A Prospective, Randomized, Open-label Clinical Trial to Assess Apnea Following Administration of 13-valent Conjugate Pneumococcal Vaccine, Diphtheria Toxoid, Tetanus Toxoid, and Acellular Pertussis Vaccine, Inactivated Polio Vaccine, Hepatitis B Vaccine, and Haemophilus Influenzae Type B Vaccine in Preterm Infants
Phase: PHASE4
Conditions: Apnea, Apnea Neonatal, Prematurity
Sponsor: Duke University

Apnea in Preterm Infants Following the  
Version 3.0 
Administration of Routine Childhood Vaccines 
 
January 22, 2024 
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 A Prospective, Randomized, Open-label Clinical Trial to Assess Apnea  Following 
Administration of 13-valent Conjugate Pneumococcal Vaccine, Diphtheria Toxoid, Tetanus 
Toxoid, and Acellular Pertussis Vaccine, Inactivated Polio Vaccine, Hepatitis B Vaccine, and 
Haemophilus influenzae Type B Vaccine in Preterm Infants 
 
Short Title: Apnea in Preterm Infants Following the Administration of Routine Childhood 
Vaccines 
 
 
Centers for Disease Control and Prevention  
Clinical Immunization Safety Assessment (CISA) Project  
 
 
Lead Site Principal Investigator: Rachel G. Greenberg, MD, MB, MHS 
Lead Site Sub-principal Investigator: Emmanuel B. Walter, MD, MPH 
 
Lead Site Sub-contractor Principal Investigator: Andrea Trembath, MD 
Lead Site Sub-contractor Sub-principal Investigator: Matt Laughon, MD 
 
Contributing Site Principal Investigator: Mary A. Staat, MD 
Contributing Site Sub-principal Investigator: Elizabeth Schlaudecker, MD 
Contributing Site Sub-principal Investigator: Brenda Poindexter, MD, MS 
 
Centers for Disease Control and Prevention (CDC) Principal Investigator: Patricia Wodi, MD  
CDC Sub-principal Investigator: Karen R. Broder, MD 
 
 
 
 
 
NCT # NCT03530124 
Version Number: 3.0 
 
January 22, 2024 
 
 

Apnea in Preterm Infants Following the  
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January 22, 2024 
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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 .............................................................................................................................. 4 
1 
BACKGROUND ................................................................................................................................... 7 
1.1 BACKGROUND .................................................................................................................................... 7 
1.2 SUMMARY & RATIONALE ................................................................................................................... 10 
2 
STUDY OBJECTIVES ....................................................................................................................... 10 
2.1 STUDY OUTCOME MEASURES AS RELATED TO OBJECTIVES ................................................................ 11 
Primary Outcome Measure (POM): .................................................................................................... 11 
Secondary Outcome Measures (SOM): ............................................................................................. 11 
3 
STUDY DESIGN ................................................................................................................................. 12 
4 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................................. 13 
4.1 SUBJECT INCLUSION CRITERIA .......................................................................................................... 13 
4.2 SUBJECT EXCLUSION CRITERIA ......................................................................................................... 13 
4.3 RECRUITMENT .................................................................................................................................. 14 
4.4 REASONS FOR AND HANDLING OF WITHDRAWALS .............................................................................. 14 
4.5 TERMINATION OF STUDY ................................................................................................................... 14 
5 
STUDY SCHEDULE, PROCEDURES, & EVALUATIONS ............................................................... 14 
5.1 SCHEDULE OF EVENTS ..................................................................................................................... 15 
5.2 Parent/LAR Permission Process (Informed Consent) ............................................................... 17 
5.3 Data Collection .......................................................................................................................... 17 
DEMOGRAPHIC INFORMATION ..................................................................................................................... 17 
BIRTH AND DELIVERY INFORMATION ............................................................................................................ 17 
MEDICAL HISTORY ..................................................................................................................................... 17 
5.4 Reporting Adverse Events ............................................................................................................ 21 
5.5 FOLLOW-UP ON DAYS 3-14 FOR INFANTS IN THE VACCINATED GROUP .................................................. 21 
5.6 TREATMENT ASSIGNMENT PROCEDURES ........................................................................................... 21 
5.6.1 
Randomization....................................................................................................................... 21 
5.6.2 
Blinding .................................................................................................................................. 22 
5.5.3 
Vaccine Supply, Storage, and Administration ....................................................................... 22 
6 
STATISTICAL CONSIDERATIONS .................................................................................................. 22 
6.5 SAMPLE SIZE AND POWER ESTIMATION ............................................................................................. 23 
6.6 ANALYSIS PLAN ................................................................................................................................ 23 
6.6.1 
Pilot Study ............................................................................................................................. 23 
6.6.2 
Full Study ............................................................................................................................... 23 
6.7 DATA MANAGEMENT ......................................................................................................................... 26 
6.7.1 
Research Electronic Data Capture (REDCap) ...................................................................... 27 
6.8 ROLE OF THE CDC INVESTIGATORS IN THE PROJECT ......................................................................... 27 
7 
HUMAN SUBJECTS .......................................................................................................................... 28 
7.5 HUMAN SUBJECTS INVOLVEMENT, CHARACTERISTICS, AND DESIGN .................................................... 28 
7.6 SOURCES OF MATERIAL .................................................................................................................... 28 
7.7 POTENTIAL RISKS AND BENEFITS ...................................................................................................... 28 
7.8 ADEQUACY OF PROTECTION AGAINST RISKS ..................................................................................... 29 
7.8.1 
Protections against Risk ........................................................................................................ 29 
7.8.2 
CLINICALTRIALS.GOV REQUIREMENTS ........................................................................................... 29 
7.9 HUMAN SUBJECTS ............................................................................................................................ 29 
7.9.1 
Vulnerable Subjects Research .............................................................................................. 29 
REFERENCES ............................................................................................................................................ 30 
 

Apnea in Preterm Infants Following the  
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PROTOCOL SUMMARY 
 
Title:  
A Prospective, Randomized, Open-label Clinical Trial to Assess Apnea  
Following Administration of 13-valent Conjugate Pneumococcal Vaccine, 
Diphtheria Toxoid, Tetanus Toxoid, and Acellular Pertussis Vaccine, 
Inactivated Polio Vaccine, Hepatitis B Vaccine, and Haemophilus 
influenzae Type B Vaccine in Preterm Infants 
Phase: 
Phase 4 
Population: 
Up to 300 premature infants <33 weeks and 0 days gestational age and 
6-12 weeks postnatal age who will receive 13-valent Conjugate 
Pneumococcal Vaccine (PCV13), Diphtheria Toxoid, Tetanus Toxoid, and 
Acellular Pertussis Vaccine (DTaP), Hepatitis B vaccine (HBV), and 
Haemophilus influenzae Type B Vaccine (Hib) 
Clinical Sites: 
Three: Duke University (Lead); University of North Carolina (Lead 
Subcontractor); Cincinnati Children’s (Contributing) 
Study Duration: 
28 months 
Participant 
Duration: 
Up to 14 days 
Description of 
Study Procedures: 
This is a prospective, randomized, open-label clinical trial. Infants will be 
randomized (1:1) to receive either simultaneous administration of 
PCV13, DTaP, HBV, IPV, and Hib vaccines or no vaccination. 
Unvaccinated infants will be followed for 48 hours after randomization to 
capture episodes of apnea. Vaccinated infants will be followed for 48 
hours after vaccination for apnea. In addition, vaccinated infants will be 
followed for 14 days after vaccination for adverse events using 
information documented in the medical record or obtained by phone call 
to the parent/legally authorized representative (LAR) on day 14.  
 
Objectives: 
Primary Objective (PO): 
PO 1: To compare proportions of preterm infants with apnea in a 48-hour 
monitoring period after vaccination in the “vaccinated” group versus a 48-
hour monitoring period after randomization in the “unvaccinated” group.   
 
The primary hypothesis is that the proportion of infants with apnea will be 
higher in the “vaccinated” group compared to the “unvaccinated” group. 
 
Secondary Objectives (SO): 
SO 1: To compare the clinical importance of apneic events in a 48-hour 
monitoring period after vaccination in the “vaccinated” group versus a 48-
hour monitoring period after randomization in the “unvaccinated” group. 
SO 2: To compare proportions of preterm infants with severe 
cardiorespiratory events in a 48-hour monitoring period after vaccination 
in the “vaccinated” group versus a 48-hour monitoring period after 
randomization in the “unvaccinated” group. 
 
