applied. 
 
Published systematic reviews and meta-analyses of interventions to prevent blood 
donation-related vasovagal symptoms and syncope in young donors suggest that risk 
factors for post-vaccination and post-blood-donation vasovagal (not volume depletion) 
syncope include: 1) younger (adolescents) and first time donors; 2) anxiety; 3) needle 
phobia; and 4) prior history of syncope from needle-related event(s).6,11,14,16,17,20-24  Some 
publications also cite increases in syncope among females;11,16,17,21,23-25 and among 
those with a prior history of fainting or feeling faint (due to any reason).17,22,23  Blood 
donation literature also suggests that vasovagal syncope is more common among 
Caucasians as compared to African-Americans,17,24 and in persons with lower body 
mass index (BMI) as compared to greater BMI.16 
 
Current Recommendations Related to Post-Vaccination Syncope 
There are no evidence-based recommendations for the primary prevention of post-
vaccination syncope. However, the Advisory Committee on Immunization Practices 
(ACIP) recommends that providers should take appropriate measures to prevent injuries 

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if a patient becomes weak or dizzy or loses consciousness. Adolescents and adults 
should be seated or lying down during vaccination. Vaccine providers, particularly when 
vaccinating adolescents, should consider observing patients (with patients seated or 
lying down) for 15 minutes after vaccination to decrease the risk for injury should they 
faint. If syncope develops, patients should be observed until the symptoms resolve.26 
The effectiveness of these measures is not known. One survey found that many primary 
care providers were unaware of these recommendations. Other than knowledge, the 
most commonly reported barrier to implementing the 15-minute post-vaccination 
observation period was lack of clinic space.27 
 
Prevention of Vasovagal Syncope 
Research targeting the prevention of vasovagal syncope in blood donors may offer 
relevant insights for preventing post-vaccination syncope and associated injuries. 
However, blood donation is not an ideal model for deriving strategies to prevent post-
vaccination syncope because blood donation involves a significant loss of intravascular 
volume, takes a longer period of time than vaccination, and only volunteers donate 
blood; in addition, most donors are adults ≥18 years, not among the youngest 
adolescents at highest risk for post-vaccination syncope.  
 
Although several strategies have been evaluated, two have emerged as most effective in 
the blood donation setting: acute water loading, and applied muscle tension. Review of 
blood donation literature indicates that consuming approximately 500 mL of water shortly 
before phlebotomy may help to mitigate vasovagal response to needle insertion and 
fainting, especially in young, first-time blood donors.  Consuming water stretches  
baroreceptors in the stomach wall which reflexively increases peripheral vascular tone, 
and temporarily decreases vasovagal-mediated hypotonia; this vasovagal tone 
mitigating response is also believed to be achieved through effects on the portal venous 
system from ingesting a hypo-osmolar beverage.27-29  Water can have an effect within 15 
minutes after ingestion and last up to an hour. In contrast, applied muscle tension can 
increase venous return, and thus help maintain blood pressure.  A  randomized 
prospective study found that applied muscle tension (AMT) reduced vasovagal 
symptoms in blood donors by 50%, from 16% to 8% among blood donors.22 The 
mechanism of action may involve a combination of factors, including increased venous 
return and through distraction and reduction of anxiety.22,28 However, a systematic 
review and meta-analysis of interventions to reduce vasovagal reactions in blood donors 
found no significant reduction in vasovagal reactions among 8 AMT studies that included 
3500 subjects.21  Thus far, no single intervention has been shown to be effective for 
preventing vasovagal symptoms and/or syncope during blood donation in all age 
groups.  
 
Unlike the blood donation literature, there are limited data on effective strategies to 
prevent post-vaccination vasovagal syncope. Only one randomized clinical trial has 
assessed an intervention to prevent post-vaccination syncope. A recent Clinical 
Immunization Safety Assessment (CISA) randomized clinical trial (Kemper et al, 
ClinicalTrials.gov NCT02353390)30 assessed the effectiveness of pre-vaccination 
hydration with water to prevent presyncope (used as a surrogate for syncope). Drinking 
some water before vaccination was not effective in preventing presyncope and by 
extension syncope, prompting CISA to plan evaluations of other simple interventions that 
could be used in busy clinical settings. The hydration study demonstrated the following 
as risk factors for post-vaccination presyncope among subjects 11-21 years: receiving 
more than one injectable vaccine; age younger than 15 years; having higher pre-

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vaccination anxiety levels; history of passing out or nearly passing out after a “shot” or 
blood draw within the preceding 5 years, and having higher levels of pain after 
vaccination (presumed injection-site pain).15 These predictors may inform other 
strategies for preventing pre-syncope such as reducing immediate pain after vaccination 
in addition to promoting relaxation and reducing anxiety around the time of vaccination. 
 
The use of a topical vapocoolant shortly before injection or the use of Buzzy® 
(combination vibration and cool pack applied to planned injection sites shortly before 
injections), have been shown to decrease injection site pain, which might play a role in 
decreasing injection pain-associated vasovagal symptoms.31,32 Buzzy® | Drug Free 
Pain Relief is a reusable medical device designed to reduce vaccination pain 
[https://buzzyhelps.com/]. The Buzzy® device is applied to a targeted skin area for 30-
60 seconds in order to cool/numb the area and provide vibration to desensitize pain 
receptors (nociceptors) prior to injection, then the device is moved just proximal to the 
site during injection. The device has been found to decrease pain and anxiety in 
children aged 7 years receiving DTaP in a prospective, randomized controlled trial.33 
Likewise, in a separate prospective, randomized controlled trial of 497 employees 
receiving influenza vaccine, those randomized to use Buzzy® prior to vaccination 
reported less pain.34  Another prospective, open-label randomized trial in 50 children 
between the ages of 3 and 18 demonstrated the Buzzy® lowered child-reported pain 
but did not impact child-reported anxiety or how much pain the child expected.35 
 
In children and adolescents, relaxation methods, such as listening to music, have 
shown some effectiveness in decreasing medically-related anxiety23,31,32 and pain.36  In 
particular, distraction has been investigated as a technique to reduce vaccination pain 
in children and adolescents. One systematic review identified various distraction 
techniques, including verbal distraction, video distraction, breathing tasks (e.g., blowing 
bubbles, party blowers, etc.), and musical distraction.37 Results suggested that 
breathing tasks and musical distraction showed beneficial effects in reducing pain and 
distress from vaccinations in children younger than 12.  Video distraction demonstrated 
beneficial results in reducing distress in children and adolescents. 38 An additional 
review focused specifically on the use of iPads with video games or cartoons as a 
distraction to reduce the parent’s perception of their child’s pain and distress during 
vaccinations.  This study found that the parents of the children using iPads perceived 
significantly lower levels of fear and anxiety in their children than those in the control 
group.39 The use of iPads as a distraction tool also improved parental satisfaction with 
pain reduction practices used for their child.  
 
In a recent pilot study we evaluated the feasibility and acceptability of two simple office-
based interventions aimed at reducing presyncope symptoms among adolescents 
receiving vaccines (Walter et al, ClinicalTrials.gov NCT03533829).  Adolescents 
receiving one or more vaccines (at least one administered intramuscularly) were 
randomized to use Buzzy® prior to vaccination, choose music from a streaming internet 
music service to listen to prior to and during vaccination or to do both.  Both 
interventions were found to be acceptable and feasible.  However, neither intervention 
required ongoing and active engagement of the adolescent during the vaccination 
process, and hence, may ultimately be less effective at distraction and reducing anxiety 
than an intervention requiring more active participation.23 In this study, we aim to pair 

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Buzzy® with a distraction tool or technique that requires more active participant 
involvement.   
1.2 Summary  
 
To identify best practices for preventing post-vaccination vasovagal syncope, we will 
target younger adolescents, a population that we have identified as having a higher risk 
for post-vaccination presyncope and syncope. Since post-vaccination syncope is an 
uncommon event, we will use presyncopal (vasovagal) signs and symptoms as a 
surrogate marker for syncope, as was done in the earlier CISA study. Based on our 
review of available literature, which does not identify one intervention with high efficacy, 
we plan to investigate the combination of two interventions designed to prevent post-
vaccination syncope through mitigation of immediate injection-site pain and anxiety, 
both factors that we have identified as occurring more frequently among adolescents 
with post-vaccination presyncope. In summary, we aim to assess the acceptability and 
efficacy among adolescents of using a paired intervention that includes Buzzy® to 
reduce injection site pain and a simple electronic game employed as an active 
distraction to prevent post-vaccination presyncope.  
 
 

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2 STUDY OBJECTIVES 
2.1 Primary Objective (PO): 
 
PO 1: To assess if simultaneous use of a vibration and cool pack device (Buzzy®) 
(reduces injection site pain) and an electronic game (simple active distraction 
intervention) before and during IM vaccination reduces risk for presyncope or syncope 
after vaccination in adolescents 
Research hypothesis: The Buzzy® and electronic game intervention will be at least 50% 
effective at reducing risk for post-vaccination presyncope or syncope compared with 
control. 
2.2 Secondary Objectives (SO): 
 
SO 1: To compare with control (usual care) the change in state anxiety score in 
adolescents before and after vaccination, when Buzzy® and the electronic game 
intervention are used. 
 
