A Prospective, Randomized, Open-label Clinical Trial to Assess Fever Following Simultaneous Versus Sequential Administration of PCV13, DTaP Vaccine and IIV in Young Children
Phase: PHASE4
Conditions: Fever After Vaccination, Fever, Febrile Seizure
Sponsor: Duke University

Fever after Simultaneous versus Sequential Vaccination in Young Children 
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 A Prospective, Randomized, Open-label Clinical Trial to Assess Fever Following 
Simultaneous versus Sequential Administration of 13-valent Conjugate Pneumococcal 
Vaccine, Diphtheria Toxoid, Tetanus Toxoid, and Acellular Pertussis Vaccine and 
Inactivated Influenza Vaccine in Young Children 
 
Short Title: Fever after Simultaneous versus Sequential Vaccination in Young Children 
 
 
 
Centers for Disease Control and Prevention  
Clinical Immunization Safety Assessment (CISA) Project  
 
 
Lead Site Principal Investigator: Emmanuel B. Walter, MD, MPH 
 
Contributing Site Principal Investigator: Nicola Klein, MD 
 
Centers for Disease Control and Prevention (CDC) Principal Investigator: Karen R. 
Broder, MD  
 
CDC Sub-principal Investigator: Patricia Wodi, MD 
 
 
 
 
NCT # (clinicaltrials.gov registry # NCT03165981) 
 
Version Number: 3.0 
 
March 2, 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 ...................................................................................................... 9 
1.1 BACKGROUND ....................................................................................................... 9 
1.2 SUMMARY & RATIONALE ...................................................................................... 10 
2 
STUDY OBJECTIVES ........................................................................................... 11 
2.1 STUDY OUTCOME MEASURES AS RELATED TO OBJECTIVES ................................... 12 
Primary Outcome Measure (POM):........................................................................ 12 
Secondary Outcome Measures (SOM): ................................................................. 12 
3 
STUDY DESIGN.................................................................................................... 13 
3.1 MAIN STUDY DESIGN ............................................................................................ 14 
4 
STUDY ENROLLMENT AND WITHDRAWAL ...................................................... 14 
4.1 SUBJECT INCLUSION CRITERIA ............................................................................. 15 
4.2 SUBJECT EXCLUSION CRITERIA ............................................................................ 15 
4.3 RECRUITMENT ..................................................................................................... 17 
4.4 REASONS FOR AND HANDLING OF WITHDRAWALS .................................................. 18 
4.5 TERMINATION OF STUDY ...................................................................................... 18 
5 
STUDY SCHEDULE, PROCEDURES, & EVALUATIONS .................................... 18 
5.1 SCHEDULE OF EVENTS ........................................................................................ 18 
5.2 Parent/LAR Permission Process (Informed Consent) ..................................... 23 
5.3 Demographic Information, Medical History, Immunization History .................. 23 
5.4 Temporal Artery Temperature Measurement and Fever Assessments........... 24 
5.5 TREATMENT ASSIGNMENT PROCEDURES .............................................................. 25 
5.5.1 Randomization ........................................................................................... 25 
5.5.2 Blinding ...................................................................................................... 25 
5.5.3 Vaccine (Supply, Storage, and Administration) and Educational Materials . 25 
5.6 SOLICITED SYSTEMIC ADVERSE EVENTS (DAYS 1-8 FOLLOWING VISITS 1 AND 2) .... 27 
5.7 MEDICAL CARE UTILIZATION, ANTIPYRETIC USE, AND FEBRILE SEIZURE (DAYS 1-8 
FOLLOWING VISITS 1 AND 2) ........................................................................................ 28 
5.8 ADDITIONAL SAFETY ASSESSMENTS (VISIT 1 DAY 1 – VISIT 2 DAY 8) ...................... 30 
6 
STATISTICAL CONSIDERATIONS ...................................................................... 31 
6.1 SAMPLE SIZE AND POWER ESTIMATION ................................................................ 31 
6.2 ANALYSIS PLAN ................................................................................................... 32 
6.2.1 Study Populations ...................................................................................... 32 
6.2.2 Primary Objective 1 .................................................................................... 32 
6.2.3 Secondary Objective 1 –. ........................................................................... 32 
6.2.4 Secondary Objective 2 –. ........................................................................... 33 
6.2.5 Exploratory Objectives ............................................................................... 33 
6.2.6 Sensitivity Analyses ................................................................................... 34 
6.3 DATA MANAGEMENT ............................................................................................ 34 
6.3.1 Research Electronic Data Capture (REDCap) ............................................ 35 
6.4 ROLE OF THE CDC INVESTIGATORS IN THE PROJECT ............................................. 36 

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HUMAN SUBJECTS ............................................................................................. 36 
7.1 HUMAN SUBJECTS INVOLVEMENT, CHARACTERISTICS, AND DESIGN ....................... 36 
7.2 SOURCES OF MATERIAL ....................................................................................... 36 
7.3 POTENTIAL RISKS AND BENEFITS.......................................................................... 37 
7.4 ADEQUACY OF PROTECTION AGAINST RISKS ......................................................... 38 
7.4.1 Protections against Risk ............................................................................. 38 
7.4.2 CLINICALTRIALS.GOV REQUIREMENTS .............................................................. 38 
7.5 HUMAN SUBJECTS ............................................................................................... 38 
7.5.1 Vulnerable Subjects Research ................................................................... 38 
REFERENCES .............................................................................................................. 40 
 
 

