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

Syncope Prevention Pilot Study 
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 Preventing Post-Vaccination Presyncope and Syncope in Adolescents Using Simple, 
Clinic-based Interventions: A Pilot Study 
Short Title: Syncope Prevention Study 
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 
NCT03533829
Version Number: 1.0 
April 17, 2018 

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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 & RATIONALE.................................................................................................................................................... 11 
2 STUDY OBJECTIVES ............................................................................................................................................ 13 
2.1 PRIMARY OBJECTIVE (PO): ............................................................................................................................................... 13 
2.2 EXPLORATORY OBJECTIVES (EO): .................................................................................................................................... 13 
3 STUDY OUTCOME MEASURES AS RELATED TO OBJECTIVES ............................................................... 14 
3.1 PRIMARY OUTCOME MEASURES (POM): ........................................................................................................................ 14 
3.2 EXPLORATORY OUTCOME MEASURES (EOM): .............................................................................................................. 14 
4 DEFINING PRESYNCOPE AND SYNCOPE ...................................................................................................... 16 
4.1 PRESYNCOPE ......................................................................................................................................................................... 16 
4.2 SYNCOPE ................................................................................................................................................................................ 16 
5 STUDY DESIGN...................................................................................................................................................... 18 
6 STUDY ENROLLMENT AND WITHDRAWAL................................................................................................ 19 
6.1 SUBJECT INCLUSION CRITERIA .......................................................................................................................................... 19 
6.2 SUBJECT EXCLUSION CRITERIA .......................................................................................................................................... 19 
6.3 RECRUITMENT ...................................................................................................................................................................... 19 
6.4 REASONS FOR AND HANDLING OF WITHDRAWALS ........................................................................................................ 20 
6.5 TERMINATION OF STUDY .................................................................................................................................................... 20 
7 STUDY SCHEDULE, PROCEDURES, & EVALUATIONS ............................................................................... 20 
7.1 SCHEDULE OF EVENTS ........................................................................................................................................................ 20 
7.2 Parent/Guardian(s) Permission Process (Informed Consent) ................................................................. 21 
7.3 Overview of Study Assessments ............................................................................................................................ 22 
7.4 Demographic Information, Medical History ................................................................................................... 23 
7.5 Physical Measures ..................................................................................................................................................... 23 
7.8 Randomization ........................................................................................................................................................... 24 
7.8.1 Blinding ...................................................................................................................................................................... 24 
7.9 Study Interventions ................................................................................................................................................... 24 
7.9.1 Buzzy® Intervention ............................................................................................................................................ 24 
7.9.2 Music Intervention ................................................................................................................................................. 25 
7.9.3 Music and Buzzy® Combination Intervention ........................................................................................... 25 
7.12 PRESYNCOPE AND SYNCOPE ............................................................................................................................................ 25 
7.13 ACCEPTABILITY ................................................................................................................................................................. 25 
7.14 FEASIBILITY ....................................................................................................................................................................... 26 
7.15 UNSOLICITED SAES .......................................................................................................................................................... 26 
8 STATISTICAL CONSIDERATIONS .................................................................................................................... 26 
8.1 SAMPLE SIZE AND POWER ESTIMATION .......................................................................................................................... 27 
8.2 ANALYSIS PLAN .................................................................................................................................................................... 27 
8.2.1 Study Populations .................................................................................................................................................. 27 
8.2.2 Descriptive Statistics ............................................................................................................................................ 27 
8.2.3 Primary Objective (PO) 1: ................................................................................................................................... 27 
8.2.4 Primary Objective (PO) 2: ................................................................................................................................... 28 

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8.2.5 Exploratory Objective (EO) 1: ........................................................................................................................... 28 
8.2.6 Exploratory Objective (EO) 2: ........................................................................................................................... 29 
8.2.7 Exploratory Objective (EO) 3: ........................................................................................................................... 30 
8.3 DATA MANAGEMENT .......................................................................................................................................................... 30 
8.3.1 Research Electronic Data Capture (REDCap) ............................................................................................. 30 
8.4 ROLE OF THE CDC INVESTIGATORS IN THE PROJECT .................................................................................................... 31 
9 HUMAN SUBJECTS ............................................................................................................................................... 32 
9.1 HUMAN SUBJECTS INVOLVEMENT, CHARACTERISTICS, AND DESIGN .......................................................................... 32 
9.2 SOURCES OF MATERIAL ...................................................................................................................................................... 32 
9.3 POTENTIAL RISKS AND BENEFITS ..................................................................................................................................... 32 
9.4 ADEQUACY OF PROTECTION AGAINST RISKS .................................................................................................................. 32 
9.4.1 Protections against Risk ...................................................................................................................................... 32 
9.4.2 CLINICALTRIALS.GOV REQUIREMENTS ......................................................................................................................... 33 
9.5 HUMAN SUBJECTS ................................................................................................................................................................ 33 
9.5.1 Vulnerable Subjects Research ........................................................................................................................... 33 
10 REFERENCES ....................................................................................................................................................... 34 
 