SO 2: To compare with control (usual care) injection-site pain after vaccination of 
adolescents, when Buzzy® and the electronic game intervention are used.  
 
SO 3: To assess acceptability of Buzzy® and the electronic game intervention among 
the adolescents. 
2.3 Exploratory Objectives (EO): 
 
EO 1:  To assess if using Buzzy® and an electronic game before and during IM 
vaccination reduces risk for presyncope or syncope after vaccination using alternate 
case definitions for presyncope. 
 
EO 2: To assess for factors associated with post-vaccination presyncope in adolescents 
in the control and intervention groups. 
 
 
 

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3 STUDY OUTCOME MEASURES AS RELATED TO OBJECTIVES 
3.1 Primary Outcome Measures (POM): 
 
POM 1: Proportion of adolescents with presyncope or syncope after vaccination in the 
intervention and usual care groups. 
3.2 Secondary Outcome Measures (SOM): 
 
SOM 1.1:  Categorical change (positive, negative, no change) in pre- and post- 
vaccination state anxiety. 
 
SOM 1.2: Numeric change (mean and 95% CI) in pre- minus post- vaccination state 
anxiety. 
 
SOM 2.1: Mean injection-site pain scores on the Wong-Baker Faces Pain Scale© at ≤ 1 
minute following vaccination. 
 
SOM 2.2: Proportion of adolescents reporting an injection site pain score ≥ 2, on the 
Wong-Baker Faces Pain Scale©, ≤ 1 minute following vaccination. 
 
SOM 2.3: Proportion of adolescents reporting an injection site pain score ≥ 4, on the 
Wong-Baker Faces Pain Scale©, ≤ 1 minute following vaccination. 
 
SOM 2.4: Mean injection-site pain scores on the Wong-Baker Faces Pain Scale© at 
(approximately) 10 minutes following vaccination. 
 
SOM 2.5: Proportion of adolescents reporting an injection site pain score ≥ 2, on the 
Wong-Baker Faces Pain Scale©, at (approximately) 10 minutes following vaccination. 
 
SOM 2.6: Proportion of adolescents reporting an injection site pain score ≥ 4, on the 
Wong-Baker Faces Pain Scale©, at (approximately) 10 minutes following vaccination. 
 
SOM 3: Proportion of adolescents reporting positive and negative perceptions about 
their vaccination experience will be determined for each survey item. 
3.3 Exploratory Outcome Measures (EOM): 
 
EOM 1: Proportion of adolescents with presyncope or syncope after vaccination in the 
intervention and usual care groups using the alternate case definitions for presyncope. 
 
EOM 2: Descriptive results of factors associated with post-vaccination presyncope and 
syncope using the primary and alternate case definitions for presyncope. 

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4 DEFINING PRESYNCOPE AND SYNCOPE 
4.1 Presyncope 
 
For this study, the case definition of presyncope was based on review of the literature, 
an amended Blood Donations Reactions Inventory (BDRI) which was used in previous 
studies including the CISA Hydration Study, expert opinion, and prior experience with 
the CISA hydration study.12-14 Although there may be measurable physiological changes 
with presyncope (e.g., decrease in heart rate or blood pressure), there are no 
established cut-offs that define presyncope.  Therefore, the case definition is based on 
subjective criteria.  The case definition previously used in CISA hydration study to 
Prevent Post-Vaccination Presyncope (“Water and Vaccines Study”) is outlined below 
and will be used as the primary definition of presyncope in this study: 
 
Primary definition: Sudden onset of one or more of the following symptoms (reported as 
“a little bit”, “somewhat” or “a lot”) or signs during the post-vaccination observation period 
in the clinic: 
 
Symptoms  
• 
Feeling like you might “pass out” or faint 
• 
Feeling dizzy, like the room is spinning  
• 
Feeling weak 
• 
Feeling like your face is getting red and warm (or hot), like blushing or flushing 
• 
Noticing any change in your vision, like spots or flickering lights, tunnel vision, or 
loss of vision 
• 
Experiencing ringing in your ears, decreased hearing, or sounds seem far away 
• 
Feeling lightheaded 
• 
Feeling like your heart is beating fast or hard or pounding 
• 
Feeling hot or sweaty 
• 
Feeling cold or “clammy” 
• 
Feeling like you are breathing fast or hard 
• 
Feeling like you might throw up (nausea)  
 
Signs  
• 
Pallor 
• 
Sweatiness 
• 
Facial flush 
• 
Decreased interactivity (decreased level of arousal or responsiveness) 
 
AND  
• 
Not syncope  
• 
Not due to another cause 
• 
Not clearly present at baseline  
 
In exploratory analyses we will employ two alternate case definitions for presyncope. 
 
Alternate definition 1: Sudden onset of one or more of the above symptoms (reported as 
“somewhat” or “a lot”) or signs during the post-vaccination observation period in the 
clinic. 
 

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Alternate definition 2: Sudden onset of one or more of the following symptoms limited to 
feeling like you might pass out, dizziness, weakness, or lightheadedness symptoms 
(reported as “a little bit”, “somewhat” or “a lot”) or signs during the post-vaccination 
observation period in the clinic.  
4.2 Syncope 
 
Syncope (fainting) that occurs in an otherwise healthy person after receipt of a vaccine 
or during venipuncture is usually attributed to vasovagal syncope, and may occur alone 
(simple syncope) or may be associated with tonic-clonic movements (convulsive 
syncope, anoxic seizure).12,13  For the purposes of this study, we have defined syncope 
as:  Any sudden and brief loss of consciousness or postural tone after vaccination from 
which recovery is spontaneous and is not attributed to another cause (e.g., anaphylaxis).  
For purposes of this study, cases counted as syncope must occur during the post-
vaccination observation period.  
 
Usual clinical care will be provided to any subject who develops syncope. 

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5 STUDY DESIGN 
 
This study is a prospective, randomized clinical trial that will be conducted in 
adolescents (10 through 14 years of age) receiving at least one recommended 
intramuscularly administered vaccine to evaluate the efficacy and acceptability of using 
two different, simultaneously administered interventions that might prevent post-
vaccination presyncope, and by extension syncope.   The two interventions to be 
evaluated together are Buzzy®, which is a medical device designed to reduce 
vaccination pain, and an electronic game.  We will evaluate both interventions when 
administered simultaneously (Buzzy® and electronic game).  We will enroll 
approximately 340 subjects into this study.  Eligible adolescents will be randomized (1:1) 
to either the intervention or control group: 1) intervention (Buzzy® and electronic game); 
or 2) control (usual care) to assess for acceptability and efficacy. Detailed data will be 
collected and described from study participants including demographics, medical history, 
baseline anxiety, and needle phobia. Participants will be observed for 20 minutes 
following receipt of vaccines and reassessed for post-vaccination anxiety, immediate 
and subsequent post-vaccination pain (within 1 minute and at 10 minutes), and the 
occurrence of witnessed syncope or presyncope, and presyncopal symptoms as rated 
by the modified BDRI. For the primary objective, we will assess the efficacy of the 
intervention to decrease presyncope symptoms or signs as compared to usual care. For 
the secondary objectives we will assess the pre- and post-vaccination anxiety score, the 
immediate post-vaccination injection-site pain score, and the acceptability of the 
intervention.  For the exploratory objectives we will assess the efficacy of the 
intervention to decrease presyncope symptoms or signs as compared to usual care 
using alternate case definitions for presyncope and we will assess factors associated 
with post-vaccination presyncope. 

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6 STUDY ENROLLMENT AND WITHDRAWAL  
Subject Inclusion and Exclusion Criteria will be reviewed at Visit 1 to assess eligibility for 
study participation. 
6.1 Subject Inclusion Criteria 
 
Subjects who meet all of the following criteria will be eligible to participate in this 
interventional study.   
1. 10 years through 14 years of age 
2. The subject must be receiving at least one vaccine delivered intramuscularly 
3. The parent/guardian must be willing and capable of providing written informed 
consent for the adolescent and the adolescent must be willing and capable of 
providing assent. 
4. The subject must be willing to stay for the completion of all study-related 
activities. 
5. Parent/guardian and adolescent must speak and read English by self-report  
6. Parent/guardian must be willing to let their child select an electronic game to play 
during the study  
6.2 Subject Exclusion Criteria   
 
Subjects who meet any of the following criteria will not be eligible to participate in 
this study: 
1. Receipt of investigational or experimental vaccine or medication within the 
previous two weeks 
2. Receipt of routine injectable medication 
3. Permanent indwelling venous catheter 
4. Blood drawn within the past hour or scheduled for a blood draw during the post-
vaccination observation period 
5. Injection of medication during the past hour or scheduled for injection of 
medication during the observation period.  
6. Cold intolerance or cold urticaria 
7. Raynaud’s phenomenon 
8. Sickle cell disease 
9. Significant visual impairment or blindness 
10. Significant auditory impairment or deafness 
11. Febrile(>38.0°C)  or acutely ill individuals  
12. Upper arm or shoulder pain or injury 
13. Has the subject had video game-induced seizures? 
14. Adolescent or parent/guardian is an immediate relative of study staff or an 
employee who is supervised by study staff. 
15. Any condition that would, in the opinion of the site investigator, place the 
participant at an unacceptable risk of injury or render the participant unable to 
meet the requirements of the protocol 
6.3 Recruitment 
 
The 340 participants in this study will be male or female adolescents 10 to 14 years of 
age. Adolescents will be recruited from designated study sites affiliated with the Duke 
University Health System (Duke Children’s Primary Care, Durham Pediatrics, and 

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Regional Pediatrics).  Adolescents will primarily be recruited at the time of well child 
visits.   
6.4 Reasons for and Handling of Withdrawals 
 
The following may be reasons for study withdrawal: 
• 
As deemed necessary by the principal investigator (PI). 
• 
Parent(s)/Legally Authorized Representative(s) (Guardian(s)) withdrawal of 
permission for their adolescent to participate. 
• 
Termination of the study by the sponsor. 
 