Exploratory Objectives (EO): 
EO 1: To compare proportions of preterm infants with temperature 
instability in a 48-hour monitoring period after vaccination in the 
“vaccinated” group versus a 48-hour monitoring period after 
randomization in the “unvaccinated” group. 

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EO 2: To compare proportions of preterm infants with other clinically 
important adverse events in a 48-hour monitoring period after 
vaccination in the “vaccinated” group versus a 48-hour monitoring period 
after randomization in the “unvaccinated” group. 
EO 3: To compare clinically important adverse events occurring between 
48 hours and 14 days after vaccination among infants in the vaccinated 
group who do, and do not have apnea in a 48-hour monitoring period 
after vaccination. 
Outcome Measures: Primary Outcome Measure (POM):  
POM 1.1: Proportion of infants with ≥ 1 apneic event in a 48-hour 
monitoring period after vaccination in the “vaccinated” group and a 48-
hour monitoring period after randomization in the “unvaccinated” group. 
Secondary Outcome Measures (SOM): 
SOM 1.1: Average number of apneic episodes in a 48-hour monitoring 
period after vaccination in the “vaccinated” group and a 48-hour 
monitoring period after randomization in the “unvaccinated” group. 
SOM 1.2: Average duration of apneic episodes in a 48-hour monitoring 
period after vaccination in the “vaccinated” group and a 48-hour 
monitoring period after randomization in the “unvaccinated” group. 
SOM 1.3:  Proportion of infants requiring any increase in respiratory 
support in a 48-hour monitoring period after vaccination in the 
“vaccinated” group and a 48-hour monitoring period after randomization 
in the “unvaccinated” group. 
SOM 2.1: Proportion of infants with ≥1 severe cardiorespiratory event in 
a 48-hour monitoring period after vaccination in the “vaccinated” group 
and a 48-hour monitoring period after randomization in the 
“unvaccinated” group. 
SOM 2.2: Proportion of infants requiring positive pressure ventilation in a 
48-hour monitoring period after vaccination in the “vaccinated” group and 
a 48-hour monitoring period after randomization in the “unvaccinated” 
group. 
Exploratory Outcome Measures (EOM): 
EOM 1.1: Proportion of infants with fever in a 48-hour monitoring period 
after vaccination in the “vaccinated” group and a 48-hour monitoring 
period after randomization in the “unvaccinated” group. 
EOM 1.2: Proportion of infants with hypothermia in a 48-hour monitoring 
period after vaccination in the “vaccinated” group and a 48-hour 
monitoring period after randomization in the “unvaccinated” group. 
EOM 2.1: Average number of oxygen desaturation events in a 48-hour 
monitoring period after vaccination in the “vaccinated” group and a 48-
hour monitoring period after randomization in the “unvaccinated” group. 
EOM 2.2: Average number of bradycardia events in a 48-hour monitoring 
period after vaccination in the “vaccinated” group and a 48-hour 
monitoring period after randomization in the “unvaccinated” group. 
EOM 2.3: Proportion of infants requiring blood culture for and/or 
antibiotics (intravenously or intramuscularly) in the setting of blood 
culture for sepsis evaluation in a 48-hour monitoring period after 
vaccination in the “vaccinated” group and a 48-hour monitoring period 
after randomization in the “unvaccinated” group. 

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EOM 2.4: Proportion of infants with a serious adverse event in a 48-hour 
monitoring period after vaccination in the “vaccinated” group and a 48-
hour monitoring period after randomization in the “unvaccinated” group. 
EOM 3.1: Proportion of hospitalized infants with ≥ 1 episode of clinical 
apnea between 48 hours and 14 days after vaccination.  
EOM 3.2: Proportion of hospitalized infants requiring any increase in 
respiratory support between 48 hours and 14 days after vaccination. 
EOM 3.3. Proportion of hospitalized infants requiring blood culture and/or 
antibiotics (intravenously or intramuscularly) in the setting of blood 
culture for sepsis evaluation in between 48 hours and 14 days after 
vaccination. 
EOM 3.4. Proportion of hospitalized infants requiring positive pressure 
ventilation in between 48 hours and 14 days after vaccination. 
EOM 3.5. Proportion of discharged infants readmitted to the hospital 
within 14 days of vaccination.  
 
Estimated Time to 
Complete 
Enrollment: 
Approximately 28 months  

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1 BACKGROUND  
1.1 Background 
Premature infants (<37 weeks gestational age at birth) are at high risk for undervaccination. 
Despite concerns regarding the immaturity of the premature infant immune system, the majority 
of premature infants achieve antibody concentrations generally accepted to correlate with 
protection.1 The Centers for Disease Control and Prevention Advisory Committee on 
Immunization Practices (ACIP) and the American Academy of Pediatrics have thus 
recommended that in most cases with the exception of hepatitis B vaccine, premature infants 
should receive all routinely recommended vaccines at the same chronological age as term 
infants.2 Despite this recommendation, premature infants have been shown to be 
underimmunized at 6 months,3 12 months,3,4 24 months,5 and 36 months6 chronological age. 
Infants who are discharged from the neonatal intensive care unit (NICU) after lengths of stay 
≥60 days are at particularly high risk, with only approximately 50% up-to-date at the time of 
discharge.7 Vaccination delay at this earlier age thus contributes to undervaccination at later 
ages.  
Premature infants are underimmunized for multiple reasons. In the general healthy infant 
population, vaccination rates are linked to a variety of factors, including socioeconomic status,8 
parental anxiety,8 and young maternal age.9 While these issues still may play a role for 
premature infants, especially considering the increased burden of prematurity among mothers of 
low socioeconomic status,10 it is clear that additional factors have an impact on vaccination 
rates for premature infants hospitalized in the NICU. Some studies have shown lower birth 
weight to be a risk factor for undervaccination,5,6 possibly indicating that more critical disease 
status may affect the decision to administer vaccines. On the contrary, diagnoses of congenital 
heart disease and bronchopulmonary dysplasia were associated with increased vaccination 
rates in another study of infants discharged from the NICU.7 It is likely that factors affecting 
vaccination rates vary according to geographic region and individual NICU. 
The perceived risk of reappearance or worsening of apnea after vaccination in premature 
infants likely contributes to undervaccination. Apnea is a common symptom noted in the NICU 
in the presence or absence of vaccination due to apnea of prematurity. Apnea of prematurity is 
a developmental disorder characterized by cessation of breathing and often accompanied by 
bradycardia, cyanosis, or pallor. Apneic events can be divided into 3 subtypes: central (failure of 
the infant to initiate a breath; obstructive (related to pharyngeal obstruction); and mixed 
(combination of central and obstructive). The pathogenesis of apnea of prematurity involves 
persistence of immature reflexes and immature responses to hypoxia and hypercapnia. The 
incidence of apnea is inversely proportional to the gestational age (GA) at birth, with essentially 
all infants ≤28 weeks’   gestation diagnosed with apnea and 20% of those born at 34 weeks’ 
gestation.11 Most, but not all, of the U.S. Food and Drug Administration labels for the commonly 
administered infant vaccines mention premature infants (Table 1). While none of the 
vaccinations are specifically indicated in premature infants, several labels provide warnings that 
advise of the risk of apnea following vaccination in premature infants (Table 1). Awareness of 
this potential risk has originated from a number of retrospective and observational studies that 
have evaluated vaccination safety in premature infants (Table 2). The incidence of 
cardiorespiratory events (i.e. apnea and/or bradycardia) following vaccination ranged from 0-
47% in these studies. Risk factors for cardiorespiratory events in some studies included lower 
gestational age and higher clinical disease severity (such as longer period of ventilation and 
presence of chronic lung disease). In several of these studies, infants served as their own 
controls, as they were observed pre-vaccination.  
The relationship between vaccination and apnea has been studied extensively but the 
evidence is inconclusive for a causal association. While retrospective and prospective 
observational studies suggest a possible link between vaccination and apnea in premature 
infants, there are several inherent problems with these studies. Each study examines different 

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combinations of vaccinations, and they commonly have small sample sizes, use retrospective 
data, and vary in inclusion criteria and definition of adverse events. Observational studies that 
use immunized infants as their own controls also have an important flaw: clinicians are most 
likely to immunize an infant at a period of high stability. Thus, a small window of time prior to 
vaccination is likely to contain fewer cardiorespiratory events. After vaccination, infants may 
experience events associated with prematurity and disease status. Only one randomized 
controlled trial has been performed and showed no difference in prolonged apneic events 
between the immunized and control groups.12 Infants in this study were enrolled at 56-60 days 
postnatal age.  However, some infants in this study received DTaP alone, while others received 
DTaP-HBV-IPV.  The variability in the evidence makes it inconclusive if the apnea described 
after vaccination in preterm infants is vaccine-related or a complication of underlying 
prematurity. 
 