 

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PROTOCOL SUMMARY 
 
Title:  
Preventing Post-Vaccination Presyncope and Syncope in Adolescents 
Using Simple, Clinic-based Interventions: A Pilot Study 
Population: 
Up to 30 adolescents, 10 to 17 years of age, who will receive at least one 
intramuscularly administered vaccine  
Clinical Sites: 
One: Duke University  
Study Duration: 
6 weeks 
 
Participant 
Duration: 
1 day 
Description of 
Study Procedures: 
This is a randomized controlled open-label trial.  During the study, 
adolescents scheduled to receive at least one IM vaccine will receive 
either Buzzy®, Music, or Buzzy® and Music intervention(s) in addition to 
standard care to evaluate the feasibility and acceptability of these 
interventions prior to being used in a larger study to assess the 
effectiveness of the interventions in preventing post-vaccination 
presyncope and syncope.  Feasibility will be assessed according to study 
staff ability to successfully administer the protocol specified clinic-based 
interventions and per both study staff and healthcare provider responses 
to written feasibility assessments.  Acceptability will be assessed 
according to the participant’s self-report. In addition, baseline needle 
phobia and anxiety, post-vaccination pain and presyncope symptoms, 
and pre- and post- vaccination state anxiety will be assessed per 
participant written self-report to standardized survey questions.  
Objectives: 
Primary Objectives (PO): 
 PO 1: To assess the feasibility of using simple clinic-based interventions 
(Buzzy® alone, music alone, or Buzzy® and music together) to inform 
the development of a larger study designed to assess the effectiveness 
of the interventions in preventing post-vaccination presyncope in 
adolescents 
PO 2: To assess the acceptability of using simple clinic-based 
interventions (Buzzy® alone, music alone, or Buzzy® and music 
together) to inform the development of a larger study designed to assess 
the effectiveness of the interventions in preventing post-vaccination 
presyncope in adolescents 
Exploratory Objectives (EO): 
EO1: To describe the proportion of adolescents with presyncope or 
syncope after vaccination by intervention group when Buzzy® is applied 

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alone, music is played alone, or Buzzy® and music interventions are 
employed simultaneously 
EO2: To describe injection-site pain immediately after and after a brief 
wait period following vaccination of adolescents, when Buzzy® is applied 
alone, music is played alone, or Buzzy® and music interventions are 
employed simultaneously. Injection-site pain will be measured using 
Wong-Baker Faces Pain Scale©.  The scales ranges from 0 – 10, where 
a value of 0 indicates “No Hurt” and a value of 10 indicates “Hurts 
Worst”. 
EO3: To describe the change in state (momentary) anxiety score in 
adolescents before and after vaccination, when Buzzy® is applied alone, 
music is played alone, or Buzzy® and music interventions are employed 
simultaneously  
Outcome Measures: Primary Outcome Measures (POM):  
POM 1.1: The proportion of adolescents meeting each feasibility 
benchmark.  
POM 1.2: Descriptive results of feasibility survey among study 
coordinators   
POM 1.3: Descriptive results of feasibility survey among study healthcare 
providers 
POM 2: Descriptive results of study intervention acceptability surveys 
among study adolescents 
Exploratory Outcome Measures (EOM): 
EOM 1.1: The proportion of adolescents with presyncope symptoms as 
described in the modified Blood Donations Reactions Inventory (BDRI) 
after vaccination or witnessed presyncope after vaccination in the 
absence of a BDRI assessment   
EOM 1.2: Describe any post-vaccination syncope events occurring in the 
study population 
EOM 2.1: The proportion of adolescents reporting an injection site pain 
score ≥2, on the Wong-Baker Faces Pain Scale©, ≤1 minute following 
vaccination  
EOM 2.2: The proportion of adolescents reporting an injection site pain 
score ≥ 4, on the Wong-Baker Faces Pain Scale©, ≤1 minute following 
vaccination 
EOM 2.3: The proportion of adolescents reporting an injection site pain 
score ≥2, on the Wong-Baker Faces Pain Scale©, at (approximately) 10 
minutes following vaccination. 
EOM 2.4: The proportion of adolescents reporting an injection site pain 
score ≥ 4, on the Wong-Baker Faces Pain Scale©, at (approximately) 10 
minutes following vaccination 
EOM 2.5: Describe average injection-site pain scores on the Wong-
Baker Faces Pain Scale© at ≤1 minute following vaccination 

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EOM 2.6: Describe average injection-site pain scores on the Wong-
Baker Faces Pain Scale© at (approximately) 10 minutes following 
vaccination 
EOM 3.1:  Describe the categorical change (positive, negative, no 
change) in pre- and post- vaccination state anxiety 
EOM 3.2: Describe the numeric change (mean and range) in pre- minus 
post- vaccination state anxiety 
Estimated Time to 
Complete 
Enrollment: 
Approximately 6 weeks 

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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 Syncope is fairly 
common and more frequently occurs among females, with a peak incidence between 15 
and 19 years of age.2  Although uncommon, syncope can occur following immunization 
and result in serious injury.3   
 
Vasovagal (neurocardiogenic) syncope is the most common form of syncope.4 
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. 
 