A parent/guardian may withdraw permission for their adolescent to participate at any 
time and for any reason, without penalty. Subjects who are withdrawn from the study 
after receiving intervention will not be replaced.  For subjects who received intervention, 
data collected prior to withdrawal in the study will be included in the study.  
6.5 Termination of Study  
 
This study may be terminated for safety concerns of the principal investigators from the 
research site, CDC, or participating Institutional Review Board (IRB).   
 
7 STUDY SCHEDULE, PROCEDURES, & EVALUATIONS 
7.1 Schedule of Events 
 
Adolescents meeting the proposed eligibility criteria will be recruited and if enrolled the 
subject could spend up to two hours in the clinic. Written permission for the adolescent 
to participate will be obtained from parent(s)/guardian(s) prior to conducting any study 
procedures.  Written or verbal assent, depending on the age of the adolescent, will also 
be obtained. Table 1 describes the proposed schedule of study visits.   
Table 1: Schedule of Study Events:  
 
 
Procedure 
Pre-Vaccination 
Day 1 
Vaccination 
Day 1 
 Post-Vaccination 
Day 1 
Informed consent / Assent 
X 
 
 
Inclusion/Exclusion 
X 
 
 
Demographics  
X 
 
 
Medical history  
X 
 
 
Concomitant medications 
X 
 
 
Beverage and food intake assessment on 
day of vaccination 
X 
 
 
PROMIS Pediatric Anxiety Short Form  
X 
 
 
Needle phobia assessment 
X 
 
 
State Anxiety assessment  
X 
 
X1  
(20 minutes) 
Record/obtain physical measures (height 
and weight) and vital signs (blood pressure 
and pulse and baseline pain assessment 
done per usual care) 
X 
 
 
 
Randomization 
X 
 
 

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Simultaneous Buzzy® and electronic game 
intervention or usual care  
X 
 
 
Administer vaccines (not a study procedure) 
 
X 
 
 
Injection site pain assessment 
 
 
X  
(within 1-3 and at 
10 minutes)  
Presyncope symptoms assessment  
 
 
X  
(15 minutes) 
Acceptability Assessment  
 
 
X  
(20 minutes)  
1 Complete prior to acceptability assessment  
 
Visit 1, Study Day 1 Clinic Visit Prevaccination Assessments 
• 
Obtain parent(s)/guardian(s) permission by written informed consent  
• 
Review and confirm study eligibility (Section 4.1 and 4.2) 
• 
Obtain medical history  
• 
Obtain demographic data  
• 
Obtain concomitant medication use within one week of enrollment 
• 
Record height and weight and vital signs (blood pressure and pulse) from the 
medical record.  Obtain measures if not already taken and recorded at clinic 
intake.  Record baseline pain assessment if determined as part of clinical care 
• 
Complete beverage and food intake assessment for the day of vaccination 
• 
Complete the needle phobia assessment 
• 
Complete the general anxiety assessment and the state anxiety assessment 
• 
Randomize study participant to one of the two study arms  
• 
Administer assigned study intervention if randomized to that group 
 
Visit 1, Study Day 1 Clinic Visit Vaccination 
• 
Vaccines administered by clinic staff (Not a study procedure) 
• 
Vaccines administered as usual care will be recorded by study team 
 
Visit 1, Study Day 1 Clinic Visit Post Vaccination Assessments 
• 
Complete the Wong-Baker Faces Pain assessment for each arm an injection is 
given in (immediately after withdrawal of the needle after the last vaccination 
within 1 minute (up to 3) after last injection and at 10 (up to 15) minutes after the 
last vaccination). If multiple injections are given in the same arm only 1 Wong-
Baker Faces Pain assessment will be performed for that arm at 1-3 minutes and 
10 (up to 15) minutes after the last injection.  
• 
Complete the presyncope symptoms assessment modified BDRI (15 (up to 20) 
minutes post vaccination) 
• 
Complete the state anxiety assessment (20 [up to 25] minutes post vaccination) 
• 
Complete the acceptability assessment (20 [up to 30] minutes post vaccination) 
7.2 Parent/Guardian(s) Permission Process (Informed Consent) 
 
The consent/assent process will take place in research or clinic exam rooms behind 
closed doors to assure privacy of the prospective participant.  Study staff will be 
available to answer all parent/adolescent questions before and after permission is 
obtained.  After initial discussion of the study, parent(s)/guardian(s) will be given as 

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much time as needed to decide whether or not to give permission for their child to 
participate in this study.  We anticipate that the initial consent/assent discussion, 
including presenting the information in the consent/assent document and answering 
questions will take about 30 minutes.  During the consent/assent process, it will be 
stressed that participation is voluntary and that parents can withdraw permission for their 
adolescent to participate at any time.  Permission will not be obtained from 
parent(s)/guardian(s) who do not read, who are blind, or who do not read/understand 
English. Parent(s)/Guardian(s) will be given a copy of the signed informed consent to 
take home with them.  The original copy of the consent/assent will be kept in the study 
records and a third copy will be included in the adolescent’s medical record per local 
requirements. Eligibility of the adolescent will also be assessed. 
7.3 Overview of Study Assessments 
 
Table 2 briefly outlines factors of interest that are potentially associated with pre-
syncope or syncope.  A more complete description of some of the specific 
measurements and questionnaires follows the table. 
 
Table 2: Factors of Interest that are Possibly Related with Pre-syncope or 
Syncope 
Domains of Interest 
Source of Information 
Information obtained 
Demographics 
Participant and/or parent 
report 
Participant’s gender, age, 
race, ethnicity 
Underlying Health 
(Chronic or acute 
illness) 
Participant and/or parent 
report  
Review of medical record 
 
 
 
Medical history information: 
(history of pre-syncope, 
syncope, cardiac 
conditions, seizures, 
hypoglycemia, diabetes, 
prescription and over-the 
counter medications in 
preceding week, 
supplements in preceding 
week)  
Physical Measures  
Height, weight, pulse rate 
and blood pressure 
measurements (from 
medical record if obtained 
or measured, otherwise 
measured by study staff) 
Pain at baseline (from 
medical record) 
Height, weight and 
calculated BMI 
Pulse rate and blood 
pressure 
Pain assessment at 
baseline 
 
Fatigue/ tiredness 
Participant response 
Estimated hours of sleep 
the previous night 
Feeling tired 
Hunger 
Participant response 
Last food eaten 
Hunger estimation 
Thirst 
Participant response 
Time/type of last beverage 
consumed prior to 
vaccination 

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Quantification of last 
beverage 
Thirst estimation 
Needle-related fear 
Participant response 
Needle phobia 
questionnaire 
Global question about fear 
of injections 
Anxiety 
Participant response  
PROMIS Pediatric Anxiety 
Short Form pre-vaccination, 
and state anxiety 
questionnaire pre- and 
post-vaccination 
Number of Injections 
Medical record review 
(EHR/electronic health 
record or State 
Immunization Registry) 
Number / name / site of 
injections administered in 
clinic 
Pain 
Participant response 
Wong-Baker Faces Pain 
Scale score post 
vaccination 
Past history of 
presyncope or syncope 
after injection or blood 
draw during the past 5 
years 
Participant response 
Questions about past 
history of almost fainting or 
fainting and circumstance 
 
7.4 Demographic Information, Medical History 
 
The participant’s gender, age, and race/ethnicity will be obtained from parent/guardian 
report at the time of enrollment. The participant’s medical history including: history of 
pre-syncope, syncope, cardiac history, seizures, hypoglycemia, diabetes, prescription 
and over-the counter medications in the preceding week, and supplements in the 
preceding week will be obtained by review of the electronic health record (EHR) and will 
be reviewed and confirmed with the parent/guardian at the time of enrollment.   
7.5 Physical Measures 
 