Table 1. U.S. FDA labels for routine infant immunizations: indications and warnings for 
premature infants. 
Immunization 
brand name 
Component 
vaccines 
Specific indication 
for premature infants 
Warning in label for premature infants 
Pediarix13 
Diphtheria, 
tetanus, and 
acellular 
pertussis 
Hepatitis B 
recombinant 
Inactivated 
poliovirus 
No 
“Apnea following intramuscular vaccination has been observed 
in some infants born prematurely. Decisions about when to 
administer an intramuscular vaccine, including PEDIARIX, to 
infants born prematurely should be based on consideration of 
the individual infant’s medical status, and the potential benefits 
and possible risks of vaccination.” 
Pentacel14 
Diphtheria, 
tetanus, and 
acellular 
pertussis 
Inactivated 
poliovirus 
Haemophilus 
b conjugate 
No 
“Apnea following intramuscular vaccination has been observed 
in some infants born prematurely. The decision about when to 
administer an intramuscular vaccine, including Pentacel, to an 
infant born prematurely should be based on consideration of 
the individual infant's medical status and the potential benefits 
and possible risks of vaccination. The potential risk of apnea 
and the need for respiratory monitoring for 48 – 72 hours 
should be considered when administering the primary 
immunization series to very premature infants (born ≤ 28 weeks 
of gestation) and particularly for those with a previous history of 
respiratory immaturity. As the benefit of vaccination is high in 
this group of infants, vaccination should not be withheld or 
delayed.” 
Prevnar-1315 
Pneumococcal 
13-valent 
conjugate 
No 
“Apnea following intramuscular vaccination has been observed 
in some infants born prematurely. Decisions about when to 
administer an intramuscular vaccine, including Prevnar 13, to 
infants born prematurely should be based on consideration of 
the individual infant's medical status, and the potential benefits 
and possible risks of vaccination.” 
ActHIB16 
Haemophilus 
b conjugate 
No 
None 
Engenerix-B17 
Hepatitis B 
recombinant 
No 
“The potential risk of apnea and the need for respiratory 
monitoring for 48 to 72 hours should be considered when 
administering the primary immunization series to very 
premature infants (born ≤28 weeks of gestation) who remain 
hospitalized at the time of vaccination and particularly for those 
with a previous history of respiratory immaturity. It is generally 
understood that the benefit of vaccination is high in very 
premature infants. The decision to vaccinate should be based 

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on careful consideration of the potential benefits and possible 
risks.” 
 
Table 2. Evidence of adverse cardiorespiratory events (including apnea) after 
immunization in premature infants.1 
Immunization 
Study 
design 
N 
Mean 
gestational age 
(weeks) 
Cardiorespiratory 
(apnea and/or 
bradycardia) 
events 
Follow-up 
Factors 
associated with 
events 
DTwP18 
Retrospective  
97 
28 
20% 
24 hours 
Younger gestational 
age 
Longer ventilation 
Chronic lung 
disease 
DTwP ± Hib19 
Prospective 
observational 
98 
27 
17% 
24 hours 
Receipt of DTwP 
alone 
Hib, HBV, 
DTaP, IPV20 
Retrospective 
48 
26 
0% 
48 hours 
N/A 
DTwP+Hib21 
Prospective 
observational 
97 
27 
12% 
72 hours 
Lower weight 
More severe apnea 
of prematurity 
Chronic lung 
disease 
DTwP, Hib, 
HBV22 
Prospective 
observational 
79 
28 
30% 
24 hours 
N/A 
DTaP, IPV, 
Hib23 
Retrospective 
observational 
78 
28 
47% 
48 hours 
Severe clinical 
course 
Persistence of 
cardiorespiratory 
symptoms at time of 
immunization 
DTaP, IPV, 
Hib, HBV24 
Retrospective 
53 
28 
13% 
72 hours 
N/A 
DTaP12 
Randomized 
controlled 
191 
27 
“Prolonged apnea” 
16%: DTaP group 
20%: control group 
48 hours 
N/A 
DTaP, IPV, 
Hib, HBV25 
Prospective 
observational 
45 
27 
11% 
72 hours 
Chronic diseases 
Multiple, 
including HBV, 
DTaP, Hib, 
OPV26 
Retrospective 
411 
27 
5% 
7 days 
Previous sepsis 
Longer prior 
duration of CPAP 
Multiple, 
including HBV, 
DTaP, Hib, 
IPV, OPV, 
Strep pneumo, 
influenza27 
Retrospective 
497 
Not provided 
13% 
48 hours 
Younger postnatal 
age 
Lower birth weight 
More severe clinical 
illness 

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DTaP, IPV, 
Hib or DTwP, 
IPV, HiB28 
Retrospective 
124 
27 
45% 
72 hours 
Lower weight 
DTaP, Hib, 
meningococcal 
serogroup C29 
Retrospective 
76 
27 
38% 
24 hours 
N/A 
DTwP=diphtheria, tetanus, whole cellular pertussis; DTaP=Diphtheria, tetanus, acellular pertussis; HBV = hepatitis B 
virus; Hib = Haemophilus influenzae type B; IPV=inactivated poliovirus; OPV=oral poliovirus. 
 
1.2 Summary & Rationale 
Premature infants are at high risk for apnea. Current published recommendations state that 
this group of infants should receive vaccinations according to chronological age, but frequently 
this does not occur. Clinicians often delay administration of vaccinations due to concern about 
the reappearance or worsening of apnea, but evidence to support a causal association is 
inconclusive. Further study is warranted to quantify the risk and clinical importance of apnea in 
premature infants after vaccination. 
We therefore propose to conduct a randomized clinical trial to assess the risk of apnea in 
premature infants following routine vaccination. In addition, the study would provide more 
information about other adverse events following vaccination in the context of current US 
childhood vaccination practices.  This study will provide evidence about the risk and clinical 
importance of apnea after vaccination in preterm infants and will broaden understanding of 
adverse events after vaccination in the context of current US vaccination practices. A better 
understanding of the safety of routine vaccination in preterm infants will assist with clinical 
decision-making and anticipatory guidance to parents which may improve timely vaccination in 
preterm infants. Information from this study will also help guide future research efforts to identify 
potential risk factors and prevention strategies for apnea after vaccination. 
 
2 STUDY OBJECTIVES 
 
Primary Objective (PO): 
PO 1: To compare proportions of preterm infants with apnea in a 48-hour monitoring period after 
vaccination in the “vaccinated” group versus a 48-hour monitoring period after randomization in 
the “unvaccinated” group.   
The primary hypothesis is that the proportion of infants with apnea will be higher in the 
“vaccinated” group compared to the “unvaccinated” group. 
 
Secondary Objectives (SO): 
SO 1: To compare the clinical importance of apneic events in a 48-hour monitoring period after 
vaccination in the “vaccinated” group versus a 48-hour monitoring period after randomization in 
the “unvaccinated” group. 
 
SO 2: To compare proportions of preterm infants with severe cardiorespiratory events in a 48-
hour monitoring period after vaccination in the “vaccinated” group versus a 48-hour monitoring 
period after randomization in the “unvaccinated” group. 
 
Exploratory Objectives (EO): 
EO 1: To compare proportions of preterm infants with temperature instability in a 48-hour 
monitoring period after vaccination in the “vaccinated” group versus a 48-hour monitoring period 
after randomization in the “unvaccinated” group. 
 

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EO 2: To compare proportions of preterm infants with other clinically important adverse events 
in a 48-hour monitoring period after vaccination in the “vaccinated” group versus a 48-hour 
monitoring period after randomization in the “unvaccinated” group. 
 
EO 3: To compare clinically important adverse events occurring between 48 hours and 14 days 
after vaccination among infants in the vaccinated group who do, and do not have apnea in a 48-
hour monitoring period after vaccination. 
 
2.1 Study Outcome Measures as Related to Objectives 
 
Primary Outcome Measure (POM):  
POM 1.1: Proportion of infants with ≥ 1 apneic event in a 48-hour monitoring period after 
vaccination in the “vaccinated” group and a 48-hour monitoring period after randomization in the 
“unvaccinated” group. 
 
Secondary Outcome Measures (SOM): 
SOM 1.1: Average number of apneic episodes in a 48-hour monitoring period after vaccination 
in the “vaccinated” group and a 48-hour monitoring period after randomization in the 
“unvaccinated” group. 
 