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.5 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).6  The 
median age of onset of blood-injury-injection phobia is 7-11 years.7 
 
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.8 Although uncommon, with an estimated 
rate of 1 per 1000 in the adolescent age group,9 syncope after vaccination can lead to 
serious injury. An analysis of cases reported to VAERs in the 1990s described cases of 
syncope following immunization.3 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.7,12 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 and 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 universally 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).7,11,14,16,17,20-24  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 

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(ACIP) recommends that providers should take appropriate measures to prevent injuries 
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 increases 
peripheral vascular tone by stretching of baroreceptors in the stomach wall, and is also 
believed to be achieved through effects on the portal venous system from ingesting a 
hypo-osmolalar beverage.27-29  Water can have an effect within 15 minutes 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 interveion 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-
vaccination anxiety levels; history of passing out or nearly passing out after a “shot” or 

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blood draw, 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 
promoting relaxation, mitigating anxiety, and reducing immediate pain after vaccination.  
 
1.2 Summary & Rationale 
 
In children and adolescents, distraction and relaxation methods, such as listening to 
music, have shown some effectiveness in decreasing medically-related anxiety23,31,32 
and pain.33  Further, other interventions, such as 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 
To identify best practices for preventing post-vaccination vasovagal syncope, we will 
target adolescents, a higher-risk population for post-vaccination 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 blood donation literature, which does not 
identify one intervention with high efficacy, we plan to investigate two distinct previously 
unstudied interventions to prevent post-vaccination syncope through mitigation of 
immediate injection-site pain and anxiety. We will also assess use of a combination of 
these interventions.  
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 73% 
in children aged 7 years receiving Tdap in a prospective , randomized controlled trial,  
and the cost of the device ranges from $40 - $100 for an individual Buzzy® 
[https://buzzyhelps.com/store/buzzy-professional].34  
Consumer reviews of Buzzy® are positive. As seen on Amazon.com, the ‘Buzzy Mini 
Personal Striped’ has received 4 out of 5 stars from 552 customers.35 The top positive 
review, as designated by the Amazon website, spoke positively of the device for use 
with at-home injections. The top critical review noted that a two-year-old child was 
unreceptive to the cold features of the device (Customer Reviews). Additional web 
searches identified several personal blogs, mostly written by mothers who had 
purchased the device for their child’s injections, which were generally positive. 
Additionally, clinical settings have started using the device including the Shriners 
Hospitals for Children in Greenville, South Carolina (Shriner’s Hospitals). 
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 with a toy, and musical 
distraction.36 Results suggested these distraction techniques showed beneficial effects 
in reducing pain and distress from vaccinations.37 An additional review focusing 
specifically on the utility of music in mitigating procedural pain and anxiety among youth 
demonstrated reduced anxiety and improved experience of pain even after controlling 
for covariates.38 The effects of music on anxiety have been demonstrated across 
outcome measures spanning self-report, parent-report, observer-report, and 

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physiological functioning (Heart Rate).  Moreover, based on subgroup analyses, they 
further concluded that passive music therapy (i.e., listening to music) may be as 
effective as active music therapy (i.e., working with a specified music therapist), and 
that music when combined with other modalities (e.g., may be more effective than when 
presented alone.39 Importantly, music is a low-cost and practical intervention for use in 
clinical settings.23,40 To the extent that that listening to music is an effective independent 
and/or adjunctive strategy in improving pain/or anxiety associated with injections, it may 
also help mitigate the role of these factors in the development of presyncopal 
symptoms. 
In summary, we aim to first assess the feasibility and acceptability among adolescents 
of using Buzzy® alone, music distraction alone, or both Buzzy® and music distraction 
together to prevent post-vaccination presyncope. Results of pilot study assessments 
will be used to guide the development of a full study to assess the effectiveness of the 
most feasible and acceptable intervention. 
 

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2 STUDY OBJECTIVES 
 
2.1 Primary Objective (PO): 
 
PO 1: To assess the feasibility of using simple clinic-based interventions (Buzzy® alone, 
music alone, or Buzzy® and music together) to inform the development of a larger study 
designed to assess the effectiveness of the interventions in preventing post-vaccination 
presyncope in adolescents 
PO 2: To assess the acceptability of using simple clinic-based interventions (Buzzy® 
alone, music alone, or Buzzy® and music together) to inform the development of a larger 
study designed to assess the effectiveness of the interventions in preventing post-
vaccination presyncope in adolescents 
2.2 Exploratory Objectives (EO): 
 
EO1: To describe the proportion of adolescents with presyncope or syncope after 
vaccination by intervention group when Buzzy® is applied alone, music is played alone, 
or Buzzy® and music interventions are employed simultaneously   
 
EO2: To describe injection-site pain immediately after and after a brief wait period 
following vaccination of adolescents, when Buzzy® is applied alone, music is played 
alone, or Buzzy® and music interventions are employed simultaneously. Injection-site 
pain will be measured using Wong-Baker Faces Pain Scale©.  The scales ranges from 0 
– 10, where a value of 0 indicates “No Hurt” and a value of 10 indicates “Hurts Worst”.  
 