Participants’ height, weight and calculated BMI will be obtained at enrollment or from the 
clinical measurements collected at the visit. Pulse-rate and blood pressure will also be 
obtained at baseline from the clinical measurements. Height, weight, pulse rate, and 
blood pressure measurements will be performed by the study team if they are not 
otherwise available. In addition, the clinic baseline pain assessment will be recorded.  
7.6 Needle Related Fear  
 
Fear of having blood drawn has been shown to be predictive of vasovagal reactions in 
young blood donors.6 In blood donors fear was assessed using a global question. “How 
afraid are you of having blood drawn from your arm?”  A similarly worded global question 
will be used to assess fear of vaccination.  “How afraid are you of getting a vaccine 
(shot) in your arm?”  Responses will be graded using a Likert scale which will have a 
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addition, we will use the American Psychiatric Association Severity Measure for Specific 
Phobia to assess needle related phobia.  This assessment is a 10-item scale which 
specifically assesses phobia around blood, needles or injections in persons 11-17 years 
of age. 6,19 
7.7 Anxiety  
 
Prior to vaccination the study coordinator will have each subject complete a 
questionnaire to assess generalized anxiety using the Patient Reported Outcome 
Measurement Information System (PROMIS) Pediatric Anxiety Short Form v2.0 8a 
instrument for adolescents (11-17 years) to categorize their overall degree of anxiety.40  
 
Participants will also complete a questionnaire specifically designed for this study to 
measure state anxiety both prior to and 20 minutes following vaccination. State anxiety 
is defined as an unpleasant emotional arousal in face of threatening demands or 
dangers.41,42  
7.7.1 Risk Mitigation Procedure 
If the subject scores into the severe category for anxiety measured from the PROMIS 
Pediatric Anxiety Short Form, the subject’s score and answers will be shared with the 
subject’s primary care physician.  
7.8 Randomization 
 
Participants will be randomized (1:1) to receive either Buzzy® and electronic game or 
the control using a permuted block randomization scheme.  A minimum of 170 
participants will be enrolled in the intervention group and 170 in the control group. The 
project statistician at Duke University will generate randomization schemes, which will be 
uploaded to REDCap. The randomization schedule will not be available to the study 
staff, so the next randomization allocation will not be known before randomization 
occurs. Following confirmation of study eligibility criteria during Visit 1, participant 
randomization will be through REDCap with treatment allocation recorded on the CRF. 
 
7.8.1 Blinding 
Study staff and subjects will not be blinded to treatment arm assignments. 
 
7.9 Study Interventions 
 
7.9.1 Buzzy® and Electronic Game Intervention 
Participants randomized to Buzzy® and the electronic game will apply or have Buzzy® 
applied by a member of the study team. Buzzy® XL Healthcare Professional will be 
applied as described in the package insert on the deltoid vaccination site for 30-60 
seconds. Then, the Buzzy® will be moved proximal to the injection site keeping 
Buzzy’s® switch/head toward the brain or spine during injection. The procedures for 
applying Buzzy® are consistent with the procedures on the package insert (Appendix 
A).  If vaccines are given in more than one arm, Buzzy® will be placed on both arms with 
the assistance of the study coordinator. Buzzy® will be removed from the vaccination 
site(s) following vaccination. The start and stop time of Buzzy® placement will be 
recorded. If more than one vaccination is given in a single arm only one Buzzy® device 
will be applied per package instructions.  

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For the electronic game, participants will be instructed to select a game from a 
prepopulated list of games on a tablet provided by the study team.  The game will be 
played for a minimum of 3 to 5 minutes prior to vaccination, throughout the procedure 
and for a minimum of 1 minute and up to 15 minutes after vaccination.   
 
Although preferable for participants to remain in the same exam room during the post-
vaccination observation period, participants may have to shift rooms during the post-
vaccination observation period.  The participant will be provided with the guidance 
(derived from the Advisory Committee on Immunization Practices (ACIP) General Best 
Practices Guidelines for Immunization)26 that they may choose to sit or lie down during 
the post-vaccination wait period.   Movement from room to room or if the patient decides 
to stand should be noted by the study staff.  No instruction will be provided to the 
participant regarding sitting or standing unless the participant starts to exhibit signs of 
presyncope. 
 
7.9.2 Control Group 
This intervention group will receive usual care during vaccination. Usual care will include 
not receiving the Buzzy® and electronic game combination intervention and will also 
consist of the patient waiting in the exam room for 20 minutes post-vaccination. The 
participant will also be provided with the ACIP guidance that they may choose to sit or lie 
down during the post-vaccination wait period.  Although preferable for participants to 
remain in the same exam room during the post-vaccination observation period, 
participants may have to shift rooms during the post-vaccination observation period.  
Movement from room to room should be noted by the study staff. 
 
 
7.10 Immunizations Administered During Visit 
 
Vaccines received as part of usual care during the visit will be documented by the 
research staff.  Documentation will include: product name and brand, lot number, site 
and date/time of vaccine administered during study participation.  
 
7.11 Post Vaccination Pain Assessment  
 
The Wong Baker Faces Pain Scale will be used to assess pain.43   The Wong- Baker 
Faces Pain Scale scores pain on a 0-10 metric with 2 point intervals and shows a close 
linear relationship with visual analog pain scales across the ages from 11-17 years and 
is acceptable for use with younger adolescents as well.  Pain will be assessed at 1 
minute (up to 3 minutes) and at 10 minutes (up to 15 minutes) after vaccination for each 
arm in which a vaccine was received.  The study coordinator will be responsible for 
recording pain scores after vaccination. The time for assessment will start after the last 
injection is received.   
 
7.12 Presyncope and Syncope  
 
At 15 minutes (up to 20 minutes) following vaccination, study participants will complete 
the BDRI. During the 15 minute (up to 20 minute) observation period, research staff 

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will also record any observed signs (pallor, sweating, facial flush or decreased 
interactivity) or spontaneous subject reports of symptoms of witnessed presyncope as 
described in Section 4.1.  Subjects who developed post-vaccination syncope as 
described in Section 4.2 regardless of presyncope are classified as having syncope.  
Usual clinical care will be provided to any subject who develops presyncope or 
syncope.  
7.13 Acceptability 
 
At the end of the study visit, we will survey participants about the acceptability of the 
intervention to which they were assigned.  Where appropriate, a Likert scale (strongly 
agree, agree, neither, disagree, strongly disagree) will be used to assess acceptability 
responses.  Alternately, a yes or no response to survey questions will be solicited. 
7.14 Unsolicited SAEs 
 
Administration of vaccine is not itself a study procedure in the study population, and 
thus vaccine adverse events, including presyncope or syncope, are not considered 
study related adverse events. If indicated, however, vaccine-related SAEs will be 
reported to the Vaccine Adverse Event Reporting System (VAERS) in accordance 
with standard procedures. Information about such events will be included in the 
study data as noted on the VAERS website (https://VAERS.hhs.gov).  
 
All serious adverse events (SAEs) occurring during the period of study participation 
will be reported to the IRBs overseeing this study and to the CDC within 24 hours of 
study staff awareness of the event. Given the short duration of study participation 
and nature of the study, SAEs would not be expected to occur in this study. 
 
An SAE is defined as an AE that meets one of the following conditions: 
•Results in death during the period of protocol-defined surveillance  
•Is life-threatening (defined as immediate risk of death at the time of the event) 
•Requires inpatient hospitalization during the period of protocol-defined surveillance 
or results in prolongation of existing inpatient hospitalization (other than routine 
hospital admission for labor & delivery).  
•Results in congenital anomaly or birth defect 
•Results in a persistent or significant disability/incapacity 
•Any other important medical event that may not result in death, be life threatening, 
or require hospitalization, may be considered an SAE when, based upon 
appropriate medical judgment, the event may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that 
do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse. 
 
8 STATISTICAL CONSIDERATIONS 
Data will be handled according to the Duke Vaccine and Trials Unit SOP (DVTU M010) 
and captured on paper CRFs and entered into the REDCap database. All data for this 
study will reside on a secure Duke server maintained by Duke Health Technology 
Solutions (DHTS).  A database will be developed and a dataset without personal 

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identifiers will be made available to the CDC for analysis purpose.  All analyses will be 
performed using SAS version 9.4. 
8.1 Sample Size and Power Estimation 
 
The study has approximately 82.0% power to reject the null hypothesis of no difference 
in the proportion of adolescents with presyncope or syncope after vaccination in the 
intervention (vibration and cool pack device [Buzzy®] and an electronic game) group 
compared to the control (usual care) group based on a two-side alpha 0.05 chi-square 
test with N=160 per group. This assumes that the proportion of adolescents with 
presyncope or syncope after vaccination will be 25% in the control group and 2-fold 
lower (12.5%) in the intervention group.15 This assumption is based on a review of the 
literature and expert opinion. We plan to enroll approximately 340 adolescents for this 
study with the assumption of a 5% drop out rate, thus providing at least 160 subjects per 
group to have approximately 82% power. 
8.2 Analysis Plan 
 
8.2.1 Study Populations  
The study will enroll adolescents, female and male, ages 10-14 years, receiving at least 
one ACIP recommended vaccine administered intramuscularly.  Participants will be 
randomized into either of the two groups: intervention (vibration and cool pack device 
[Buzzy®] and an electronic game) or the control (usual care).     
 