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PROTOCOL SUMMARY 
 
Title:  
A Prospective, Randomized, Open-label Clinical Trial to Assess Fever 
Following Simultaneous versus Sequential Administration of 13-valent 
Conjugate Pneumococcal Vaccine, Diphtheria Toxoid, Tetanus Toxoid, 
and Acellular Pertussis Vaccine and Inactivated Influenza Vaccine in 
Young Children 
Phase: 
Phase 4 
Population: 
Up to 280 children, 12-16 months of age, who will receive 13-valent 
conjugate pneumococcal vaccine (PCV13), Diphtheria Toxoid, Tetanus 
Toxoid, and Acellular Pertussis Vaccine (DTaP), and  inactivated influenza 
vaccine (IIV) during the 2017-2018 influenza season  
Clinical Sites: 
Two: Duke University (Lead); Kaiser Permanente (Contributing) 
Study Duration: 
8 months during the 2017-2018 influenza season 
 
Participant 
Duration: 
Up to 37 days 
Description of 
Study Procedures: 
This is a prospective, randomized, open-label clinical trial. Young 
children will be randomized (1:1) to receive either simultaneous 
administration of PCV13, DTaP, and IIV vaccines (Visit 1) followed by a 
health education visit without vaccination  ~ 2 weeks later (Visit 2), or 
sequential administration of PCV13 and DTaP (Visit 1) followed by IIV 
and health education ~ 2 weeks later (Visit 2). 
 
Parents or a legal authorized representative (LAR) will assess fever and 
other solicited systemic adverse events on the day of, the next 7 days 
(through Day 8) following Visit 1 and Visit 2 using either a web-based 
data collection system or a paper diary card. Febrile seizure and serious 
adverse events will be captured during the entire study period.  
Parental/LAR perceptions about their child’s vaccine schedule will be 
assessed on the 8th day following Visit 2. 
Objectives: 
Primary Objective (PO): 
PO 1: To compare the proportions of children with fever following 
simultaneous versus sequential vaccination with PCV13, DTaP, and IIV 
during 2 visits. Children in the sequential vaccination group will receive 
PCV13 and DTaP at Visit 1 followed by IIV and health education at Visit 
2.   Children in the simultaneous vaccination group will receive PCV13, 
DTaP, and IIV at Visit 1, followed by a health education visit without 
vaccination at Visit 2. Fever will be assessed on the visit day of, and the 
day after (days 1-2) each visit. 

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The primary hypothesis is that the proportion of children with fever will be 
higher in children after the simultaneous vs. the sequential schedule. 
Secondary Objectives (SO): 
SO 1: To compare the proportions of children with fever on day 1 and/or 
day 2 after Visit 1 and Visit 2 separately, in the simultaneous versus 
sequential vaccination group. 
SO 2: To compare the clinical importance of fever on day 1 and/or day 2 
after Visit 1 and Visit 2 (separately and combined) in the simultaneous 
versus sequential group. Clinical importance is assessed based on 
severity of fever, duration of fever, and medical care utilization for fever. 
Exploratory Objectives (EO): 
EO 1: To compare the height and duration of fever on day 1 and/or day 2 
after Visit 1 and Visit 2 (separately and combined) in the simultaneous 
versus sequential group 
EO 2: To compare the use of antipyretics for fever on day 1 and/or day 2 
after Visit 1 and Visit 2 (separately and combined) in the simultaneous 
versus sequential group. 
EO 3: To describe and compare the level of severity of fever following 
Visit 1 and Visit 2 (separately) in the simultaneous versus sequential 
group 
EO 4: To compare the proportions of children with fever 3-8 days after 
Visit 1 and Visit 2 (separately and combined) in the simultaneous versus 
sequential group. 
EO 5: To compare the clinical importance of fever occurring 3-8 days 
after Visit 1 and Visit 2 (separately and combined) in the simultaneous 
versus sequential group. Clinical importance is assessed based on 
severity of fever, duration of fever, and medical care utilization for fever. 
EO 6: To describe and compare the occurrence of solicited systemic 
adverse events on day 1-8 after Visit 1 and Visit 2 in the simultaneous 
versus sequential group. 
EO 7: To describe and compare the occurrence of febrile seizure and/or 
serious adverse events during the period of enrollment (i.e. from Visit 1 
through 8 days after Visit 2) in the simultaneous versus sequential group. 
EO 8: To describe and compare the perceptions among parents/ legally 
authorized representatives (LARs) of the simultaneous versus sequential 
schedule experience.   
Outcome Measures: Primary Outcome Measure (POM):  
POM 1.1: Proportion of children with fever (temperature ≥ 38.0°C or ≥ 
100.4°F) on day 1 and/or day 2 following Visit 1 and/or Visit 2  
Secondary Outcome Measures (SOM): 
SOM 1.1:  Proportion of children with fever (temperature ≥ 38.0°C or ≥ 
100.4°F) on day 1 and/or day 2 following Visit 1. 
SOM 1.2: Proportion of children with fever (temperature ≥ 38.0°C or ≥ 
100.4°F) on day 1 and/or day 2 following Visit 2 