EO3: To describe the change in state (momentary) anxiety score in adolescents before 
and after vaccination, when Buzzy® is applied alone, music is played alone, or Buzzy® 
and music interventions are employed simultaneously 
 

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3 STUDY OUTCOME MEASURES AS RELATED TO OBJECTIVES 
3.1 Primary Outcome Measures (POM): 
 
POM 1.1: The proportion of adolescents meeting each feasibility benchmark 
 
POM 1.2: Descriptive results of feasibility survey among study coordinators   
 
POM 1.3: Descriptive results of feasibility survey among study healthcare providers 
 
POM 2: Descriptive results of study intervention acceptability surveys among study 
adolescents  
3.2 Exploratory Outcome Measures (EOM): 
 
EOM 1.1: The proportion of adolescents with presyncope symptoms as described in the 
modified Blood Donations Reactions Inventory (BDRI) after vaccination or witnessed 
presyncope after vaccination in the absence of a BDRI assessment   
 
EOM 1.2: Describe any post-vaccination syncope events occurring in the study 
population 
 
EOM 2.1: The proportion of adolescents reporting an injection site pain score ≥2, on the 
Wong-Baker Faces Pain Scale©, ≤1 minute following vaccination 
 
EOM 2.2: The proportion of adolescents reporting an injection site pain score ≥ 4, on 
the Wong-Baker Faces Pain Scale©, ≤1 minute following vaccination 
 
EOM 2.3: The proportion of adolescents reporting an injection site pain score ≥2, on the 
Wong-Baker Faces Pain Scale©, at (approximately) 10 minutes following vaccination 
 
EOM 2.4: The proportion of adolescents reporting an injection site pain score ≥ 4, on 
the Wong-Baker Faces Pain Scale©, at (approximately) 10 minutes following vaccination 
 
EOM 2.5: Describe average injection-site pain scores on the Wong-Baker Faces Pain 
Scale© at ≤1 minute following vaccination 
 
EOM 2.6: Describe average injection-site pain scores on the Wong-Baker Faces Pain 
Scale© at (approximately) 10 minutes following vaccination 
 
EOM 3.1:  Describe the categorical change (positive, negative, no change) in pre- and 
post- vaccination state anxiety 
 

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EOM 3.2: Describe the numeric change (mean and range) in pre- minus post- 
vaccination state anxiety  

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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, 
the Blood Donations Reactions Inventory (BDRI), expert opinion, and prior experience 
with the 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 Oral Water Hydration to 
Prevent Post-Vaccination Presyncope (“Water and Vaccines Study”) is below: 
 
Sudden onset of one or more of the following symptoms or signs during the post-
vaccination observation period in the clinic: 
 
Symptoms  
• 
Feeling lightheaded, 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 like your heart is beating fast or hard or pounding 
• 
Feeling hot AND sweaty 
• 
Feeling cold AND sweaty, or “clammy” 
• 
Feeling like you are breathing fast or hard 
• 
Feeling like you might throw up (nausea)  
 
Signs  
• 
Pallor 
• 
Sweaty 
• 
Facial flush 
• 
Decreased interactivity (decreased level of arousal or responsiveness) 
 
AND  
• 
Not Syncope  
• 
Not Due to another Cause 
• 
Not clearly present at baseline  
 
For the purpose of this study, presyncope will be defined as any response of self-report 
of “some,” or “a lot,” to the modified BDRI or study staff noting signs or symptoms on 
study documents if the subject requires medical attention and does not complete the 
BDRI form 
 
Usual clinical care will be provided to any subject who develops presyncope. 
 
4.2 Syncope 
 

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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 pilot study is a prospective, randomized, open-label clinical trial that will be 
conducted in adolescents (10-17 years of age) receiving at least one recommended 
intramuscularly administered vaccine to evaluate the feasibility and acceptability of using 
two different interventions that might prevent post-vaccination presyncope, and by 
extension syncope.   The two interventions to be evaluated are 1) Buzzy® Drug Free 
Pain Relief which is a medical device designed to reduce vaccination pain and 2) 
Listening to music as a distraction technique.  We will also evaluate both interventions 
when administered simultaneously (Buzzy® and music).  We will enroll approximately 30 
subjects into this pilot study.  Eligible adolescents will be randomized (1:1:1) to receive 
one of the three above named interventions: 1) Buzzy® alone; 2) Music alone; or 3) 
Buzzy® and Music together to assess for feasibility and acceptability. Eligible 
adolescents must have an identified risk factor for the development of presyncope 
including being either of younger age (10-13 years) or receiving 2 or more injectable 
vaccines (one of which must be received intramuscularly).  A minimum of 20% of 
adolescents enrolled across all intervention groups will be 10-13 years of age and a 
minimum of 20% of adolescents enrolled across all intervention groups will be 14-17 
years of age.  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), the occurrence of witnessed syncope or 
presyncope, and presyncopal symptoms as rated by the modified BDRI. For the primary 
objective, we will assess the acceptability and feasibility of both interventions separately 
or together.  For the exploratory objectives, we will assess presyncope symptoms 
following vaccination, post-vaccination pain, and change in anxiety from baseline for the 
adolescents randomized to each of the intervention groups.  Using lessons learned 
during the Pilot, if feasible and acceptable, we will evaluate the most feasible and 
acceptable presyncope prevention strategy in a larger effectiveness trial. 