There will be two study populations used for data analysis in this study. These are 
defined below:   
• 
Modified Intent-to-treat (MITT) population:  is defined as those 
subjects who are enrolled, randomized into the study, and received an 
intramuscular vaccine.   
• 
Per-protocol population:   is defined as those subjects who are 
randomized, have received at least one dose of an intramuscularly 
administered vaccine, have completed all study procedures, and have 
no protocol violations that are likely to affect the objectives. 
 
The primary and exploratory objective analyses will be performed in the MITT and Per-
protocol populations, or only the MITT population if no subject is excluded from the per 
protocol population.  No adjustments will be made to the alpha level (two-sided 
alpha=0.05) for the study objectives described below.  
 
8.2.2 Descriptive Statistics 
Descriptive analyses will be conducted for demographic variables and for baseline 
characteristics (e.g., fatigue, hunger, thirst, needle fear and phobia, and an anxiety rating 
scale score).  Continuous variables will be summarized with standard descriptive 
statistics including means, medians, 95% CI, and standard deviations.  Categorical 
variables will be summarized with frequencies and percentages.  Ninety-five percent 
confidence intervals will be provided for descriptive statistics, as warranted. The 
descriptive statistics will be analyzed in the MITT and Per-protocol populations.   
 

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8.2.3 Primary Objective (PO 1):  
The primary objective is to assess if simultaneous use of a vibration and cool pack 
device (Buzzy®) and an electronic game before and during intramuscular vaccination 
will reduce risk for presyncope or syncope after vaccination in adolescents. The 
proportion of adolescents with presyncope or syncope after vaccination will be compared 
between the control and intervention groups using a chi-square test.   
 
8.2.4 Secondary and Exploratory Objectives 
Secondary Objective (SO 1):  
The first secondary objective is to compare the change in state anxiety score for 
adolescents before and after vaccination in the control group to the intervention 
group. The categorical change in the anxiety score (positive, negative, and no change) 
in pre- and post- vaccination state anxiety will be presented by group in a tabular format.  
A comparison of the two study groups will be made using a Mantel-Haenszal statistic 
(row mean scores difference with standardized midranks scores [modified ridit scores]). 
Descriptive statistics (e.g., mean, 95% CI, min, max) of the pre- minus post- vaccination 
state anxiety will be presented by group and compared using Mann-Whitney U/Wilcoxon 
rank-sum test. 
 
Secondary Objective Measure (SO 2):   
The second secondary objective is to compare the change in injection-site pain after 
vaccination of adolescents in the control group to the intervention group. The following 
four outcomes will be compared between groups using a chi-square test or a logistic 
regression model to control for covariates: 
• 
The proportion of adolescents reporting an injection site pain score ≥ 2, on the 
Wong-Baker Faces Pain Scale©, ≤ 1 minute following vaccination 
• 
The proportion of adolescents reporting an injection site pain score ≥ 4, on the 
Wong-Baker Faces Pain Scale©, ≤ 1 minute following vaccination 
• 
The proportion of adolescents reporting an injection site pain score ≥ 2, on the 
Wong-Baker Faces Pain Scale©, at (approximately) 10 minutes following 
vaccination 
• 
The proportion of adolescents reporting an injection site pain score ≥ 4, on the 
Wong-Baker Faces Pain Scale©, at (approximately) 10 minutes following 
vaccination. 
 
Descriptive statistics (e.g., mean, 95% CI , min, max) of injection-site pain scores on the 
Wong-Baker Faces Pain Scale© at ≤ 1 and minute and at (approximately) 10 minutes 
following vaccination will be presented by group and compared using Mann-Whitney 
U/Wilcoxon rank-sum test. 
 
 
Secondary Objective Measure (SO 3):   
The third secondary objective is to assess the acceptability of the intervention among the 
adolescents based on their positive or negative responses for each survey item. The 
groups will be compared for each survey item using a chi-square test.  
 
Exploratory Objective (EO 1): 

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The first exploratory objective is to assess if using Buzzy® and an electronic game 
before and during intramuscular vaccination will reduce risk for presyncope or syncope 
after vaccination using alternate case definitions for presyncope.  The proportion of 
adolescents with presyncope or syncope, using the two alternate case definitions for 
presyncope described in Section 4, after vaccination will be compared between the 
control and intervention groups will be compared using a chi-square test. 
 
Exploratory Objective (EO 2): 
This exploratory objective is to assess for factors associated with post-vaccination 
presyncope in adolescents in the control and intervention groups. This objective will be 
conducted using the primary and alternate case definitions for presyncope described in 
Section 4. A logistic regression model with select covariates (e.g., demographic data, 
hunger, thirst, fear, phobia, anxiety level, pain) will be used to evaluate factors 
associated with post-vaccination presyncope and syncope. The relative risk and 
associated 95% confidence interval will also be reported. 
8.3 Data Management 
 
The amount of data that will be collected for the proposed project will be substantial and 
will require a sophisticated, practical and flexible system that can accommodate different 
modes of data collection and several separate linked surveys. The Vanderbilt-designed 
resource developed specifically for online collection of research information, the 
Research Electronic Data Capture (REDCap) platform, will be used to design study 
forms, including the reaction forms, and short customized questionnaires to collect 
information from study subjects. This system will be used by Duke for data management.  
All electronic linkages will fulfill regulations for protection of human subjects and 
requirements to minimize the risk of breach of confidentiality. After initial set-up, the work 
load required for electronic data collection will be substantially reduced (description of 
REDCap resources below).44 All study-related documents containing protected health 
information, e.g. enrollment logs, case report forms, memory aids completed by study 
participants, will be maintained in secure research offices at Duke, which are accessible 
to research staff only. 
 
8.3.1 Research Electronic Data Capture (REDCap)  
Investigators within the NIH-funded Clinical and Translational Research Unit at 
Vanderbilt have developed REDCap (http://project-redcap.org/), to collect and manage 
data for diverse clinical and translational research studies. REDCap was designed 
around the concept of giving research teams an easy method to specify project needs 
and rapidly develop secure, web-based applications for collection, management and 
sharing of research data. REDCap accomplishes these key functions through use of a 
single study metadata table referenced by presentation-level operational modules. 
Based on this abstracted programming model, databases are developed in an efficient 
manner with little resource investment beyond the creation of a single data dictionary. 
The concept of metadata-driven application development is well established, and the 
critical factor for successful data collection lies in creating a simple workflow 
methodology allowing research teams to autonomously develop study-related metadata 
in an efficient manner. REDCap includes secure institutional data hosting and includes 
full audit-trails in compliance with Health Insurance Portability and Accountability Act 
(HIPAA) security requirements. The REDCap Consortium is comprised of 2318 active 

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29 
institutions.  The REDCap currently supports 68,000 projects with over 89,000 users 
spanning numerous research focus areas across the consortium.  The current project 
will use this software application for the design of electronic forms to collect information 
from study participants, to link the baseline data, sample collection date, and laboratory 
results in an automated database family, to perform data cleaning and data quality 
assurance efficiently, and to design an analytical dataset for the analysis of the project 
data.  
 
Data will be entered directly into the REDCap database by members of the study team.  
Study investigators will be responsible for assuring that all paper records are securely 
stored according to the requirements of their IRBs.  The study investigators will be 
responsible for assuring the accuracy of the data entered from the paper forms into 
REDCap, as appropriate.  Only the assigned identifiers will be used in REDCap. 
Therefore, personal health identifiers will not appear in the REDCap database. 
 
In order to perform data cleaning and data quality assurance efficiently, numerous built-
in filters and checks for consistency of the data including range and limit checks, 
branching logic and pull down menus to limit choices for categorical variables to a pre-
specified list will be implemented and performed automatically to minimize data entry 
error. The data will be randomly sampled and checked against source records on a 
regular basis. The data and related analytical datasets will also be stored with secured 
password-protected computers. Coded data without personal identifiers will be made 
available to the CDC and transferred using a secure transfer method.  
8.4 Role of the CDC Investigators in the Project 
 
This study is funded by a CDC contract with Duke University as Task Orders in the CISA 
Project Contract. The Duke University PI (Emmanuel “Chip” Walter) will oversee the 
study.  CDC staff will collaborate with the site to develop the protocol, conduct the study, 
ensure the study is aligned with US Department of Health and Human Services public 
health priorities, and analyze the data and disseminate the results. CDC may receive 
access to coded data not containing any directly identifying information. 
 
9 HUMAN SUBJECTS  
9.1 Human Subjects Involvement, Characteristics, and Design 
 
Duke investigators will be responsible for submitting the protocol, informed consent 
(Appendix B), recruitment letters, flyers, and any written or verbally conveyed materials 
specific to this project to their institutional review boards.  CDC staff will be responsible 
for submitting materials to the CDC for review and obtain reliance on Duke IRB.   
  