SOM 1.2: Average duration of apneic episodes in a 48-hour monitoring period after vaccination 
in the “vaccinated” group and a 48-hour monitoring period after randomization in the 
“unvaccinated” group. 
 
SOM 1.3:  Proportion of infants requiring any increase in respiratory support in a 48-hour 
monitoring period after vaccination in the “vaccinated” group and a 48-hour monitoring period 
after randomization in the “unvaccinated” group. 
 
SOM 2.1: Proportion of infants with ≥1 severe cardiorespiratory event in a 48-hour monitoring 
period after vaccination in the “vaccinated” group and a 48-hour monitoring period after 
randomization in the “unvaccinated” group. 
 
SOM 2.2: Proportion of infants requiring positive pressure ventilation in a 48-hour monitoring 
period after vaccination in the “vaccinated” group and a 48-hour monitoring period after 
randomization in the “unvaccinated” group. 
 
Exploratory Outcome Measures (EOM): 
EOM 1.1: Proportion of infants with fever in a 48-hour monitoring period after vaccination in the 
“vaccinated” group and a 48-hour monitoring period after randomization in the “unvaccinated” 
group. 
 
EOM 1.2: Proportion of infants with hypothermia in a 48-hour monitoring period after vaccination 
in the “vaccinated” group and a 48-hour monitoring period after randomization in the 
“unvaccinated” group. 
 
EOM 2.1: Average number of oxygen desaturation events in a 48-hour monitoring period after 
vaccination in the “vaccinated” group and a 48-hour monitoring period after randomization in the 
“unvaccinated” group. 
 

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EOM 2.2: Average number of bradycardia events in a 48-hour monitoring period after 
vaccination in the “vaccinated” group and a 48-hour monitoring period after randomization in the 
“unvaccinated” group. 
 
EOM 2.3: Proportion of infants requiring blood culture for and/or antibiotics (intravenously or 
intramuscularly) in the setting of blood culture for sepsis evaluation in a 48-hour monitoring 
period after vaccination in the “vaccinated” group and a 48-hour monitoring period after 
randomization in the “unvaccinated” group. 
 
EOM 2.4: Proportion of infants with a serious adverse event in a 48-hour monitoring period after 
vaccination in the “vaccinated” group and a 48-hour monitoring period after randomization in the 
“unvaccinated” group. 
 
EOM 3.1: Proportion of hospitalized infants with ≥ 1 episode of clinical apnea between 48 hours 
and 14 days after vaccination.  
 
EOM 3.2: Proportion of hospitalized infants requiring any increase in respiratory support 
between 48 hours and 14 days after vaccination. 
 
EOM 3.3. Proportion of hospitalized infants requiring blood culture and/or antibiotics 
(intravenously or intramuscularly) in the setting of blood culture for sepsis evaluation in between 
48 hours and 14 days after vaccination. 
 
EOM 3.4. Proportion of hospitalized infants requiring positive pressure ventilation in between 48  
hours and 14 days after vaccination. 
 
EOM 3.5. Proportion of discharged infants readmitted to the hospital within 14 days of 
vaccination.  
 
 
3 STUDY DESIGN 
This study is a prospective, randomized, open-label clinical trial to assess apnea in the 48 hours 
after  randomization (“unvaccinated” group) versus 48 hours after vaccination (“vaccinated” 
group)with 13-valent Conjugate Pneumococcal Vaccine (PCV13), Diphtheria Toxoid, Tetanus 
Toxoid, and Acellular Pertussis Vaccine (DTaP), Hepatitis B vaccine (HBV), Inactivated Polio 
Vaccine (IPV), and Haemophilus influenzae Type B Vaccine (Hib) vaccines in premature infants 
<33 weeks and 0 days gestation at birth who have been hospitalized since birth and eligible to 
receive 2-month vaccines per the ACIP schedule.30 
At least 300 infants will be enrolled over a period of 28 months at  Duke University (Duke), 
University of North Carolina at Chapel Hill (UNC) and Cincinnati Children’s Hospital Medical 
Center (CCHMC).  The first 12 infants (Duke: 4, UNC: 4, CCHMC: 4) will be enrolled in a pilot 
study to assess the feasibility of the protocol and study instruments. The remaining 288 will be 
enrolled after the pilot study; 86 infants at Duke, 86 infants at UNC and 116 infants at CCHMC. 
 
On day 1, eligible infants will be randomized 1:1 to a “vaccinated” or “unvaccinated” group. 
Infants in the “vaccinated” group will be continued on cardiorespiratory and pulse oximetry 
monitoring and PCV13, DTaP, HBV, IPV, and Hib vaccines will be given within 6 hours of 
randomization. Vaccines will be administered per ACIP recommendations.2  Infants in the 
“unvaccinated” group will be continued on cardiorespiratory and pulse oximetry monitoring and 
no vaccines will be administered.  Continuous cardiorespiratory and pulse oximetry monitoring 

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are standard of care procedures for infants hospitalized in NICU. The study will collect data from 
the continuous cardiorespiratory and pulse oximetry monitors from randomization to 48 hours 
after randomization for infants in the unvaccinated group, and from randomization to 48 hours 
after vaccination for infants in the vaccinated group.  Blinded analyst(s) at Duke University will 
evaluate data recorded by the cardiorespiratory and pulse oximeter monitors during this time 
period to determine the occurrence of apnea, bradycardia, and desaturation. In addition, 
information will be collected on increased respiratory support, sepsis evaluation and serious 
adverse events.  
 For infants in the “vaccinated” group, the study will also collect adverse events of clinical 
interest and serious adverse events occurring between the end of the 48-hour monitoring period 
and 14 days after vaccination. This information will be collected through parental report and 
review of medical records.  
 
4 STUDY ENROLLMENT AND WITHDRAWAL  
Subject Inclusion and Exclusion Criteria will be reviewed at Day 1 to assess eligibility for study 
participation. 
4.1  Subject Inclusion Criteria 
Subjects who meet all of the following criteria will be eligible to participate in this study.   
1. <33 and 0 days weeks gestational age at birth 
2. ≥6 weeks and 0 days and ≤12 weeks and 0 days postnatal age at randomization 
3. Remains hospitalized after birth (has never been discharged home) 
4. Treating clinician deems infant eligible to receive 2-month vaccines 
5. English- or Spanish-speaking parent(s)/legally authorized representative(s) (LAR(s)) 
6. Not planned for discharge within 60 hours of study entry 
7. The parent/guardian must be willing to provide permission for their child to participate 
through the written informed consent process 
 
4.2 Subject Exclusion Criteria 
Subjects who meet any of the following criteria will not be eligible to participate in this 
study: 
1. Receipt of DTaP, IPV, PCV13, or Hib prior to enrollment. Previous administration of the 
first dose of HBV is permitted 
2. Anticipated receipt of any vaccine other than DTaP, IPV, HBV, PCV13, or Hib during 
the first 60 hours after randomization 
3. History of a severe allergic reaction (e.g. anaphylaxis) to a previous dose of any 
hepatitis B vaccine 
4. History of a severe allergic reaction (e.g. anaphylaxis) to any component of the 
vaccines used in the study including neomycin, yeast and polymyxin B  
5. History of latex allergy 
6. Fever ≥38°C within 48 hours prior to randomization* 
*This may result in a temporary delay of randomization  
7. Active known respiratory infection within 48 hours prior to randomization* 
*This may result in a temporary delay of randomization  
8. Active infection being treated with systemic antimicrobials* 
*This may result in a temporary delay of randomization  
9. Requiring mechanical ventilation or support with nasal intermittent positive pressure 
ventilation (NIPPV)* 
*This may result in a temporary delay of randomization  
10. History of unstable progressive neurologic disorder of unknown cause 
11. Known cause of apnea other than apnea of prematurity 
12. Cyanotic heart disease (congenital or acquired) 

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13. Major invasive medical or surgical procedure (including circumcision) within 48 hours 
prior to  randomization or anticipated to have major invasive medical or surgical 
procedure during the first 60 hours after randomization* 
*This may result in a temporary delay of randomization  
14. Child or parent/LAR 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 
 
4.3 Recruitment 
Participants will be recruited from Duke, UNC and CCHMC. Infants hospitalized in the NICU 
will be screened for eligibility daily by study staff.  Parent(s)/LAR(s) of the infants will be 
approached for consent. Infants’ parent(s)/LAR(s) may be approached for consent when the 
infant is eligible to receive 2-month vaccines, or for pre-consent prior to being eligible to 
receive 2-month vaccines. Initial discussions regarding the study may occur over the phone 
(see section 5.2), but written informed consent will be obtained prior to any study 
procedures. The clinical care team will be consulted prior to approaching parents (LARs) for 
consent.   
 