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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 17 years of age 
2. If 10 through 13 years of age, the subject must be receiving at least one vaccine 
delivered intramuscularly 
3. If 14 through 17 years of age, the subject must be receiving at least two 
injectable vaccines one of which must be delivered intramuscularly 
4. 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. 
5. The subject must be willing to stay for the completion of all study-related 
activities. 
6. Parent/guardian and adolescent must speak and read English by self-report  
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. Inability to hear  
10. Significant visual impairment or blindness 
11. Febrile or acutely ill individuals 
12. Upper arm or shoulder pain or injury 
13. Adolescent or parent/Guardian is an immediate relative of study staff or an 
employee who is supervised by study staff. 
14. 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 30 participants in this study will be male or female adolescents 10 to 17 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 
Regional Pediatrics).  Adolescents will primarily be recruited at the time of well child 
visits.   

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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 
prior to randomization or intervention will be replaced. 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 
Lead or Contributing sites, CDC, or participating Institutional Review Boards (IRBs).   
 
7 STUDY SCHEDULE, PROCEDURES, & EVALUATIONS 
7.1 Schedule of Events 
Adolescents meeting the proposed eligibility criteria will be recruited. Written permission 
for the adolescent to participate will be obtained from parent(s)/Guardian(s) prior to 
conducting any study procedures.  Assent will also be obtained from the adolescents. 
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 
 
 
Youth General Anxiety Assessment 
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 standard of care) 
X 
 
 
X (blood pressure, 
pulse) (20 minutes) 
Randomization 
X 
 
 
Buzzy® alone, Music alone, Simultaneous 
Buzzy® and Music Distraction 
X 
 
 
Administer vaccines (not a study procedure) 
 
X 
 
 
Injection site pain assessment 
 
 
X  

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(within <1 and  at 
10 minutes)  
Presyncope symptoms assessment  
 
 
X  
(15 minutes) 
Tolerability and Acceptability Assessment  
 
 
X  
(20 minutes)  
1. Complete prior to tolerability and 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 2 weeks 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 three intervention arms  
• 
Administer assigned study intervention 
 
Visit 1, Study Day 1 Clinic Visit Vaccination 
• 
Vaccines administered by clinic staff (Not a study procedure) 
• 
Vaccines administered as standard of 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 but 
no longer than 1 minute after 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 minute and 10 (up to 
15) minutes after the last injection.  
• 
Complete the presyncope symptoms assessment modified BDRI (15 (up to 20) 
minutes post vaccination) 
• 
Obtain second assessment of vital signs (blood pressure, and pulse).  
• 
Complete the state anxiety assessment (20 (up to 25) minutes post vaccination) 
• 
Complete the acceptability assessment (20 (up to 30) minutes post vaccination) 
• 
Study team to complete the feasibility assessment 
• 
Coordinator feasibility assessment 
• 
Healthcare provider feasibility assessment  
 
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.  Parent(s)/Guardian(s) will be given as much time as needed after being 
approached about their adolescent participating in the study and needing to decide 

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whether or not to participate.  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, health 
insurance status, and 
country of origin 
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, 
headaches, prescription 
and over-the counter 
medications in preceding 
week, supplements in 
preceding week )  
Physical Measures  
Height and weight 
measurement (from 
medical record if obtained 
or measured) 
Temperature 
measurement 
Pulse rate measurement 
Blood pressure 
measurement 
Pain at baseline 
(anywhere) 
Height, Weight and 
Calculated BMI 
 
Body temperature 
Pulse rate pre- and post-
vaccination 
Blood pressure pre- and 
post –vaccination 
Fatigue/ tiredness 
Participant  
Estimated hours of sleep 
the previous night 
Feeling tired 

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Hunger 
Participant  
Meals eaten on day of 
vaccination 
Last meal and type 
Last food eaten 
Hunger estimation 
Thirst 
Participant  
Time/type of last beverage 
consumed prior to 
vaccination 
Quantification of last 
beverage 
Thirst estimation 
Needle-related fear 
Participant response 
Needle phobia 
questionnaire 
Global question about fear 
of injections 
Anxiety 
Participant response  
PROMIS anxiety rating 
scale 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, race/ethnicity, and country of origin will be obtained from 
parent/guardian report at the time of enrollment. The insurance payer status for the 
adolescent will be obtained from the electronic health record (EHR). The participant’s 
medical history including: history of pre-syncope, syncope, cardiac conditions, seizures, 
hypoglycemia, diabetes, headaches, prescription and over-the counter medications in 
preceding week, supplements in preceding week will be obtained by review of the 
electronic health record (EHR) and will be reviewed and confirmed by 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 either through standard of care measurements or the study team 
will perform these assessments if they are not otherwise available. In addition, the clinic 
baseline pain assessment will be recorded. Blood pressure, and pulse will also be 
reassessed 20 minutes post-vaccination. 