To facilitate subject recruitment at the practices, we will request a waiver of consent and 
HIPAA authorization for ascertainment (identification, selection) and/or recruitment of 
potential subjects while recording identifiable private health information (PHI) prior to 
obtaining the subject’s consent.  This information will be obtained from review of the 
electronic scheduling and medical record systems in the clinics in order to determine 
eligibility for study enrollment. We will review only the minimum amount of information 
necessary to determine potential eligibility. This information will be used to recruit and 

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30 
screen only. Use of PHI in this manner involves no more than minimal risk to subjects 
and no information will leave the study sites. 
 
Continuing reviews will be submitted to Duke’s IRB on an annual basis.  Protocol 
deviations or concerns about study integrity will be reported promptly to the overseeing 
IRB in accordance with institutional requirements. CDC staff will be responsible for 
submitting materials to the CDC for review and obtain reliance on Duke IRB.   
9.2 Sources of Material 
 
Medical history, immunization history and concomitant medication history will be 
obtained from the medical record and from patient report.  Demographic information will 
be obtained from the medical record and patient report.  The research staff will 
administer the beverage and food intake assessment, needle phobia assessment, 
anxiety assessment, pain assessment, presyncope symptoms assessment, repeat 
anxiety assessment and the acceptability assessment to the subjects.    
9.3 Potential Risks and Benefits 
 
There is the potential risk of loss of confidentiality about information obtained as part of 
this study.  
 
There is the also the potential that adolescent subjects could experience some 
discomfort from the intervention they are randomized to such as annoyance or 
movement limitation due to the electronic game or the cold sensation of the Buzzy®. 
 
In addition, talking to or reporting about feelings of anxiety may temporarily increase a 
subject’s awareness of this experience and increase distress. 
 
One potential benefit includes less injection site pain due to administration of Buzzy® on 
the subject’s arm.  Adolescents may also be distracted from the vaccination by playing 
the electronic game.   
 
9.4 Adequacy of Protection Against Risks 
 
9.4.1 Protections against Risk 
 Every effort possible will be made to keep information about participants confidential. 
Computerized participant information will be kept in password protected files on secured 
servers.   Paper case report forms will be kept in locked files belonging to the study 
personnel.   Any publications resulting from this work will not contain any identifiable 
participant information. 
Every effort possible will be made to minimize discomfort caused by the interventions by 
allowing patients to play a game of their choosing from a predetermined list and 
following the precise guidelines for using the Buzzy®. 
In addition, for participants with significant anxiety, the study team will notify the health 
care provider caring for the participant. 
 

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31 
9.4.2 ClinicalTrials.gov Requirements 
The project is registered on ClinicalTrials.gov. (NCT04772755).  
 
9.5 Human Subjects 
 
In obtaining and documenting informed consent, the Investigator and study team will 
comply with the applicable regulatory requirements, Good Clinical Practices, and ethical 
principles. The parent or guardian must sign and date the written informed consent form 
prior to initiation of any study procedure.   
 
9.5.1 Vulnerable Subjects Research 
Vulnerable subjects 
Children are a vulnerable research population and require additional protections when 
they are potential research subjects. This is a minimal risk study, involving the 
administration of Buzzy® and an electronic game intervention.  Because this study is no 
more than minimal risk, the permission of only one parent/guardian will be obtained.  We 
will also obtain the adolescents assent either verbally or in writing as necessitated by 
their age.   
 
 
 

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Webber BJ, Cropper TL, Federinko SP. Syncope among U.S. Air Force basic 
military trainees, August 2012-July 2013. MSMR 2013;20:2-4. 
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Ost LG. Blood and injection phobia: background and cognitive, physiological, and 
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McMurtry CM, Pillai Riddell R, Taddio A, et al. Far From “Just a Poke”: Common 
Painful Needle Procedures and the Development of Needle Fear. The Clinical Journal of 
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Raj SR, Coffin ST. Medical therapy and physical maneuvers in the treatment of 
the vasovagal syncope and orthostatic hypotension. Prog Cardiovasc Dis 2013;55:425-
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Kemper AR, Barnett ED, Walter EB, et al. Drinking Water to Prevent 
Postvaccination Presyncope in Adolescents: A Randomized Trial. Pediatrics 2017;140. 
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Trouern-Trend JJ, Cable RG, Badon SJ, Newman BH, Popovsky MA. A case-
controlled multicenter study of vasovagal reactions in blood donors: influence of sex, 
age, donation status, weight, blood pressure, and pulse. Transfusion 1999;39:316-20. 
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Graham DT. Prediction of fainting in blood donors. Circulation 1961;23:901-6. 
18. 
Bravo M, Kamel H, Custer B, Tomasulo P. Factors associated with fainting: 
before, during and after whole blood donation. Vox Sang 2011;101:303-12. 
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Meade MA, France CR, Peterson LM. Predicting vasovagal reactions in 
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Ditto B, France CR, Albert M, Byrne N. Dismantling applied tension: mechanisms 
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Fisher SA, Allen D, Doree C, Naylor J, Di Angelantonio E, Roberts DJ. 
Interventions to reduce vasovagal reactions in blood donors: a systematic review and 
meta-analysis. Transfus Med 2016;26:15-33. 

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Holly CD, Balegh S, Ditto B. Applied tension and blood donation symptoms: the 
importance of anxiety reduction. Health Psychol 2011;30:320-5. 
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Uman LS, Birnie KA, Noel M, et al. Psychological interventions for needle-related 
procedural pain and distress in children and adolescents. Cochrane Database Syst Rev 
2013:CD005179. 
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van den Berg K, Lam J, Bruhn R, Custer B, Murphy EL. Water administration and 
the risk of syncope and presyncope during blood donation: a randomized clinical trial. 
Transfusion 2012;52:2577-84. 
25. 
Centers for Disease C, Prevention. Syncope after vaccination--United States, 
January 2005-July 2007. MMWR Morb Mortal Wkly Rep 2008;57:457-60. 
26. 
Kroger AT, Duchin J, Vázquez M. General best practice guidelines for 
immunization. Best practices guidance of the Advisory Committee on Immunization 
Practices (ACIP). 2017. 
27. 
Wieling W, France CR, van Dijk N, Kamel H, Thijs RD, Tomasulo P. Physiologic 
strategies to prevent fainting responses during or after whole blood donation. 
Transfusion 2011;51:2727-38. 
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Hanson SA, France CR. Predonation water ingestion attenuates negative 
reactions to blood donation. Transfusion 2004;44:924-8. 
29. 
Newman B, Tommolino E, Andreozzi C, Joychan S, Pocedic J, Heringhausen J. 
The effect of a 473-mL (16-oz) water drink on vasovagal donor reaction rates in high-
school students. Transfusion 2007;47:1524-33. 
30. 
Kemper AR, Barnett, E.D., Walter, E.B., Hornik, C., Pierre-Joseph, N., Broder, 
K.R., Silverstein, M., Harrington, T. Oral Hydration to Prevent Post-Vaccine Presyncope 
in Adolescents: A Randomized Trial. Submitted 2017. 
31. 
Sahiner NC, Bal MD. The effects of three different distraction methods on pain 
and anxiety in children. J Child Health Care 2016;20:277-85. 
32. 
Shah V, Taddio A, McMurtry CM, et al. Pharmacological and Combined 
Interventions to Reduce Vaccine Injection Pain in Children and Adults: Systematic 
Review and Meta-Analysis. Clin J Pain 2015;31:S38-63. 
33. 
Canbulat Sahiner N, Inal S, Sevim Akbay A. The effect of combined stimulation 
of external cold and vibration during immunization on pain and anxiety levels in children. 
J Perianesth Nurs 2015;30:228-35. 
34. 
Redfern RE, Micham J, Seegert S, Chen JT. Influencing Vaccinations: A Buzzy 
Approach to Ease the Discomfort of a Needle Stick-a Prospective, Randomized 
Controlled Trial. Pain Manag Nurs 2018. 
35. 
Redfern RE, Chen JT, Sibrel S. Effects of Thermomechanical Stimulation during 
Vaccination on Anxiety, Pain, and Satisfaction in Pediatric Patients: A Randomized 
Controlled Trial. J Pediatr Nurs 2018;38:1-7. 
36. 
Bradt J, Dileo C, Magill L, Teague A. Music interventions for improving 
psychological and physical outcomes in cancer patients. Cochrane Database Syst Rev 
2016:CD006911. 
37. 
Uman LS, Chambers CT, McGrath PJ, Kisely S. Psychological interventions for 
needle-related procedural pain and distress in children and adolescents. Cochrane 
Database Syst Rev 2006:CD005179. 
38. 
Birnie KA, Chambers CT, Taddio A, et al. Psychological Interventions for Vaccine 
Injections in Children and Adolescents: Systematic Review of Randomized and Quasi-
Randomized Controlled Trials. Clin J Pain 2015;31:S72-89. 
39. 
Shahid R, Benedict C, Mishra S, Mulye M, Guo R. Using iPads for distraction to 
reduce pain during immunizations. Clin Pediatr (Phila) 2015;54:145-8. 
40. 
Pilkonis PA, Choi SW, Reise SP, Stover AM, Riley WT, Cella D. Item Banks for 
Measuring Emotional Distress From the Patient-Reported Outcomes Measurement 

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Information System (PROMIS®): Depression, Anxiety, and Anger. Assessment 
2011;18:263-83. 
41. 
Spielberger CD. Anxiety: Current trends in theory and research: Elsevier; 2013. 
42. 
Spielberger CD, Gorsuch RL, Lushene RE. Manual for the state-trait anxiety 
inventory. 1970. 
43. 
Hicks CL, von Baeyer CL, Spafford PA, van Korlaar I, Goodenough B. The Faces 
Pain Scale–Revised: toward a common metric in pediatric pain measurement. Pain 
2001;93:173-83. 
44. 
Influenza activity--United States and worldwide, 2007-08 season. MMWR Morb 
Mortal Wkly Rep 2008;57:692-7. 
 