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SOM 2.1: Proportions of children with moderate/severe fever (GRADE 2 
and/or 3) on day 1 and/or day 2 following Visit 1, Visit 2, and Visit 1 and 
Visit 2 combined 
SOM 2.2: Average number of consecutive days of fever (temperature ≥ 
38.0°C or ≥ 100.4°F) per subject for fever starting on day 1 or 2 following 
Visit 1, Visit 2 and Visit 1 and Visit 2 combined. 
    Note: fever starting on day 1 or 2 could continue through day 8. 
SOM 2.3: Proportion of children with medical care utilization  (telephone 
call, medical office visit, emergency department visit, or hospital 
admission) for fever on day 1 and/or day 2 following Visit 1, Visit 2 and 
Visit 1 and Visit 2 combined. 
Exploratory Outcome Measures (EOM): 
EOM 1.1: Average peak temperature of children with fever (temperature 
≥ 38.0°C or ≥ 100.4°F) on day 1 and/or day 2 following Visit 1, Visit 2, 
and Visit 1 and Visit 2 combined. 
EOM 1.2: Total number of fever degree-days (temperature ≥ 38.0°C or ≥ 
100.4°F) on day 1 and/or day 2 per subject following Visit 1, Visit 2, and 
Visit 1 and Visit 2 combined. 
EOM 2.1: Proportion of children with antipyretic use for fever on day 1 
and/or day 2 following Visit 1, Visit 2 and Visit 1 and Visit 2 combined. 
EOM 3.1: Proportions of children with fever at different levels of severity 
(Grades 1, 2, and 3) on day 1 and/or day 2 following Visit 1 and Visit 2 
EOM 3.2: Proportions of children with fever at different levels of severity 
(Grades 1, 2, and 3) on days 3-8 following Visit 1 and Visit 2 
EOM 3.3: The proportion of children with fever at different levels of 
severity (Grades 1, 2,3 and all Grade) on days 1-8 following Visit 1 and 
Visit 2 
EOM 4.1: Proportion of children with fever (temperature ≥ 38.0°C or ≥ 
100.4°F) on at least one day on day 3-8 following Visit 1. 
EOM 4.2: Proportion of children with fever (temperature ≥ 38.0°C or ≥ 
100.4°F) on at least one day on day 3-8 following Visit 2.  
EOM 4.3: Proportion of children with fever (temperature ≥ 38.0°C or ≥ 
100.4°F) on at least one day on day 3-8 following Visit 1 and Visit 2 
combined. 
EOM 5.1: Proportions of children with moderate/severe fever (GRADE 2 
and/or 3) on at least one day during days 3-8 following Visit 1, Visit 2, 
and Visit 1 and Visit 2 combined 
EOM 5.2: Average number of consecutive days of fever (temperature ≥ 38.0°C 
or ≥ 100.4°F) per subject for fever starting on 3-8 days following Visit 1, Visit 2, 
and Visit 1 and Visit 2 combined. 
 Note: fever starting on day 3-8 could continue through day 8.  
EOM 5.3 Proportion of children with medical care utilization (telephone 
call, medical office visit, emergency department visit, or hospital 
admission) for fever on 3-8 days following Visit 1, Visit 2, and Visit 1 and 
Visit 2 combined). 

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EOM 6.1: The proportion of children with solicited systemic adverse 
events (excluding fever) at different levels of severity (Grades 1, 2, 3, 
and all Grades) on day 1-8 following Visit 1 and Visit 2 
EOM 7.1: The proportion of children with febrile seizure and/or serious 
adverse events during the period of enrollment (i.e. from Visit 1 through 8 
days after Visit 2). 
EOM 8.1: Proportion of parents reporting positive and negative 
perceptions about their vaccination schedule experience will be 
determined for each survey item.  
Estimated Time to 
Complete 
Enrollment: 
Approximately 7 months for enrollment season 

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1 BACKGROUND  
1.1 Background 
 
Fever is commonly observed in children following receipt of their routine immunizations.1 
The CDC vaccine information statements (VIS) designate fever as a side effect following 
numerous childhood vaccines including: Hepatitis B; diphtheria, tetanus, and acellular 
pertussis (DTaP); Haemophilus influenza type B (Hib); 13-valent conjugate 
pneumococcal (PCV13); inactivated influenza vaccine (IIV); measles,  mumps, and 
rubella (MMR); varicella; and measles, mumps, rubella and varicella (MMRV) 
(https://www.cdc.gov/vaccines/hcp/vis/current-vis.html}.  While the exact mechanisms 
and functions of fever are not completely understood, some have suggested fever has a 
beneficial role in response to infection 2. However, in the context of immunization, fever 
is considered an adverse event that leads to increased medical visits, and can contribute 
to reluctance to vaccinate 3. 
In most cases, the fever following childhood vaccination is mild and resolves within a few 
days; however, in a small proportion of cases, fever can be clinically severe.  For young 
children, fever following immunizations can also trigger the occurrence of a febrile 
seizure (FS) which is the most common neurological event in childhood 4. As also noted 
in the VIS, FS occur as a potential side effect following several different vaccines 
including MMR, varicella, and MMRV vaccines.  In addition, the VIS for IIV notes that 
young children receiving IIV along with PCV13 or DTaP may be more likely to have a 
FS.  Likewise, the VIS for PCV13 notes that children receiving IIV at the same time as 
PCV13 may be more likely to have a FS.  The DTaP VIS discusses fever in children with 
a history of seizure, but FS are not specifically mentioned as a potential complication. 
While a potential complication of fever following pediatric vaccinations, FS can also 
occur in the setting of other fever triggering illnesses in young children.  Typically, FS 
are most commonly observed in children between 6 months and 3 years of age with the 
peak occurrence at 18 months of age.5 Approximately, 2-5% of children experience at 
least one FS before the age of 5 years 6.  Besides a prior FS, a family history of FS is 
also a risk factor for FS occurrence 7. For children experiencing a FS, the recurrence 
rate is generally believed to be 30% but may approach 50% in the youngest children. 
Although generally considered a benign condition, the occurrence of a FS can be quite 
frightening and anxiety provoking in parents of these children. 
The current statements regarding risks for FS following IIV and PCV13 vaccines, as 
noted above, were included in the VIS following clinical and study observations made 
during the 2010-2011 influenza season.  In 2010 an increased risk of FS was noted 
among southern hemisphere children within 24 hours of receiving CSL influenza 
vaccine.8  With a heightened awareness after the southern hemisphere experience, 
during the 2010-2011 influenza season, the Vaccine Adverse Event Reporting System 
(VAERS) detected a signal for an increased occurrence of FS among children younger 
than 2 years of age who had received IIV.9  As Fluzone was the only US licensed 
vaccine for children of this age, the increased occurrence was specific to this IIV 
product. A study by the Vaccine Safety Datalink (VSD) to assess FS after the 2010-
2011 influenza vaccine noted an elevated risk of FS on the day of and day following 
(days 1-2) the first dose of trivalent influenza vaccine (IIV3).10 The risk was elevated for 
both IIV3 and PCV13 and was highest when IIV3 was co-administered with PCV13.  
Among children 6 to 59 months of age in this VSD study, 16 month-olds had the highest 
risk for FS.  The VSD continued with additional studies to further explore this 