4.4 Reasons for and Handling of Withdrawals 
The following may be reasons for study withdrawal: 
• 
As deemed necessary by the principal investigator (PI). 
• 
Parent(s)/LAR(s) withdrawal of permission for their infant to participate. 
• 
Loss to follow-up. 
• 
Termination of the study by the sponsor. 
 
A parent/LAR may withdraw permission for their infant to participate at any time and for any 
reason, without penalty. Subjects who are withdrawn from the study prior to randomization will 
be replaced. Subjects who are withdrawn from the study after randomization will not be 
replaced.  For subjects who were randomized, data collected prior to withdrawal from the study 
will be included in the study.  
 
4.5 Termination of Study  
This study may be terminated for safety concerns of the principal investigators from any of the 
enrolling sites, the CDC, or participating Institutional Review Boards (IRBs).   
 
5 STUDY SCHEDULE, PROCEDURES, & EVALUATIONS 
 
 
 

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5.1 Study day definitions 
 
Table 3. Study Day definitions 
 
Vaccinated group 
Unvaccinated group 
Day 1 
R  V + 23:59 hours:minutes 
R  R + 23:59 hours:minutes 
Day 2 
V + 24 hours  V + 47:59 hours:minutes 
R + 24 hours  R + 47:59 hours:minutes 
Day 3 
V + 48 hours  V + 95:59 hours:minutes 
 
Day 4 
V + 96 hours  V + 119:59 hours:minutes 
 
Day 5 
V + 120 hours  V + 143:59 hours:minutes  
Day 6 
V + 144 hours  V + 167:59 hours:minutes  
Day 7 
V + 168 hours  V + 191:59 hours:minutes  
Day 8 
V + 192 hours  V + 215:59 hours:minutes  
Day 9 
V + 216 hours  V + 239:59 hours:minutes  
Day 10 
V + 240 hours  V + 263:59 hours:minutes  
Day 11 
V + 264 hours  V + 287:59 hours:minutes  
Day 12 
V + 288 hours  V + 311:59 hours:minutes  
Day 13 
V + 312 hours  V + 335:59 hours:minutes  
Day 14 
V + 336 hours  V + 359:59 hours:minutes  
R = time of randomization. V = time of vaccination. If infants in the vaccinated group are 
not vaccinated, then “V” should be replaced by “R + 12 hours”. Note that for vaccinated 
group, “Day 1” will be longer than 24 hours. 
 
5.2 Schedule of Events 
Infants meeting the proposed eligibility criteria will be recruited. Written informed consent for the 
infants to participate will be obtained from parent(s)/LAR(s) prior to conducting any study 
procedures. Table 3 describes the proposed schedule of study visits.   
 
 

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Table 3. Study Procedures. 
Procedure 
Day -60 to 
Day 1 
Day 1 
Days 1-2 
Days 3-14 
Location of procedure 
NICU 
NICU 
NICU 
NICU or 
phone call 
Group (Vaccinated, 
Unvaccinated, or Both) 
Both 
Vaccinated 
Unvaccinated 
Both 
Vaccinated  
Informed consent & Medical 
Release of Information 
X 
 
 
 
 
Review Eligibility Criteria 
X 
X 
X 
 
 
Demographic information  
X 
 
 
 
 
Birth and delivery information 
X 
 
 
 
 
General medical history 
 
X 
X 
 
 
Targeted medical history 
 
X 
X 
 
 
Respiratory support at time of 
randomization/vaccination 
 
X 
X 
 
 
Concomitant medications 
 
X 
X 
X 
X 
Randomization 
 
X 
X 
  
 
Procedures  
 
 
 
X 
 
Cardiorespiratory monitoring 
data capture 
 
 
 
X 
 
Vaccination  
 
X 
 
  
 
Clinically important adverse 
events 
 
X 
X 
X 
X 
Serious adverse events 
 
X 
X 
X 
X 
 
Study Day -60 to Day 1  
• Obtain parental permission by written informed consent and a release of medical record 
information 
• Review and confirm study eligibility, or likely study eligibility for pre-consent 
• Obtain demographic, birth, and delivery information 
 
Study Day 1 
• Review and confirm study eligibility 
• Obtain medical history both general and targeted (including respiratory support at time of 
randomization/vaccination and previous history of Hepatitis B vaccination) 
• Obtain concomitant medication use within 1 week prior to randomization 
• Randomize study participant to vaccination (vaccinated group) or no vaccination 
(unvaccinated group) (Section 5.5.1) 
• Administer study vaccines to vaccination group. In order to limit differences between the two 
groups due to lag in vaccination after randomization, vaccines will be administered within 6 
hours of randomization; however, vaccination up to 12 hours post-randomization will be 
permitted. A time window for vaccination is provided in order to allow for flexibility in coordination 
of vaccination with care/assessment times, family visits, other procedures. 
• Record clinically important adverse events (including apnea) and serious adverse events 
 
Study Days 1-2 
• Cardiorespiratory monitoring (standard of care), with collection of printed or digital output 
• Pulse oximetry monitoring (standard of care)  
• Record concomitant medications 

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• Record standard of care procedures (including, but not limited to, any surgical procedures, 
eye exams, central line placements) 
• Record clinically important adverse events (including apnea) and serious adverse events 
• Of note, the unvaccinated group completes the study 48 hours after randomization.  
 
Study Days 3-14 (Vaccinated group only) 
*This period of time (day 3-14) will begin at 48 hours after vaccination.  
• Record clinically important adverse events (including apnea) and serious adverse events in 
vaccinated group only 
• 
If infant is discharged from the hospital prior to day 14, then follow-up of events 
will occur via telephone call with the parent/LAR and/or chart review of outpatient 
clinic notes or inpatient clinic notes (if infant is rehospitalized and these are 
available). 
 
5.3 Parent/LAR Permission Process (Informed Consent) 
The consent process will take place in the NICU or in a private conference room if preferred by 
the parent(s)/LAR(s).  Initial discussions regarding the study may occur over the phone. Study 
staff will be available to answer all parent/LAR questions before and after permission is 
obtained.  Parent(s)/LAR(s) will be given as much time as needed after being approached about 
their infant participating in the study and needing to decide whether or not to participate.  We 
anticipate that the initial consent discussion, including presenting the information in the consent 
document and answering questions will take about 30 minutes.  Parent(s)/LAR(s) will have the 
opportunity to take the consent form home and discuss the document with other family 
members or friends.  During the consent process, it will be emphasized that participation is 
voluntary and that parents can withdraw permission for their infant to participate at any time.  
Permission will not be obtained from parent(s)/LAR(s) who do not read, who are blind, or who 
do not read/understand English or Spanish. Parent(s)/LAR(s) will be given a copy of the signed 
informed consent to take home with them.  The original copy of the consent will be kept in the 
study records and a third copy will be included in the infant’s medical record per local 
requirements.  
 
5.4 Data Collection 
Study staff will collect participant data at times according to Table 1.  
Demographic information 
The participant’s postnatal age (days), race/ethnicity, sex, and insurance payer status will be 
obtained from the electronic health record (EHR) at the time of randomization.  
 
Birth and delivery information 
The subject’s birth and delivery information including gestational age, birth weight, multiple birth, 
reason/indication for premature delivery will be captured from the EHR. 
 
Medical history 
The participant’s medical history including but not limited to the following (apnea of prematurity, 
respiratory support at 36+0 weeks postmenstrual age (if ≥36+0 weeks postmenstrual age at 
randomization), necrotizing enterocolitis, intraventricular hemorrhage and grade, periventricular 
leukomalacia, and seizures) be captured by the EHR. Current weight will also be recorded. 
 
Respiratory support at time of randomization/vaccination 

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Respiratory support at time of randomization in the unvaccinated group and vaccination in the 
vaccinated group, including mode (noninvasive positive pressure ventilation, continuous positive 
airway pressure (CPAP), nasal cannula >1 liters per minute, nasal cannula <1 LPM, or none) 
and fraction of inspired oxygen (FiO2), will be obtained from the EHR. 
 
Concomitant medications 
The participant’s exposure to all prescribed medications in the 1 week prior to randomization will 
be obtained from the EHR. Start and stop dates will be collected. In addition, caffeine and 
acetaminophen administration will be collected during the study period with start/stop dates. 
 