 
 

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Appendix A – Buzzy® instructions 
 
 

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Appendix B – Informed Consent Form 

Consent to Participate in a Research Study
Preventing Post-Vaccination Presyncope and Syncope in 
Adolescents Using Simple, Clinic-based Interventions
Page 1 of 7
Parent/Guardian*Initials_________
Form
M0345
We are asking you to allow your child to take part in a research study because they are scheduled to 
have a routine vaccine.  Research studies are voluntary and include only people who choose to take part.  
Please read this consent form carefully and take your time making your decision. Please ask the study 
doctor or study staff to explain anything that you do not clearly understand.  The nature of the study, 
risks, inconveniences, discomforts, and other important information about the study are listed below.
Please tell the study doctor or study staff if your child is taking part in another research study.
Dr. Emmanuel Walter will conduct the study and it is being funded by the Centers for Disease Control 
and Prevention (CDC).  The sponsor of this study, the CDC, will pay Duke University to perform this 
research, and these funds may pay part of Dr. Walter’s salary.
WHO WILL BE MY DOCTOR ON THIS STUDY?
If you decide to have your child participate, Dr. Walter will be your child’s doctor for the study.  He will 
be in contact with your child’s regular health care provider while your child is in the study and 
afterwards, if needed.
CONCISE SUMMARY
This is a research study to test a strategy designed to prevent fainting (syncope) or symptoms that 
might occur before fainting (presyncope) in adolescents 10 through 14 years of age who are 
receiving at least one injected vaccine.  
Adolescents in this study will be randomly assigned (like flipping a coin) to one of two groups.  
Adolescents in Group 1 will select an electronic game to play and have a vibrating cooling device 
(like a small ice pack) named Buzzy® placed on the arm/s where they will receive their shot/s.  
Adolescents in Group 2 will receive usual care.  They will not choose and play an electronic game 
and Buzzy will not be applied on the upper arm at the time of vaccination.  Adolescents will answer 
questions about whether they have a fear of needles, if they have anxiety before or after the vaccine 
injection, how they feel after vaccination, if they have pain from the needles.  Adolescents will also 
be asked about their vaccination experience, and those in Group 1 will be asked about the electronic 
game and Buzzy.
Only minor risks are expected from this study.  Your child may feel slight discomfort from the 
vibration and coolness of the Buzzy®.  Your children may also experience some uneasiness 
answering some of the questions.
If you are interested in learning more about this study, please continue reading below.  
DUHS IRB
IRB NUMBER: Pro00107635
IRB REFERENCE DATE: 02/10/2021
IRB EXPIRATION DATE: 02/10/2022

Consent to Participate in a Research Study
Preventing Post-Vaccination Presyncope and Syncope in 
Adolescents Using Simple, Clinic-based Interventions
Page 2 of 7
Parent/Guardian*Initials_________
Form
M0345
WHY IS THIS STUDY BEING DONE?
The purpose of this study is to see how well a strategy designed to prevent fainting or symptoms related 
to fainting following vaccination works in children 10 through 14 years of age who are receiving one or 
more injected vaccines. Our strategy is to apply a cold, vibrating device named Buzzy® on their arm/s 
where they are getting their shot/s just prior to and during the shot/s.  If your child is in this group, they 
will also play an electronic game for 5 minutes prior to, during and after their shot/s. In this study, we 
will look at whether applying Buzzy® on the arm and playing an electronic game versus usual care 
makes people feel better during and after receiving vaccinations.  Those receiving Buzzy® and the game 
will have Buzzy® applied to the arm for 30-60 seconds prior to vaccination and during the vaccination.  
The electronic game will be played for about 5 minutes before vaccination, during vaccination, and for a 
minimum of 1 minute and up to 15 minutes following vaccination.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
Approximately 340 children will take part in this study at Duke.
WHAT IS INVOLVED IN THE STUDY?
If you agree for your child to be in this study, you will be asked to sign and date this consent form.  
Your child must also agree to participate in the study.  We will also ask your child if he/she agrees to 
participate, and if 12 years or older, we will ask him/her to sign this form.  
A member of the study staff will ask you questions regarding your child’s health (including medical 
history and current medications).  The medical history is obtained to make sure that your child is healthy 
and is eligible to participate.  If your child is not eligible, he/she will not be enrolled, and no further 
procedures will be done.
Your child will be randomly assigned (like flipping a coin) to one of 2 groups:
Group 
Strategy
What is involved
1
Buzzy® + 
electronic 
game
Wear Buzzy® on arm just prior to and during shot/s and play an electronic 
game 3-5 minutes prior to, during, and 1-15 minutes after vaccination
2
Control
This intervention group will receive usual care during vaccination. 
Your child will have an equal chance of being assigned to each of the groups.  Regardless of which 
group your child is assigned to, he/she will receive the usual standard of care for vaccinations, including 
monitoring for about 20 minutes after being vaccinated.
FOR ALL PARTICIPANTS:
All participants will be asked about their medical history, current health status, recent sleep, and about 
the last time they ate or drank.  We will also ask questions about fear of shots, pain, and anxiety.  In 
DUHS IRB
IRB NUMBER: Pro00107635
IRB REFERENCE DATE: 02/10/2021
IRB EXPIRATION DATE: 02/10/2022

Consent to Participate in a Research Study
Preventing Post-Vaccination Presyncope and Syncope in 
Adolescents Using Simple, Clinic-based Interventions
Page 3 of 7
Parent/Guardian*Initials_________
Form
M0345
addition, we will measure temperature, weight, height, pulse rate and blood pressure if not already 
measured by the clinic staff before receiving shots.  All subjects will be monitored for about 20 minutes 
after the vaccination, also called the wait period.  Your child will also be provided with the CDC’s 
Advisory Committee on Immunization Practices guidance that they may choose to sit or lie down during 
the post-vaccination wait period.
FOR PARTICIPANTS ASSIGNED TO THE BUZZY® + ELECTRONIC GAME GROUP:
In addition to the activities that occur for all participants, those who are assigned to the Buzzy® + 
electronic game group will be asked to play an electronic game on an iPad provided by the study team.  
They will play the electronic game for 3 to 5 minutes prior to vaccination, during their vaccination, and 
for 1-15 minutes following vaccination.  Buzzy® will be applied on their upper arm/s near the area 
where they will get their shot/s for 30-60 seconds prior to getting their shots.  Buzzy® will be moved 
further up on their upper arm during the actual vaccine injection.  If getting shots in both arms, Buzzy® 
will be applied on both upper arms before and during the injection.  
HOW LONG WILL MY CHILD BE IN THIS STUDY?
If you agree for your child to take part in this study, your child’s involvement may last for up to two 
hours.
You can choose to have your child stop participating at any time without penalty or loss of any benefits 
to which you or your child are entitled.  However, if you decide to stop participating in the study, we 
encourage you to talk to your study doctor first.
WHAT ARE THE RISKS OF THE STUDY?
Your child is receiving vaccinations today as part of their routine care and not as a part of this study.
Your child’s health care provider will explain the risks related to the vaccines to you before your child is 
vaccinated. 
As a result of your child participating in this study, they are at risk for the following side effects.  You 
should discuss these with the study doctor and your child’s regular health care provider if you choose.  
There may be some temporary discomfort associated with wearing Buzzy® on the arm as it applies a 
cold sensation, like wearing an ice pack, and vibrations to the arm. There are few known risks to 
interacting with an age-appropriate electronic game, and these may include fatigue or boredom.
Your child may also experience some uneasiness from answering some of the questions. These 
questions will be asked verbally by study staff or in a written format. 
There is also the potential risk of loss of confidentiality about information obtained as part of this study.  
Please see below for additional information regarding confidentiality.
There may be risks, discomforts, or side effects that are not yet known.
DUHS IRB
IRB NUMBER: Pro00107635
IRB REFERENCE DATE: 02/10/2021
IRB EXPIRATION DATE: 02/10/2022