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7.6 Needle Related Fear  
Fear of having blood drawn has been shown to be predictive of vasovagal reactions in 
young blood donors.7 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: 1- not at all afraid; 
2- slightly afraid; 3- somewhat afraid; 4-very afraid; 5- extremely afraid.  In 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. 7,19 
 
7.7 Anxiety  
Prior to vaccination the study coordinator will have each subject complete a 
questionnaire to assess generalized anxiety using the Patient-Reported Outcomes 
Measurement Information System (PROMIS) anxiety short form instrument for 
adolescents (11-17 years) to categorize their overall degree of anxiety.41 A resource list 
of mental health providers will be made available to parents upon request.  
 
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.42,43  
 
 
7.8 Randomization 
Participants will be randomized (1:1:1) to receive either music intervention alone, 
Buzzy® alone, or combination music and Buzzy® using a permuted block randomization 
scheme.  A minimum of 6 participants per age strata (10-13 and 14-17 years) will be 
enrolled across all intervention groups. 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® Intervention 
Participants randomized to Buzzy® will apply or have applied by a member of the study 
team Buzzy® XL Healthcare Professional as described in the package insert on the 
deltoid vaccination site for 30-60 seconds, then move Buzzy® proximal to 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 
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will be recorded. If more than one vaccination is given in a single arm only one Buzzy® 
device will be applied per package instructions.  
 
7.9.2 Music Intervention 
Participants randomized to Music Distraction will be instructed to select music from a 
prepopulated playlist or music streaming service on an iPod, iPad, or similar device 
provided by the study team. Music will be played for a minimum of 3 to 5 minutes prior to 
vaccination over a Bluetooth speaker that can easily be transported between clinic 
rooms and clinics.   Music will be played until the time of the pain assessment – 10 
minutes following vaccination.  The start and stop time of music distraction will be 
recorded.  
 
7.9.3 Music and Buzzy® Combination Intervention 
This intervention group will receive a combination of music therapy and Buzzy®. The 
music will be administered the same way as that for the music only intervention group 
with Bluetooth speakers playing music the subjects select from an IPad provided to 
them. The Buzzy® will be applied after the music intervention has begun prior to 
vaccination. Buzzy® will be applied as described above in Section 7.9.1. Start and stop 
times for both interventions will be recorded. 
 
7.10 Immunizations Administered During Visit 
 
Vaccines received as part of standard of 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.44   The Wong- Baker 
Faces Pain Scale scores pain on a 0-10 metric and shows a close linear relationship 
with visual analog pain scales across the ages from 11-17 years, this scale is acceptable 
to use on younger adolescents as well.  Pain will be assessed at within 1 minute 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 20 minute (up to 25 minute) observation period, research staff 
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 (Appendix B).  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 will be solicited. 

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7.14 Feasibility 
For each participant encounter, feasibility will be assessed by determining the degree of 
ease the study staff member had with assuring that the participant had complying with 
the study interventions - Buzzy® or Music.    In addition, for each participant encounter, 
the feasibility of study interventions will also be assessed by the provider administering 
vaccines to the participants. Where appropriate, a Likert scale will be used to assess 
feasibility responses.   Benchmarks for intervention feasibility in addition to benchmarks 
for completion of assessments are listed in Appendix C. No identifiable information will 
be collected from either the coordinator or the provider.  They will not be considered 
study participants. 
7.15 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 
(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 
In collaboration with Duke, the research team at the CDC will oversee the statistical 
analysis. The 30 children enrolled in this study are considered part of a pilot to assess 
intervention acceptability and feasibility and make adjustments in study design if 
necessary to guide a potential future larger study design and conduct.    All data for this 
study will reside on a secure Duke server maintained by Duke Health Technology 
Solutions (DHTS).  For the pilot study, a database will be developed and a dataset 
without personal identifiers will be made available to the CDC for analysis purpose.  All 
analyses will be performed using SAS version 9.4. 

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8.1 Sample Size and Power Estimation 
The Pilot phase of the study aims to enroll up to 30 participants. This is an acceptability 
and feasibility assessment and is not a powered study. 
8.2 Analysis Plan 
 
8.2.1 Study Populations  
The study will enroll adolescents, female and male, ages 10-17 years, receiving at least 
one ACIP recommended vaccine administered intramuscularly administered.  
Participants will be randomized into one of three intervention groups: Buzzy® only, 
Music only, Buzzy® and Music together.     
     