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association.  A subsequent analysis by VSD for the 2013-2014 and 2014-2015 seasons 
noted an increased FS risk on the day of and day following the ﬁrst dose of IIV3 during 
the 2014–2015 season in children aged 6–23 months.11  An analysis including both 
seasons noted that the relative risk of FS was signiﬁcantly elevated for IIV3 and IIV4 
with concomitant PCV13 vaccination and not for IIV3 or IIV4 alone. Finally, the VSD did 
a study of children 6 through 23 months of age during the periods from 2006 to 2011. 
The concomitant administration of IIV3 + PCV and IIV3 + DTaP-containing vaccines 
had higher risks of FS than when the vaccines were given independently. The 
concomitant administration of PCV + DTaP + IIV-containing vaccines had the highest 
relative risk. These increased risks with concomitant vaccination were observed in all 
influenza seasons studied.12 A separate study conducted by the Post-Licensure Rapid 
Immunization Safety Monitoring Program (PRISM) was unable to confirm the VSD 
findings and did not detect an increased risk of FS for 2010–2011 IIV3 or PCV13, when 
adjusting for concomitant vaccines.13  It is unclear why the VSD and PRISM studies did 
not find comparable results.   
As an elevated risk of FS has been noted, particularly with concomitant administration 
of PCV13 and IIV, one would expect to observe higher rates of fever when PCV13 is 
administered with IIV compared to when they are administered separately.  An 
observational study conducted by Clinical Immunization Safety Assessment (CISA) 
investigators in 2011-2012, a season during which the vaccine was unchanged from 
2010-2011 when higher rates of FS were detected, noted that on day of and day 
following vaccination, children aged 6-23 months, receiving IIV3 and PCV13 
simultaneously had higher rates of fever than those receiving IIV3 or PCV13 without the 
other product.14 Temperatures were measured using a temporal artery thermometer. 
The proportion of children with fever ≥ 38°C in the 1-2 days after vaccination was 7.5% 
in those receiving IIV3 alone, 9.5 % in those receiving PCV13 alone and 37.6%, in 
those receiving both vaccines. This effect was greater following the first dose of IIV3 
when compared to the second dose.  These data lend support to findings of the VSD 
investigations suggesting a higher rate of FS occurring after concomitant administration 
of PCV13 and IIV.  In addition, in an early 2003 study of IIV in children 6 through 23 
months of age, we noted the percentage of children with axillary temperatures > 37.8°C 
within 3 days of IIV was 7% when IIV3 was given concomitantly with pneumococcal 
conjugate vaccine, 4% when given with any diphtheria-tetanus toxoid-acellular pertussis 
combination vaccine, and 5% when given alone.15 
1.2 Summary & Rationale 
 
Fever after vaccination is relatively common and may serve as a proxy for febrile seizure 
risk.  Given the uncertainties about the association of simultaneously administered 
PCV13, DTaP, and IIV in young children and risk for febrile seizure, a prospective 
randomized clinical study could provide much-needed data on risks of increased fever 
and hence the potential for the development of FS. Although one potential strategy for 
preventing FS is the use of antipyretic medications around the time of vaccination, the 
use of antipyretics to prevent FS in the setting of fever has not been shown to be an 
effective strategy.16 Furthermore, an antipyretic strategy to prevent FS following 
vaccination has yet to be proven to work and has the potential for blunting of vaccine 
immune responses particularly for PCV and DTaP vaccines.17  An alternate strategy is 
administering vaccines sequentially rather than concomitantly when their concomitant 
use has been shown to result in more fever and resulting FS. Furthermore, clinics 
frequently administer influenza vaccine as a stand-alone vaccine; among children who 

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received IIV in the VSD 2010-11 study, 54% of children received it alone. 10  It is likely to 
be logistically feasible to separate visits between influenza vaccine and other non-
influenza childhood vaccines; this could be done without a child becoming delayed on 
the recommended immunization schedule.  Parents and providers would benefit from 
knowing if separating the IIV vaccine from other recommended vaccines actually 
reduces fever and hence the overall risk for febrile seizure after vaccination or if it just 
spreads the risk over two time points.   
 
We therefore propose to conduct a study to assess fever following simultaneous vs. 
sequential PCV13, DTaP and IIV administration in children of an age of peak FS risk.   
This study will provide evidence that may help healthcare providers who care for children 
at high risk for FS make vaccination decisions.  The current study will not include 
children at high risk of FS, as anecdotally it has been noted that some of these children 
per recommendations from their provider may already be receiving PCV13/DTaP and IIV 
sequentially.  Although the study will not include these at risk children, the findings will   
provide indirect evidence on whether spacing IIV and other childhood vaccines over two 
visits might potentially be useful as a strategy to prevent fever and febrile seizures after 
inactivated vaccines in children at high risk for febrile seizure.   This study could help 
quantify the number of additional fevers, if any, which occur after simultaneous vs 
sequential vaccination.  This information would also provide anticipatory guidance to 
parents about fever after simultaneous vaccination.   
 