Cardiorespiratory monitoring data capture 
All participants will have data captured from their continuous cardiorespiratory and pulse 
oximetry monitoring after randomization.  Capture of continuous monitoring data will begin at 
randomization and end at 48 hours after vaccination (vaccinated group) or randomization 
(unvaccinated group).  If infants in the vaccinated group are not vaccinated by 12 hours after 
randomization, capture of monitoring data will end at 60 hours after randomization.  At the end 
of the 48-hour monitoring period, study staff at all enrolling sites will collect digital or printed 
output of data from cardiorespiratory monitors for all infants and send to the analysts at Duke 
University who will be blinded to the randomization group of the participants.  To ensure the 
analysts are blinded to the treatment arms, the data obtained from the monitor for each infant 
will not include any personal or study identifiable information. Each output will be assigned a 
non-sequential coded number before they are sent to the analysts.  The blinded analysis will 
interpret the output and record the date, time, and duration of each cardiorespiratory event 
(apnea, bradycardia, desaturation, and severe cardiorespiratory event) as defined below.   
Procedures 
Any procedures done as part of routine care (including, but not limited to, surgical procedures, 
eye exams, and central line placements) that occur beginning at randomization and ending at 
48 hours after vaccination (vaccinated group) or randomization (unvaccinated group) will be 
recorded. Procedures occurring >60 hours after randomization in the vaccinated group will not 
be recorded. Data recorded will include the type of procedure, date/time of the procedure, 
length of the procedure, and a narrative describing any other important clinical information 
regarding the procedure. 
 
Clinically important adverse events: days 1-2 
Clinically important adverse events will be collected from randomization to 48 hours following 
randomization (unvaccinated group) or vaccination (vaccinated group). The following clinically 
important adverse events will be collected: 
1. Apnea (POM 1.1, SOM 1.1, SOM 1.2) 

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a. Definition: Apnea will be defined as a pause in respirations of >20 seconds, or a 
pause in respirations of >15 seconds with 
associated bradycardia (heart rate <80 beats 
per minute). 
b. Method of collection: Obtained from the 
cardiorespiratory monitor as described above. 
2. Increase in mode of respiratory support (SOM 1.3) 
a. Definition: Increase in mode of respiratory 
support will be defined as progression from 
any lower level at baseline (at time of 
randomization in the unvaccinated group and 
vaccination in the vaccinated group) to any 
higher level (Figure 2). In addition, any 
increase in nasal cannula flow rate, or 
continuous positive airway pressure (CPAP) 
will be considered an increase in mode of 
respiratory support. 
b. Method of collection: Respiratory data will be 
collected from the EHR daily, and the highest 
level of support that is maintained for >1 hour 
will be recorded. In addition, start/stop 
date/time for NIPPV and mechanical 
ventilation will be recorded. 
3. Severe cardiorespiratory event (SOM 2.1) 
a. Definition: Respiratory pause of >30 seconds 
in duration or bradycardia of <60 beats per minute for >10 seconds 
b. Method of collection: Obtained from the cardiorespiratory monitor as described 
above. 
4. Positive pressure ventilation delivered via bag-valve mask (SOM 2.2) 
a. Definition: Infant with unexpected clinical decompensation requiring positive pressure 
ventilation via bag-valve mask. 
b. Method of collection: Obtained from the EHR as documented by a clinical provider 
(e.g., physician, nurse, respiratory therapist). 
5. Fever (EOM 1.1) 
a. Definition: Elevated temperature ≥38°C.  
b. Method of collection: Highest daily temperature will be recorded from the EHR, in 
addition to how the temperature was obtained (skin, axillary, rectal, etc.) and infant’s 
environment (open crib, radiant warmer or isolette). 
6. Hypothermia (EOM 1.2) 
a. Definition: Decreased temperature <36°C.  
b. Method of collection: Lowest daily temperature will be recorded from the EHR, in 
addition to how the temperature was obtained (skin, axillary, rectal, etc.) and infant’s 
environment (open crib, radiant warmer or isolette).  
7. Oxygen desaturation (EOM 2.1) 
a. Definition: Oxygen desaturation will be defined as a SpO2 <88% for >10 seconds. 
b. Method of collection:  Obtained from the cardiorespiratory monitor as described 
above. 
8. Bradycardia (EOM 2.2) 
a. Definition: Bradycardia will be defined as a heart rate <80 beats per minute lasting 
>10 seconds. 
Figure 2. Progression in respiratory 
support. 
 
 
 
CPAP=continuous positive airway 
pressure. NIPPV=non-invasive positive 
pressure ventilation 

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b. Method of collection:  Obtained from the cardiorespiratory monitorg as described 
above. 
9. Blood culture for sepsis evaluation (EOM 2.3) 
a. Definition: A sepsis work-up will be defined each day as a blood draw to obtain blood 
culture.   
b. Method of collection: Data will be collected from the EHR (date/time of blood culture). 
10. Antibiotics administered due to sepsis evaluation (EOM 2.3) 
a. Definition: New receipt of intravenous or intramuscular antibiotics will be recorded if 
they were started in conjunction with a blood culture during the 48-hour monitoring 
period after vaccination in the “vaccinated” group and the 48-hour monitoring period 
after randomization in the “unvaccinated” group 
b. Method of collection: Data will be collected from the EHR (date/time of start of the 
first new antibiotic). 
 
 
Clinically important adverse events: days 4-14 (vaccinated group only) 
 
1. Clinical apnea (EOM 3.1) 
a. Definition: Clinical apnea will be defined as an apneic event that is documented by 
the nurse as part of standard care.  
b. Method of collection: Events will be reviewed and collected from the EHR. Date, 
time, and duration of events will be noted when available from nursing 
documentation. Associated bradycardia and desaturation will be collected if 
available.  
2. Increase in mode of respiratory support (EOM 3.2) 
a. Definition: Increase in mode of respiratory support will be defined as progression 
from any lower level at baseline (end of study period on day 3) to any higher level 
(Figure 2). In addition, any increase in nasal cannula flow rate, CPAP pressure, or 
NIPPV pressure will be considered an increase in mode of respiratory support. 
b. Method of collection: Respiratory data will be collected from the EHR daily, and the 
highest level of support that is maintained for >1 hour will be recorded.  
3. Blood culture for sepsis evaluation (EOM 3.3) 
a. Definition: A sepsis work-up will be defined as a blood draw to obtain blood culture.   
b. Method of collection: Data will be collected from the EHR (date/time of blood culture). 
4. Antibiotics administered due to sepsis evaluation (EOM 3.3) 
a. Definition: New receipt of intravenous or intramuscular antibiotics will be recorded if 
they were started in conjunction with a blood culture  
a. Method of collection: Data will be collected from the EHR (date/time of start of the 
first new antibiotic). 
5. Positive pressure ventilation delivered via bag-valve mask (EOM 3.4) 
a. Definition: Infant with unexpected clinical decompensation requiring positive pressure 
ventilation via bag-valve mask. 
b. Method of collection: Obtained from the EHR as documented by a clinical provider 
(e.g., physician, nurse, respiratory therapist). 
6. Hospital readmission (EOM 3.5) 
a. Definition: Among infants who are discharged from the hospital, hospital readmission 
(yes/no) will be recorded along with date of readmission and reason for readmission. 
Scheduled, elective readmissions (e.g. surgical procedures) will not be counted. 
b. Method of collection: Data will be collected from the EHR and/or follow-up phone call 
to parent/guardian 
 

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Serious adverse events (SAEs) (EOM 2.4) 
An SAE is defined as an adverse event that results in one of the following outcomes during the 
infant’s participation in the study: 
• Results in death  
• Is life-threatening (defined as immediate risk of death at the time of the event) 
• Requires inpatient hospitalization (i.e. re-admission) or prolongation of inpatient 
hospitalization   
• 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.  
Study site investigators will assess relatedness to study procedures and vaccines for all SAEs 
(related, possibly related, or unrelated).  
5.4 Reporting Adverse Events 
SAEs will be reported to the CDC and all participating IRBs according to institutional 
requirements. 
If indicated, adverse events (AEs) will be reported to the CDC’s Vaccine Adverse Event 
Reporting System (VAERS). The National Childhood Vaccine Injury Act requires healthcare 
providers to report: 
• 
Any adverse event listed by the vaccine manufacturer as a contraindication to further 
doses of the vaccine; or 
• 
Any adverse event listed in the VAERS Table of Reportable Events Following 
Vaccination [PDF - 75KB] that occurs within the specified time period after vaccination. 
In addition, CDC encourages reporting of any clinically significant adverse event that occurs in a 
patient following a vaccination, even if there is uncertainty regarding if a  vaccine caused the 
event. 
 