Consent to Participate in a Research Study
Preventing Post-Vaccination Presyncope and Syncope in 
Adolescents Using Simple, Clinic-based Interventions
Page 4 of 7
Parent/Guardian*Initials_________
Form
M0345
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
There might be no direct benefit to your child for participating in this study, especially if your child is 
randomized to the usual care group. However, it is possible that participation in this study could 
decrease your child’s chance of fainting or feeling faint after vaccination.  There is also a possible 
benefit of decreased pain associated with vaccination due to the cold and vibration mechanism of 
Buzzy®.  We hope that in the future the information learned from this study will benefit other children.  
WILL MY CHILD’S INFORMATION BE KEPT CONFIDENTIAL?
Participation in research may involve some loss of privacy. We will do our best to make sure that 
information about your child is kept confidential, but we cannot guarantee total confidentiality. Your 
child’s personal information may be viewed by individuals involved in this research and may be seen by 
people including those collaborating, funding, and regulating the study. We will share only the 
minimum necessary information in order to conduct the research. If questionnaires suggest that your 
child is having considerable anxiety, we will inform your child’s health care provider. Your child’s 
personal information may also be given out if required by law. 
As part of the study, results of your child’s study-related procedures may be reported to CDC and its 
affiliates. In addition, your child’s records may be reviewed in order to meet federal or state regulations. 
Reviewers may include representatives and affiliates of the CDC, the Duke University Health System 
Institutional Review Board, and others as appropriate. If any of these groups review your child’s 
research record, they may also need to review your child’s entire medical record. 
The study results will be retained in your child’s research record for six years after the study is 
completed, or until your child reaches the age of 21, whichever is longer.  At that time, either the 
research information not already in your child's medical record will be destroyed or information 
identifying your child will be removed from such study results at DUHS.  Any research information in 
your child's medical record will be kept indefinitely.
This information may be further disclosed by the sponsor of this study.  If disclosed by the sponsor, the 
information is no longer covered by federal privacy regulations.  If this information is disclosed to 
outside reviewers for audit purposes, it may be further disclosed by them and may not be covered by 
federal privacy regulations.
While the information and data resulting from this study may be presented at scientific meetings or 
published in a scientific journal, your child’s name or other personal information will not be revealed. If 
the results from this study are published, you may receive notification of this by letter. 
Some people or groups who receive your child’s health information might not have to follow the same 
privacy rules. Once your child’s information is shared outside of DUHS, we cannot guarantee that it will 
remain private. If you decide to share your child’s private information with anyone not involved in the 
DUHS IRB
IRB NUMBER: Pro00107635
IRB REFERENCE DATE: 02/10/2021
IRB EXPIRATION DATE: 02/10/2022

Consent to Participate in a Research Study
Preventing Post-Vaccination Presyncope and Syncope in 
Adolescents Using Simple, Clinic-based Interventions
Page 5 of 7
Parent/Guardian*Initials_________
Form
M0345
study, the federal law designed to protect your child’s health information privacy may no longer apply to 
the information you have shared.  Other laws may or may not protect sharing of private health 
information.
This study is supported by the Centers for Disease Control and Prevention (CDC). Because of this 
support, your study information is protected by a Certificate of Confidentiality. 
With this Certificate, the investigators may not disclose research information that may identify you in 
any Federal, State, or local civil, criminal, administrative, legislative, or other proceedings, unless you 
have consented for this use. Research information protected by this Certificate cannot be disclosed to 
anyone else who is not connected with the research unless:
1) there is a law that requires disclosure (such as to report child abuse or communicable diseases 
but not for legal proceedings);
2) you have consented to the disclosure, including for your medical treatment; or
3) the research information is used for other scientific research, as allowed by federal regulations 
protecting research subjects.
Disclosure is required, however, for audit or program evaluation requested by the agency that is funding 
this project or for information that is required by the Food and Drug Administration (FDA).
You should understand that a Confidentiality Certificate does not prevent you or a member of your 
family from voluntarily releasing information about yourself or your involvement in this research. If you 
want your research information released to an insurer, medical care provider, or any other person not 
connected with the research, you must provide consent to allow the researchers to release it. This means 
that you and your family must also actively protect your own privacy.
Finally, you should understand that the investigator is not prevented from taking steps, including 
reporting to authorities, to prevent serious harm to yourself or others.
WHAT ARE THE COSTS TO YOU?
You or your insurance provider will be responsible and billed for all costs related to your child’s routine 
medical care, including copayments and deductibles. Routine medical care services are those that your 
child would have received for his/her condition if he/she were not participating in this research study. 
WHAT ABOUT COMPENSATION?
You will be reimbursed with a $40 ClinCard for your expenses related to your child’s participation 
(parking, gas, and time).
 
WHAT ABOUT RESEARCH RELATED INJURIES?
Immediate necessary medical care is available at Duke University Medical Center in the event that your 
child is injured as a result of his/her participation in this research study. However, there is no 
DUHS IRB
IRB NUMBER: Pro00107635
IRB REFERENCE DATE: 02/10/2021
IRB EXPIRATION DATE: 02/10/2022

Consent to Participate in a Research Study
Preventing Post-Vaccination Presyncope and Syncope in 
Adolescents Using Simple, Clinic-based Interventions
Page 6 of 7
Parent/Guardian*Initials_________
Form
M0345
commitment by Duke University, Duke University Health System, Inc., or your child’s Duke physicians 
to provide monetary compensation or free medical care to your child in the event of a study-related 
injury.
 
For questions about the study or research-related injury, contact Dr. Walter using the pager number at 
(919) 970-5720 during regular business hours, after hours and on weekends and holidays.
WHAT ABOUT MY RIGHTS TO DECLINE PARTICIPATION OR WITHDRAW FROM THE 
STUDY?
Your decision to allow your child to be in this study is voluntary.  You may choose not to have your 
child be in this study, or, if you agree to allow your child to be in the study, you may withdraw your 
child from the study at any time. If your child withdraws from the study, no new data about your child 
will be collected for study purposes unless the data concerns an adverse event (a bad effect) related to 
the study.
If such an adverse event occurs, we may need to review your child’s entire medical record.  All data that 
have already been collected for study purposes, and any new information about an adverse event related 
to the study, will be sent to the study sponsor. We may want to have an investigator assess your child.
Your decision for your child not to participate or to withdraw your child from the study will not involve 
any penalty or loss of benefits to which he/she are entitled, and will not affect their access to health care 
at Duke. Your child can still get vaccinated today, regardless of whether or not you agree to participate 
in the study.  If you decide to withdraw your child from the study, we ask that you notify any member of 
the study team during the visit or you can contact Dr. Walter in writing and let him know that your child 
is withdrawing from the study.  His mailing address is Duke Vaccine and Trials Unit, 2608 Erwin Road, 
Suite 210, Durham, NC 27705.
The study doctor or sponsor may withdraw your child from this study for any reason at any time even 
without your consent.  This could occur, for example, if the study doctor decides that it is in your child’s 
best interest.  
We will tell you about new information that may affect your child’s health, welfare, or willingness to 
stay in this study.
A description of this clinical trial will be available on https://www.clinicaltrials.gov/  as required by U.S. 
Law.  This Web site will not include information that can identify you or your child.  At most, the Web 
site will include a summary of the results.  You can search this Web site at any time.
DUHS IRB
IRB NUMBER: Pro00107635
IRB REFERENCE DATE: 02/10/2021
IRB EXPIRATION DATE: 02/10/2022

Consent to Participate in a Research Study
Preventing Post-Vaccination Presyncope and Syncope in 
Adolescents Using Simple, Clinic-based Interventions
Page 7 of 7
*
Form
M0345
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or a research-related injury, or if you have problems, concerns, questions 
or suggestions about the research, contact Dr. Emmanuel Walter using the 24 hour pager number at 
(919) 970-5720.  
For questions about you and your child’s rights as a research participant, or to discuss problems, 
concerns or suggestions related to the research, or to obtain information or offer input about the 
research, contact the Duke University Health System Institutional Review Board (IRB) Office at (919) 
668-5111.
STATEMENT OF CONSENT
"The purpose of this study, procedures to be followed, risks and benefits have been explained to my 
child and me.  I have been allowed to ask questions, and my questions have been answered to my 
satisfaction.  I have been told whom to contact if I have questions, to discuss problems, concerns, or 
suggestions related to the research, or to obtain information or offer input about the research.  I have 
read this consent form and agree for my child to be in this study, with the understanding that I may 
withdraw my child at any time.  I have discussed the study with my child, who agrees to be in the study. 
I have been told that I will be given a signed and dated copy of this consent form."
____________________________________
__________________
________________
Signature of Parent or Legal Guardian
Date                                       Time
____________________________________
__________________
________________
Signature of Subject (if 12 years or older)
Date                                       Time
____________________________________
____________________      _________________
Signature of Person Obtaining Consent
Date                                       Time
DUHS IRB
IRB NUMBER: Pro00107635
IRB REFERENCE DATE: 02/10/2021
IRB EXPIRATION DATE: 02/10/2022