2 STUDY OBJECTIVES 
 
Primary Objective (PO): 
PO 1: To compare the proportions of children with fever following simultaneous versus 
sequential vaccination with PCV13, DTaP, and IIV during two visits. Children in the 
sequential vaccination group will receive PCV13 and DTaP at Visit 1 followed by IIV and 
health education at Visit 2.   Children in the simultaneous vaccination group will receive 
PCV13, DTaP, and IIV at Visit 1, followed by a health education visit without vaccination 
at Visit 2. Fever will be assessed on the visit day of, and the day after (days 1-2) each 
visit. 
The primary hypothesis is that the proportion of children with fever will be higher in 
children after the simultaneous vs. the sequential schedule. 
Secondary Objectives (SO): 
SO 1: To compare the proportions of children with fever on day 1 and/or day 2 after Visit 
1 and Visit 2 separately, in the simultaneous versus sequential vaccination group. 
 
SO 2: To compare the clinical importance of fever on day 1 and/or day 2 after Visit 1 and 
Visit 2 (separately and combined) in the simultaneous versus sequential group. Clinical 
importance is assessed based on severity of fever, duration of fever, and medical care 
utilization for fever. 
 
 
 

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Exploratory Objectives (EO): 
EO 1: To compare the height and duration of fever on day 1 and/or day 2 after Visit 1 
and Visit 2 (separately and combined) in the simultaneous versus sequential group 
 
EO 2: To compare the use of antipyretics for fever on day 1 and/or day 2 after Visit 1 
and Visit 2 (separately and combined) in the simultaneous versus sequential group. 
 
EO 3: To describe and compare the level of severity of fever following Visit 1 and Visit 2 
(separately) in the simultaneous versus sequential group 
 
EO 4: To compare the proportions of children with fever 3-8 days after Visit 1 and Visit 2 
(separately and combined) in the simultaneous versus sequential group. 
 
EO 5: To compare the clinical importance of fever occurring 3-8 days after Visit 1 and 
Visit 2 (separately and combined) in the simultaneous versus sequential group. Clinical 
importance is assessed based on severity of fever, duration of fever, and medical care 
utilization for fever. 
 
EO 6: To describe  and compare the occurrence of solicited systemic adverse events on 
day 1-8 after Visit 1 and Visit 2 in the simultaneous versus sequential group. 
  
EO 7: To describe and compare the occurrence of febrile seizure and/or serious adverse 
events during the period of enrollment (i.e. from Visit 1 through 8 days after Visit 2) in the 
simultaneous versus sequential group. 
 
EO 8: To describe and compare the perceptions among parents/ legally authorized 
representatives (LARs) of the simultaneous versus sequential schedule experience.   
2.1 Study Outcome Measures as Related to Objectives 
 
Primary Outcome Measure (POM):  
POM 1.1: Proportion of children with fever (temperature ≥ 38.0°C or ≥ 100.4°F) on day 1 
and/or day 2 following Visit 1 and/or Visit 2. 
 
Secondary Outcome Measures (SOM): 
 
SOM 1.1:  Proportion of children with fever (temperature ≥ 38.0°C or ≥ 100.4°F) on day 1 
and/or day 2 following Visit 1. 
 
SOM 1.2: Proportion of children with fever (temperature ≥ 38.0°C or ≥ 100.4°F) on day 1 
and/or day 2 following Visit 2 
 
SOM 2.1: Proportions of children with moderate/severe fever (GRADE 2 and/or 3) on 
day 1 and/or day 2 following Visit 1, Visit 2, and Visit 1 and Visit 2 combined. 

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SOM 2.2: Average number of consecutive days of fever (temperature ≥ 38.0°C or ≥ 
100.4°F) per subject for fever starting on day 1 or 2 following Visit 1, Visit 2 and Visit 1 
and Visit 2 combined. 
    Note: fever starting on day 1 or 2 could continue through day 8.  
 
SOM 2.3: Proportion of children with medical care utilization  (telephone call, medical 
office visit, emergency department visit, or hospital admission) for fever on day 1 and/or 
day 2 following Visit 1, Visit 2 and Visit 1 and Visit 2 combined. 
 
Exploratory Outcome Measures (EOM): 
EOM 1.1: Average peak temperature of children with fever (temperature ≥ 38.0°C or ≥ 
100.4°F) on day 1 and/or day 2 following Visit 1, Visit 2, and Visit 1 and Visit 2 
combined. 
 
EOM 1.2: Total number of fever degree-days (temperature ≥ 38.0°C or ≥ 100.4°F) on 
day 1 and/or day 2 per subject following Visit 1, Visit 2, and Visit 1 and Visit 2 combined. 
 
EOM 2.1: Proportion of children with antipyretic use for fever on day 1 and/or day 2 
following Visit 1, Visit 2 and Visit 1 and Visit 2 combined. 
 
EOM 3.1: Proportions of children with fever at different levels of severity (Grades 1, 2, 
and 3) on day 1 and/or day 2 following Visit 1 and Visit 2  
 
EOM 3.2: Proportions of children with fever at different levels of severity (Grades 1, 2, 
and 3) on days 3-8 following Visit 1 and Visit 2 
 
EOM 3.3: The proportion of children with fever at different levels of severity (Grades 1, 
2,3 and all Grade) on days 1-8 following Visit 1 and Visit 2 
 
EOM 4.1: Proportion of children with fever (temperature ≥ 38.0°C or ≥ 100.4°F) on at 
least one day on day 3-8 following Visit 1. 
 
EOM 4.2: Proportion of children with fever (temperature ≥ 38.0°C or ≥ 100.4°F) on at 
least one day on day 3-8 following Visit 2.  
 