5.5 Follow-up on days 3-14 for infants in the vaccinated group 
*This period of time (day 3-14) will begin at 48 hours after vaccination.  
Infants in the vaccinated group will be followed for the above clinically important AEs, SAEs, and 
concomitant medications on days 3-14. If an infant in the vaccinated group is discharged or 
transferred prior to day 14 (with no EHR accessible), then these data will be obtained via follow-
up phone call from the study staff to the parent/guardian.  
 
5.6 Treatment Assignment Procedures 
This is an open-label, prospective, randomized study for infants who are eligible to receive 2-
month vaccinations. To the extent feasible, all infants randomized to the vaccinated group will 
be given the same type/brand of vaccines at all sites. Infants in the unvaccinated group will not 
receive any vaccine during the study.  
 
5.6.1 Randomization 
Participants will be randomized (1:1) to either vaccinated or unvaccinated groups using a 
permuted block randomization scheme stratified by gestational age (<28 weeks, ≥28 weeks) 
and study site (i.e. Duke University Medical Center, University of North Carolina at Chapel Hill 

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Hospital, and Cincinnati Children’s Hospital Medical Center). Randomization will occur within 6 
hours of anticipated vaccination of infants in the vaccinated group, but infants will be allowed to 
receive vaccines up to 12 hours post-randomization. The first 12 infants enrolled in the Pilot 
Phase I will be randomized in a separate permuted block by manual randomization (e.g., 
envelopes). The project statistician at Duke University will generate permuted block 
randomization schemes, which will be uploaded to REDCap for the full study. 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, participant randomization will be through REDCap with treatment allocation 
recorded on the case report form. In the event that REDCap is unavailable, manual 
randomization will occur through the use of envelopes. The project statistician will prepare 20 
envelopes per site that will use the same randomization strategy as the primary scheme 
embedded in REDCap. When manually randomizing, the team member will pull the next 
envelope in order. In order to capture the allocation per subject, a separate form in REDCap will 
be used by the personnel to add the assignment. A log will need to be kept at the site capturing 
these instances. 
 
5.6.2 Blinding 
This study will be open label and study staff, caregivers, and parent(s)/LAR(s) will not be 
blinded to treatment arm assignments. The output from the cardiorespiratory monitors will be 
read by analysts who are blinded to the treatment arm assignments. 
 
5.5.3 Vaccine Supply, Storage, and Administration  
Vaccine Supply and Storage 
Pharmacy-supplied US licensed vaccines will be administered to the vaccination group as part 
of this study. The following vaccine brands will be used for this study: PCV13 (Prevnar® 13, 
Pfizer); DTaP-IPV-HBV (Pediarix®, GlaxoSmithKline); and Hib (ActHib®, Sanofi Pasteur). 
However, given the potential for unforeseen manufacturing issues/specific product shortages, 
the use of alternate U.S.-licensed vaccines may be required.  
  
Vaccine Administration 
Only infants randomized to the vaccinated group will be vaccinated during the protocol specified 
observation period. A single administration of PCV13 and DTaP-HBV-IPV and Hib comprises 
intramuscular delivery of 0.5 mL total volume of each vaccine. For each infant, all vaccines will 
be administered simultaneously by licensed nurses within the study sites. Injections given in the 
same thigh should be separated by 1 inch or more, if possible, so that any local reactions can 
be differentiated.  The research staff will record vaccine brand, lot numbers, dose, date/time and 
site of vaccine administration. For continuity of care purposes, documentation of vaccine 
administration will be done in a manner that the infant’s healthcare provider can access. 
  
After administration, used study syringes will be disposed of according to standard operating 
procedure.  
 
Although oral rotavirus vaccine is recommended by the ACIP for infants at 2-months of age, this 
vaccine will not be administered during the study to prevent potential nosocomial spread of this 
live vaccine virus. 
 
6 STATISTICAL CONSIDERATIONS 
 

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6.5 Sample Size and Power Estimation 
Power considerations related to the primary objective  
 The study has approximately 84.3% power to reject the null hypothesis of no difference in 
the proportion of infants with apnea in the “vaccinated” group compared to the “unvaccinated” 
group based on a two-side alpha 0.05 chi-square test with N=135 per group.  This assumes that 
the proportion of infants with apnea will be 15% in the “unvaccinated” group and 2-fold higher 
(30%) in the “vaccinated” group. This assumption is based on a review of the literature14 and 
expert opinion. The study allows for a 10% drop out rate to give a total sample of 300 infants. 
During the pilot study, at least 12 infants will be enrolled to assess feasibility.  Following 
completion of the pilot study, a total of at least 288 infants will be enrolled.   
 
6.6 Analysis Plan 
 
6.6.1 Pilot Study 
The pilot phase of the study will include 12 infants.  There will not be any formal analysis of 
study data.  However, the feasibility benchmarks listed in Table 5 will be documented for the 
first 12 patients to assess protocol adherence.  These subjects will contribute to the final 
sample for analyses in the study objectives.   
Table 5: Benchmarks for Pilot  
Benchmark 
Target 
Among pre-screened and eligible, LARs approached for consent 
70% 
Among approached for consent, consent obtained 
40% 
Documentation of reason for non-consent (of those approached) 
80% 
Among consent obtained, percent randomized 
80% 
Administration of vaccines in the vaccination group within 6 hours of 
randomization 
60% 
Administration of vaccines in the vaccination group within 12 hours of 
randomization 
80% 
Entire 48-hour monitoring period assessed for apnea events 
80% 
 
6.6.2 Full Study  
6.6.2.1 
Study Populations 
We will define 3 study populations for the purpose of analyses.  
1) Intent-to-treat (ITT) population 
• 
Definition: The ITT population includes any infant that was enrolled and 
randomized in the study. 
 

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• 
Analysis: For the ITT analysis, study outcomes in the 48-hour monitoring after 
randomization will be evaluated in both vaccinated and unvaccinated group.  
Infants will be analyzed in their assigned treatment arms irrespective of receipt of 
vaccine. 
Figure 3. Intent to Treat (ITT) Analysis 
 
 
2) Modified intent-to-treat (mITT) population 
• 
Definition: The mITT population includes any infant that was enrolled and 
randomized in the study. 
• 
Analysis: For the mITT analysis, infants will be analyzed in their assigned 
treatment arms irrespective of receipt of vaccine. Study outcomes will be included 
in the analysis as follows: 
o Vaccinated group: study outcomes in the 48-hour monitoring after 
vaccination. If vaccination does not occur by 12 hours after randomization, 
then study outcomes will be assessed between 12 and 60 hours after 
randomization. 
o Unvaccinated group: study outcomes in the 48-hour monitoring period after 
randomization. 
 
Figure 4. Modified Intent-to-Treat (mITT) Analysis 
 
  
 
 
 
 
 
 
3) Per protocol (PP) population 
• 
Definition: The PP population includes any infant that was enrolled, randomized 
and did not have any major protocol violations as determined by the study 
investigators. 

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• 
Analysis: For the per protocol analysis, study outcomes will be included in the 
analysis as follows: 
o Vaccinated group: study outcomes in the 48-hour monitoring after 
vaccination. The analysis will exclude infants who do not receive vaccine 
by 12 hours. 
o Unvaccinated group: study outcomes in the 48-hour monitoring period after 
randomization. The analysis will exclude infants who are vaccinated during 
the study period. 
The mITT population will be the primary analysis population for all planned analyses for the 
study objectives. For comparison, pre-specified secondary analyses will also be performed 
using the ITT and PP populations. The ITT population will only be analyzed for the primary 
and secondary objectives.  The PP population will be analyzed for all planned objectives as 
supporting analyses. 
 
6.2.2.2 Interim Safety Data Review  
Given that this study involves administering U.S.-licensed vaccines recommended by the ACIP 
for preterm infants and included as part of routine clinical care, there will not be a designated 
data safety monitoring board for this study. However, due to the fragility of the study population 
and interventional design, one interim safety data review will be performed with the goal of 
identifying unexpected safety concerns of clinical importance. The safety data review will 
provide the study the opportunity to identified unexpected safety concerns and make changes to 
the protocol if needed. The interim safety data review will be done by a safety monitoring panel 
with relevant expertise, comprised of experts who are not co-investigators on this study. The 
safety population for the interim safety review will include infants who were enrolled and 
randomized. Infants who participated in the pilot study will also be included. The safety 
monitoring panel will review clinical narratives of SAEs. If the CDC and study investigators 
determine additional analyses or reviews are needed, efforts will be made to conducted 
additional analysis or reviews that will not include analyzing the primary endpoint as a first step. 
This is to avoid introducing bias or increasing sample size needs for statistical power. 
 