There will be two study populations used for data analysis in this study. These are 
defined below:   
• 
Intent-to-treat (ITT) population:  is defined as those subjects who are 
randomized and have received at least one dose of an intramuscularly 
administered 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 study procedures including all 
surveys post-vaccination through the 20-minute time-period, and have 
no protocol violations that are likely to affect the objectives. 
 
The primary and exploratory objective analyses will be performed in the ITT and per-
protocol populations, or only the ITT population if no subject is excluded from the per 
protocol population. The primary and exploratory objective analyses will be performed by 
intervention group and age group (10-13 and 14-17), as appropriate.   
 
8.2.2 Descriptive Statistics 
Descriptive analyses will be conducted for demographic variables and for baseline 
characteristics (e.g., fatigue, hunger, thirst, and PROMIS score).  Continuous variables 
will be summarized with standard descriptive statistics including means, medians, 
ranges, 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.  Figures will be provided to evaluate the data 
distribution.  The descriptive statistics will be analyzed in the ITT and per-protocol 
population, accordingly.   
 
8.2.3 Primary Objective (PO) 1:  
To assess the feasibility of using simple clinic-based interventions (Buzzy® alone, music 
alone, or Buzzy® and music together) to inform the development of  a larger study 
designed to assess the effectiveness of the interventions in preventing post-vaccination 
presyncope in adolescents 
 
Primary Objective Measure (POM) 1.1: The proportion of adolescents meeting each 
feasibility benchmark  

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• 
Assess the proportions of those achieving each feasibility benchmark (Appendix 
C) within each intervention group and overall, as applicable.  A descriptive 
summary of findings by age group will also be conducted, as appropriate.  
 
Primary Objective Measure (POM) 1.2: Descriptive results of feasibility survey among 
study coordinators   
• 
Assess study coordinator feasibility questionnaires for each survey question by 
intervention group and by age group.  Percentages, means and/or medians will 
be presented.  A descriptive summary of qualitative responses will also be 
presented.  
 
Primary Objective Measure (POM) 1.3: Descriptive results of feasibility survey among 
study healthcare providers  
• 
Assess healthcare provider feasibility questionnaires for each survey question by 
intervention group and by age group.  Percentages, means and/or medians will 
be presented. A descriptive summary of qualitative responses will also be 
presented. 
 
8.2.4 Primary Objective (PO) 2:  
To assess the acceptability of using simple clinic-based interventions (Buzzy® alone, 
music alone, or Buzzy® and music together) to inform the development of  a larger study 
designed to assess the effectiveness of the interventions in preventing post-vaccination 
presyncope in adolescents  
 
Primary Objective Measure (POM) 2:  Descriptive results of study intervention 
acceptability surveys among study adolescents  
• 
Assess intervention acceptability questionnaire for each survey question by 
intervention group and by age group.  Percentages, means and/or medians will 
be presented.  A descriptive summary of qualitative responses will also be 
presented. 
 
8.2.5 Exploratory Objective (EO) 1: 
To describe the proportion of adolescents with presyncope or syncope after vaccination 
by intervention group when Buzzy® is applied alone, music is played alone, or Buzzy® 
and music interventions are employed simultaneously  
 
 Exploratory Outcome Measure (EOM) 1.1: The proportion of adolescents with 
presyncope symptoms as described in the modified Blood Donations Reactions 
Inventory (BDRI) after vaccination or witnessed presyncope after vaccination in the 
absence of a BDRI assessment   
 
• 
Assess proportions of presyncope symptoms using the modified BDRI and/or 
witnessed signs/symptoms by study staff in participants after vaccination by 
intervention group and by age group, as appropriate.  
 
Exploratory Outcome Measure (EOM) 1.2:  Describe any post-vaccination syncope 
events occurring in the study population 
• 
Report the frequency and nature of any post-vaccination syncope events in the 
study population.  Describe the event(s) and outcomes.        

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8.2.6 Exploratory Objective (EO) 2: 
To describe injection-site pain immediately after and after a brief wait period following 
vaccination of adolescents, when Buzzy® is applied alone, music is played alone, or 
Buzzy® and music interventions are employed simultaneously. Injection-site pain will be 
measured using Wong-Baker Faces Pain Scale©.  The scales ranges from 0 – 10, 
where a value of 0 indicates “No Hurt” and a value of 10 indicates “Hurts Worst”. 
 
Exploratory Outcome Measure (EOM) 2.1: The proportion of adolescents reporting an 
injection site pain score ≥2, on the Wong-Baker Faces Pain Scale©, ≤1 minute 
following vaccination  
• 
Assess frequency and proportions of adolescents reporting injection-site pain 
score ≥2 according to Wong Baker FACES Pain Scale©, at ≤1 minute following 
vaccination by intervention group and by age group, as appropriate. (For 
adolescents receiving more than one vaccine, maximum pain score will be 
analyzed.)     
 