EOM 4.3: Proportion of children with fever (temperature ≥ 38.0°C or ≥ 100.4°F) on 
at least one day on day 3-8 following Visit 1 and Visit 2 combined. 
 
EOM 5.1:  Proportions of children with moderate/severe fever (GRADE 2 and/or 3) on at 
least one day during days 3-8 following Visit 1, Visit 2, and Visit 1 and Visit 2 combined 
 
EOM 5.2: Average number of consecutive days of fever (temperature ≥ 38.0°C or ≥ 
100.4°F) per subject for fever starting on 3-8 days following Visit 1, Visit 2, and Visit 1 
and Visit 2 combined. 

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 Note: fever starting on day 3-8 could continue through day 8.  
 
EOM 5.3 Proportion of children with medical care utilization (telephone call, medical 
office visit, emergency department visit, or hospital admission) for fever on 3-8 days 
following Visit 1, Visit 2, and Visit 1 and Visit 2 combined). 
 
EOM 6.1: The proportion of children with solicited systemic adverse events (excluding 
fever) at different levels of severity (Grades 1, 2, 3, and all Grades) on day 1-8 following 
Visit 1 and Visit 2 
 
EOM 7.1: The proportion of children with febrile seizure and/or serious adverse events 
during the period of enrollment (i.e. from Visit 1 through 8 days after Visit 2). 
 
EOM 8.1: Proportion of parents reporting positive and negative perceptions about their 
vaccination schedule experience will be determined for each survey item. 
 
3 STUDY DESIGN 
3.1 Main study design 
 
This study is a prospective, randomized open-label clinical trial that will be conducted 
during the 2017-2018 influenza season.  Results from the 2017-2018 influenza season 
will help guide whether this study will be repeated during the 2018-2019 influenza 
season under a new protocol.   During the 2017-2018 season, approximately 280 
children will be enrolled at Duke University Medical Center and Kaiser Permanente 
Northern California. Eligible children will be randomized to receive simultaneous or 
sequentially administered US-licensed PCV13, US-licensed DTaP vaccine, and US-
licensed inactivated influenza vaccine (IIV). Children in the simultaneous group will 
receive PCV13, DTaP, and IIV vaccines at Visit 1, and then return for a health education  
visit without vaccination about 2 weeks later (Visit 2).  Children in the sequential group 
will receive both PCV13 and DTaP without IIV at Visit 1, and then will receive IIV and 
health education about 2 weeks later (Visit 2).  Parents will record the occurrence of 
fever, solicited adverse events, medical care utilization, and receipt of antipyretics over 8 
days following Visit 1 and Visit 2. In addition, febrile seizures and serious adverse events 
will be recorded for the entire study period (from enrollment through 8 days following the 
Visit 2) will be assessed through parental report and chart review. 
 
Young children aged 12-16 months will be enrolled over a period of approximately 7 
months. Children will be followed for up to 37 days following enrollment.   The first 10 
children enrolled at Duke University Medical Center will be enrolled in a study pilot to 
quickly assess study feasibility benchmarks and make protocol adjustments if 
necessary.  Data from pilot participants will also contribute to the analysis of primary, 
secondary and exploratory outcomes. 
 
4 STUDY ENROLLMENT AND WITHDRAWAL  
Subject Inclusion and Exclusion Criteria will be reviewed at Visit 1 to assess 
eligibility for study participation. 

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4.1  Subject Inclusion Criteria 
Subjects who meet all of the following criteria will be eligible to participate in this 
interventional study.   
1. 12 through 16 months of age (i.e. from the 1-year birthday until the day before 17 
months of age) at the time of vaccination 
2. Stable health as determined by investigator's clinical examination and 
assessment of child's medical history 
3. Has received all immunizations recommended by Advisory Committee for 
Immunization Practices (ACIP) during the first year of life with the exception of 
rotavirus and influenza vaccines.* 
*Immunizations recommended during the first year of life include: 3 doses 
of DTaP, 3 doses of PCV13, 2- 3 doses of inactivated polio virus vaccine, 
3 doses of Hepatitis B vaccine, and 2 or 3 doses of Hib vaccine such that 
the primary Hib series is complete depending upon the brand used. 
(https://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html). 
4. The parent(s)/ legally authorized representative(s) LAR(s) intend for the child to 
receive DTaP and PCV13 in addition to this season's IIV 
5. The parent(s)/LAR(s) must be willing and capable of providing permission for 
their child to participate through the written informed consent process 
6. The parent(s)/LAR(s) must be able to comply with the requirements of the 
protocol (e.g., completion of the memory aid (either electronic or paper diary), 
return for follow-up visits, respects intervals between the visits and have 
telephone access. 
7. The parent(s)/LAR(s) must be English speaking 
8. The parent(s)/LAR(s) must agree to sign a medical release for the child so that 
study personnel may obtain medical information about the child's health (if 
needed) 
4.2 Subject Exclusion Criteria 
Subjects who meet any of the following criteria will not be eligible to participate in 
this study: 
1. History of any seizure (including febrile seizure) in the child or a febrile seizure 
in a first degree relative* 
*First degree relatives include biological parents or siblings 
2. Has already completed influenza vaccination during the current season per 
ACIP recommendations* 
*Children needing two doses of influenza vaccine per ACIP 
recommendations and who are receiving a second dose of influenza 
vaccine may be enrolled; however, an attempt will be made to 
preferentially enroll children needing two doses at the time of receipt of 
their first dose of influenza vaccine 
3. Receipt of more than 3 previous doses of DTaP 
4. Received the 3rd dose of DTaP within 6 months of Visit 1 
5. Receipt of more than 3 previous doses of PCV13 
6. Received the 3rd dose of PCV13 within 8 weeks of Visit 1 
7. History of a severe allergic reaction (e.g. anaphylaxis) to a previous dose of any  
influenza, diphtheria toxoid-, tetanus toxoid-, or pertussis-containing vaccine, or 
pneumococcal vaccine. 
8. History of a severe allergic reaction (e.g., anaphylaxis) to any component 
(including egg protein) of any of the three vaccines used in this study; or a latex 
allergy.  