Enrollment will continue during the interim safety data review. 
 
6.2.2.3 Final study analysis  
A final analysis of the data will occur after all infants have completed the study and will 
include data from infants enrolled in the pilot study. 
All proportions specified below in the objectives will be compared by group (unvaccinated 
group or vaccinated group) using a Mantel-Haenszel statistic in a stratified analysis by site 
(i.e. Duke, UNC and CCHMC) to control for the randomization blocks at the two-sided alpha 
0.05 level unless otherwise specified. The odds ratio and corresponding 95% confidence 
interval will also be calculated and presented.  There will be no adjustment to the alpha level 
made for the secondary and exploratory objectives. 
Primary Objective 1 - To compare proportions of preterm infants with apnea in a 48-hour 
monitoring period after vaccination in the “vaccinated” group versus a 48-hour monitoring 
period after randomization in the “unvaccinated” group.    
The proportion of infants with ≥ 1 apneic event apnea (as defined in Section A.5.3) will be 
presented for each group and compared using a Mantel-Haenszel statistic.  
 

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Secondary Objective 1 - To compare the clinical importance of apneic events in a 48-hour 
monitoring period after vaccination in the “vaccinated” group versus a 48-hour monitoring period 
after randomization in the “unvaccinated” group.   
For this objective we will present the proportions of infants in each group who required increase 
in respiratory support (as defined in Section A.5.3) and compare these proportions using a 
Mantel-Haenszel statistic. We will also report summary statistics regarding the number of 
distinct episodes and the duration of episodes, including mean, median, standard deviation, 
interquartile range, and range. We will compare the number of distinct episodes of apnea and 
the duration of episodes between groups using the Wilcoxon rank sum test. 
 
Secondary Objective 2 - To compare proportions of preterm infants with severe 
cardiorespiratory events in a 48-hour monitoring period after vaccination in the “vaccinated” 
group versus a 48-hour monitoring period after randomization in the “unvaccinated” group. 
For this objective we will present the proportion of infants in each group experiencing a severe 
cardiorespiratory event (as defined in Section A.5.3) or received positive pressure ventilation at 
least once during the 48 hours after randomization/vaccination and compare these proportions 
using a Mantel-Haenszel statistic.  
 
Exploratory Objective 1 - To compare proportions of preterm infants with temperature instability 
in a 48-hour monitoring period after vaccination in the “vaccinated” group versus a 48-hour 
monitoring period after randomization in the “unvaccinated” group. 
For this objective we will present the proportion of infants the proportion of infants in each group 
experiencing fever and the proportion in each group experiencing hypothermia (as defined in 
Section A.5.3) at least once during the 48 hours after randomization/vaccination and compare 
these proportions using a Mantel-Haenszel statistic.  
 
Exploratory Objective 2 - To compare proportions of preterm infants with other clinically 
important adverse events in a 48-hour monitoring period after vaccination in the “vaccinated” 
group versus a 48-hour monitoring period after randomization in the “unvaccinated” group. 
 
For this objective we will present the proportion of infants the proportion of infants in each group 
experiencing other clinically important adverse events (as defined in Section A.5.3) at least once 
during the 48 hours after randomization/vaccination and compare these proportions using a 
Mantel-Haenszel statistic. We will repeat these analyses for serious adverse events. We will 
report SAE narratives and relatedness descriptions (see section 5.3). 
 
Exploratory Objective 3 - To compare clinically important adverse events occurring between 48 
hours and 14 days after vaccination among infants in the vaccinated group who do, and do not 
have apnea in a 48-hour monitoring period after vaccination. 
For this objective we will present the proportion of infants in the vaccinated group with and 
without apnea in a 48-hour monitoring period who experience each of these clinically important 
adverse events (as defined in section A.5.3) at least once between 48 hours and 14 days after 
vaccination. These subgroup comparisons will be conducted a Fisher’s Exact Test at the alpha 
0.05 level.   
  
6.7 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. 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 

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system will be used by all the study sites (i.e. Duke, UNC, and CCHMC).  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).31 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, case 
report forms completed by study participants, will be maintained in secure research offices at 
Duke, UNC and CCHMC, which are accessible to research staff only.  
 
6.7.1 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. The product includes secure institutional data hosting and 
include 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 directly into the REDCap database by members of the study team at the 
study sites.  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 at all the study sites (i.e. Duke, UNC, and CCHMC) with secured 
password-protected computers. Coded data without personal identifiers will be made available 
to the CDC and transferred using a secure transfer method.  
 
6.8 Role of the CDC Investigators in the Project 
This study is funded by a CDC contract with Duke University (and subcontract with UNC) and 
CCHMC as Task Orders in the CISA Project Contract. The Duke University PI will oversee the 
study in partnership with the CCHMC’s PI.  CDC staff will collaborate with both sites to develop 

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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. 
 
7    HUMAN SUBJECTS  
7.5 Human Subjects Involvement, Characteristics, and Design 
 
Duke and CCHMC investigators, along with subcontractor investigators, will be responsible for 
submitting the protocol, informed consent 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 
information only the minimum amount of information necessary to determine potential eligibility, 
e.g. to consent 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. 
 
7.6 Sources of Material 
Medical history, vaccination history, and concomitant medication history will be obtained from 
the EHR.  Demographic information will be obtained from the EHR or parent/LAR.  Adverse 
events will be recorded using the output from cardiorespiratory monitors (for cardiorespiratory 
events only), EHR, and/or phone call to the parent/LAR (days 4-14).  
 
7.7 Potential Risks and Benefits 
PCV13, DTaP, IPV, HBV, and Hib are US- licensed vaccines approved for use in infants ≥6 
weeks of age. These vaccines are recommended by the ACIP for use in preterm infants.30  
Participants will be provided with the CDC Vaccine Information Statements (VIS) for infant 2-
month vaccinations (https://www.cdc.gov/vaccines/hcp/vis/vis-statements/multi.pdf).  
 
Risks of the DTaP-IPV-HBV combination include minor problems such as soreness, redness, 
swelling, or pain where the shot was given, fever, drowsiness, irritability/fussiness, vomiting, and 
loss of appetite. Other potential adverse reactions include a small increased risk of apnea in 
premature infants.  
 
Most common risks of PCV13 include fever, injection site erythema, induration, or swelling. 
Uncommon symptoms include apnea. 
 
Most common risks of Hib include injection site erythema, induration, or swelling. Uncommon 
symptoms include apnea. 
 
Problems that could happen after any injected vaccine:  
• 
Any medication can cause a severe allergic reaction, including anaphylaxis. Such 
reactions from a vaccine are very rare, estimated at about 1 in a million doses, and 

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would happen within a few minutes to a few hours after the vaccination. As with any 
medicine, there is a very remote chance of a vaccine causing a serious injury or death. 
 
There is a small potential risk that infants in the no vaccination group could develop infection 
due to one of the organisms covered by the vaccine during the 48-hour monitoring period that 
vaccination is withheld.  After their participation in the study, the study team will communicate 
with the clinical team to facilitate vaccination of these infants in a timely manner. 
 
There is the potential risk of loss of confidentiality about information obtained as part of this 
study.  
 
7.8 Adequacy of Protection Against Risks 
 
7.8.1 Protections against Risk 
Participants’ parent(s)/LAR(s) will be counseled on possible side effects following vaccination 
and followed closely during the 14 days post-vaccination for clinical status changes.  Subjects 
with a prior history of any severe reaction following HBV administration will be excluded from 
study enrollment.  
 
Infants in the unvaccinated group will complete the study 48 hours after randomization, after 
which clinicians may administer the recommended vaccines in a timely fashion, limiting the 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.  Any publications resulting from this work will not contain any identifiable participant 
information. 
 
7.8.2 ClinicalTrials.gov Requirements 
The project will be registered on ClinicalTrials.gov. 
 
7.9 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 LAR must sign and date the written informed consent form prior to initiation of any 
study procedure. 
 
7.9.1 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 routine 
infant vaccinations in a manner that is consistent with ACIP recommendations.  Because this 
study is no more than minimal risk, the permission of only one parent/LAR will be obtained.   
Because the participants will be infants they will not be capable of providing assent. 
 
 
 

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