Exploratory Outcome Measure (EOM) 2.2: The proportion of adolescents reporting an 
injection site pain score ≥ 4, on the Wong-Baker Faces Pain Scale©, ≤1 minute 
following vaccination  
• 
Assess frequency and proportions of adolescents reporting injection-site pain 
score ≥ 4 according to Wong Baker FACES Pain Scale©, at ≤1 minute 
following vaccination by intervention group and by age group, as appropriate. 
(For adolescents receiving more than one vaccine, maximum pain score will be 
analyzed.)     
 
Exploratory Outcome Measure (EOM) 2.3: The proportion of adolescents reporting an 
injection site pain score ≥2, on the Wong-Baker Faces Pain Scale©, at (approximately) 
10 minutes following vaccination  
• 
Assess frequency and proportions of adolescents reporting injection-site pain 
with score ≥2 according to Wong Baker FACES Pain Scale©, at (approximately) 
10 minutes following vaccination by intervention group and by age group, as 
appropriate. (For adolescents receiving more than one vaccine, maximum pain 
score will be analyzed.)     
 
Exploratory Outcome Measure (EOM) 2.4: The proportion of adolescents reporting an 
injection site pain score ≥ 4, on the Wong-Baker Faces Pain Scale©, at (approximately) 
10 minutes following vaccination  
• 
Assess frequency and proportions of adolescents reporting injection-site pain 
with score ≥ 4 according to Wong Baker FACES Pain Scale©, at 
(approximately) 10 minutes following vaccination by intervention group and by 
age group, as appropriate. (For adolescents receiving more than one vaccine, 
maximum pain score will be analyzed.)     
 
 
Exploratory Outcome Measure (EOM) 2.5:  Describe average injection-site pain 
scores on the Wong-Baker Faces Pain Scale© at ≤1 minute following vaccination  
• 
Assess overall mean and/or median and standard deviation of adolescent’s 
injection-site pain according to Wong Baker FACES Pain Scale©, at ≤1 minute 

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following vaccination by intervention group and by age group, as appropriate. 
(For adolescents receiving more than one vaccine, maximum pain score will be 
analyzed.) 
 
Exploratory Outcome Measure (EOM) 2.6: Describe average injection-site pain scores 
on the Wong-Baker Faces Pain Scale© at (approximately) 10 minutes following 
vaccination  
• 
Assess overall mean and/or median and standard deviation of adolescent’s 
injection-site pain according to Wong Baker FACES Pain Scale at 
(approximately) 10 minutes following vaccination by intervention group and by 
age group, as appropriate.  (For adolescents receiving more than one vaccine, 
maximum pain score will be analyzed.) 
 
8.2.7 Exploratory Objective (EO) 3:  
To describe the change in state (momentary) anxiety score in adolescents before and 
after vaccination, when Buzzy® is applied alone, music is played alone, or Buzzy® and 
music interventions are employed simultaneously  
 
Exploratory Outcome Measure (EOM) 3.1: Describe the categorical change (positive, 
negative, no change) in pre- and post- vaccination state anxiety  
• 
Assess frequency and proportions of adolescents reporting a categorical change 
(positive, negative, no change) in their overall score for anxiety according to state 
anxiety questionnaire, before and after vaccination, by intervention group and 
age group, as appropriate.  
 
Exploratory Outcome Measure (EOM) 3.2: Describe the numeric change (mean and 
range) in pre- minus post- vaccination state anxiety 
• 
Assess overall mean score and standard deviation of adolescents’ anxiety scores 
according to state anxiety questionnaire, before and after vaccination, by 
intervention group and by age group, as appropriate.   
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 novel 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)._ENREF_3345  Duke investigators have previously used the 
REDCap system for collection and analysis of large quantities of data. All study-related 
documents containing protected health information, e.g. enrollment logs, and case report 
forms, 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)  

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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 
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 into the REDCap database by members of the study team, from 
Duke using the paper case report forms utilized to record data collected as part of study 
procedures.  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.  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 will receive 
access to coded data not containing any directly identifying information, and lead the 
analysis for this study, in consultation with the study team. 
 

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9 HUMAN SUBJECTS  
9.1 Human Subjects Involvement, Characteristics, and Design 
Duke investigators will be responsible for submitting the protocol, informed consent 
(Appendix D), 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 
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 the IRBs on an annual basis.  Protocol 
deviations or concerns about study integrity will be reported promptly to the overseeing 
IRB in accordance with institutional requirements. 
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 tolerability and 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 discomfort due to music 
volume 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. 
 
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. 

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Every effort possible will be made to minimize discomfort caused by the interventions by 
adjusting music volume at patient request and following the precise guidelines for using 
the Buzzy®. 
In addition, for participants with significant anxiety, a resource list of mental health 
professionals will be made available upon request. 
9.4.2 ClinicalTrials.gov Requirements 
The project is registered on ClinicalTrials.gov. (TBD).  
 
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 music or Buzzy® 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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