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9. History of Guillain-Barré syndrome within 6 weeks following a prior dose of 
influenza, DTaP, or tetanus toxoid containing vaccine 
10. History of a progressive neurologic disorder 
11. History of encephalopathy within 7 days of a previous pertussis-containing 
vaccine 
12. History of collapse within 3 days after a prior dose of DTaP 
13. Received any other licensed vaccines within 14 days (for inactivated vaccines) 
or 28 days (for live vaccines) prior to Visit 1* 
*Concomitant vaccine administration of vaccines on ACIP recommended 
immunization schedule for children and adolescents aged 18 years and 
younger  are allowed to be administered on the first vaccination day in 
this study but at no other time in this study period unless deemed a 
personal or public health priority by the health care provider caring for this 
patient or the study team. 
14. Received an experimental/investigational agent (vaccine, drug, biologic, device, 
blood product, or medication) within 28 days prior to Visit 1, or expects to 
receive an experimental/investigational agent during the study period (up to 8 
days after visit 2)  
15. A moderate to severe acute illness within 72 hours of Visit 1* 
*All vaccines can be administered to persons with a minor illness such as 
diarrhea, mild upper respiratory infection without fever. 
16. A reported temperature greater than or equal to 100.4°F (38.0°C) within 72 
hours prior enrollment or a temperature (measured by temporal artery 
thermometer) greater than or equal to 100.4°F (38.0°C) at the time of 
enrollment*  
*This may result in a temporary delay of vaccination 
17. Receipt of an antipyretic medication (acetaminophen or ibuprofen) within 24 
hours prior to enrollment* 
*This may result in a temporary delay of vaccination 
18. Parent(s)/LAR is planning to administer a prophylactic antipyretic or medication 
on the day of, and/or within 7 days following Visit 1 or Visit 2* 
*This exclusion does not apply if the caretaker indicates he/she might 
administer antipyretics or analgesics after vaccination to reduce fever or 
pain 
19. Long term (at least 14 consecutive days) oral corticosteroids (prednisone 2 
mg/kg/day or equivalent other glucocorticoid), any parenteral steroids, high-dose 
inhaled steroids (>800 mcg/day of beclomethasone dipropionate or equivalent) 
or other immune-modifying drugs or immunosuppressants within the preceding 
6 months prior to Visit 1*  
*Topical and nasal steroids are allowed 
20. Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and or their provider's routine physical examination*  
*No laboratory testing required 
21. Has an active neoplastic disease, a history of any hematologic malignancy, 
current bleeding disorder, or taking anticoagulants. 
22. Unable to receive an intramuscular injection in the thigh* 
* For example – a broken bone or cast for treatment of broken bone in a 
lower extremity, congenital anomaly in lower extremity precluding 
administration in the affected extremity or if deemed inappropriate by the 
study investigator 

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23. Any condition deemed by the investigator to place the child at increased risk as 
a result of their participation in the study 
24. Any child or grandchild of a study investigator or study team member  
 
A modified list of Exclusion Criteria will be reviewed at Visit 2 to assess eligibility for 
continued study participation. 
Subjects who meet any of the following exclusion criteria will not be eligible to continue 
participation in this study: 
 
1. Has already completed influenza vaccination during the current season per 
ACIP recommendations 
2. History of a severe allergic reaction (e.g. anaphylaxis) to a previous dose of any 
influenza vaccine. 
3. History of a severe allergic reaction (e.g., anaphylaxis) to any component 
(including egg protein) of the influenza vaccine used in this study.  
4. History of Guillain-Barré syndrome within 6 weeks following a prior dose of any 
influenza vaccine 
5. Received an experimental/investigational agent (vaccine, drug, biologic, device, 
blood product, or medication) after randomization or expects to receive an 
experimental/investigational agent during the remaining study period (up to 8 
days after visit 2)  
6. A moderate to severe acute illness within 24 hours of Visit 2* 
* This may result in a temporary delay of Visit 2 and/or vaccination. 
All vaccines can be administered to persons with a minor illness such as 
diarrhea, mild upper respiratory infection without fever. 
7. A reported temperature greater than or equal to 100.4°F (38.0°C) within 24 
hours prior to Visit 2 or a temperature (measured by temporal artery 
thermometer) greater than or equal to 100.4°F (38.0°C) at the time of Visit 2*  
*This may result in a temporary delay of Visit 2 and/or vaccination 
8. Receipt of an antipyretic medication (acetaminophen or ibuprofen) within 24 
hours prior to Visit 2* 
*This may result in a temporary delay of Visit 2 and/or vaccination 
9. Parent(s)/LAR is planning to administer a prophylactic antipyretic or medication 
on the day of, and/or within 7 days following Visit 2* 
*This exclusion does not apply if the caretaker indicates he/she might 
administer antipyretics or analgesics after Visit 2 to reduce fever or pain 
10. Unable to receive an intramuscular injection in the thigh* 
* For example – a broken bone or cast for treatment of broken bone in a 
lower extremity, congenital anomaly in lower extremity precluding 
administration in the affected extremity or if deemed inappropriate by the 
study investigator 
11. Any condition deemed by the investigator to place the child at increased risk as 
a result of their participation in the study 
 
4.3 Recruitment 
The 280 participants in this study will be healthy male or female children 12 through 
16 months of age. Children will be recruited from designated study sites affiliated with 
the Duke University Health System (Duke Children’s Primary Care Roxboro Street, 
Duke Children’s Primary Care Southpoint, Duke Children’s Primary Care Brier Creek, 

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Durham Pediatrics, and Regional Pediatrics) or from designated Northern California 
Kaiser Permanente pediatric clinics.  Children will primarily be recruited at the time of 
well child visits.  About 160 children will be enrolled at the Duke University Health 
System Clinics and 120 children will be enrolled at the Northern California Kaiser 
Permanent pediatric clinics.  
4.4 Reasons for and Handling of Withdrawals 
The following may be reasons for study withdrawal: 
• 
As deemed necessary by the principal investigator (PI). 
• 
Meets criteria for exclusion at Visit 2  
• 
Parent(s)/LAR(s) withdrawal of permission for their child to participate. 
• 
Loss to follow-up. 
• 
No longer a member of the Kaiser Foundation Health Plan (KFHP) – only 
includes children enrolled at the Northern California Kaiser Permanent pediatric 
clinics. 
• 
Termination of the study by the sponsor. 
 
A parent/LAR may withdraw permission for their child to participate at any time and for 
any reason, without penalty. Subjects who are withdrawn from the study prior to 
randomization or first vaccination visit will be replaced. Subjects who are withdrawn from 
the study after receiving vaccine will not be replaced.  For subjects who received study 
vaccines, data collected prior to withdraw in 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 the 
Lead or Contributing sites, CDC, or participating Institutional Review Boards (IRBs).   
 
5 STUDY SCHEDULE, PROCEDURES, & EVALUATIONS 
5.1 Schedule of Events 
Children meeting the proposed eligibility criteria will be recruited. Written permission for 
the child to participate will be obtained from parent(s)/LAR(s) prior to conducting any 
study procedures. Table 1 describes the proposed schedule of study visits.  Note that 
the table includes ability for parent(s)/LAR(s) to submit memory aid information 
electronically over the internet by (REDCap) or using a paper memory aid (diary).  For 
this study, use of (REDCap) for obtaining memory aid information is the preferred option. 
 
Table 1. Proposed Study Visit Schedule 
Procedure 
Visit1 
Day 1 
Visit 1A 
Day 3 (+3) 
Visit 1B 
Day 9 (+3) 
Visit 2 
Day 15 
(+7) 
Visit 2A 
Day 3 (+3) 
Post Visit 2 
Visit 2B 
Day 9 (+6) 
Post Visit 2 
Type of contact by group 
(REDCap/Paper Form) 
Clinic 
REDCap - 
All 
Paper – All 
 
Phone/Email 
REDCap-PRN 
Paper – All 
 
Phone/Email 
REDCap-PRN 
Paper – No 
 
Clinic 
REDCap-All 
Paper – All 
 
Phone/Email 
REDCap-PRN 
Paper – All 
 
Phone/Email 
REDCap-PRN 
Paper – PRN 
 
Written Parent/LAR Permission 
& Medical Release of 
Information 
X 
 
 
 
 
 
Review Eligibility Criteria 
X 
 
 
X 
 
 

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Table 1. Proposed Study Visit Schedule 
Procedure 
Visit1 
Day 1 
Visit 1A 
Day 3 (+3) 
Visit 1B 
Day 9 (+3) 
Visit 2 
Day 15 
(+7) 
Visit 2A 
Day 3 (+3) 
Post Visit 2 
Visit 2B 
Day 9 (+6) 
Post Visit 2 
Data Collection  (Demographic 
information and Medical 
History) 
X 
 
 
 
 
 
Influenza, DTaP, and PCV13 
Vaccination History 
X 
 
 
 
 
 
Temperature measurement 
(temporal artery) 
X 
  
 
X 
 
  
Randomization 
X 
  
 
 
 
 
Vaccination with study 
vaccine(s)  
X 
  
 
X1 
 
  
Provide Educational Materials 
 
 
 
X 
 
 
Concomitant Vaccination with 
non-study vaccines  
X 
 
 
 
 
 
Dispense Memory aid (Paper2) 
& Thermometer 
X 
  
 
X3 
 
  
Complete Memory aid form  
(REDCap or Paper) for fever, 
solicited systemic adverse 
events, medical care utilization, 
antipyretic use 
X 
X 
X 
X 
X 
X 
Review REDCap and paper 
memory aid entries for 
completeness and out of range 
values for fever data 
 
X 
 
 
X 
 
Review REDCap entries for 
completeness fever, solicited 
systemic adverse events, 
medical care utilization, 
antipyretic use 
 
 
X 
 
 
X 
Review Paper Memory aid for 
completeness  fever, solicited 
systemic adverse events, 
medical service utilization, 
antipyretic use 
 
 
 
X 
 
X 
Obtain concomitant medication 
use 
X 
 
 
X 
 
 
Obtain serious adverse event 
information and febrile seizure 
information 
 
X 
X 
X 
X 
X 
Obtain parent(s)/LAR(s)  
perceptions about vaccination 
and/or the vaccination 
schedules 
 
 
 
 
 
X 
1Indicates vaccination of subjects in sequential group only. 2All subjects receive paper memory aid 3New 
thermometer dispensed only for those who have misplaced it or if not working properly 
 
Visit 1, Study Day 1 Clinic Visit 
• Obtain parent(s)/LAR(s) permission by written informed consent and a release of 

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medical record information 
• Review and confirm study eligibility (Section 4.1 and 4.2) 
• Obtain information on parent(s)/LAR(s) preferred method for submitting memory 
aid information – either direct entry by the parent(s)/LAR(s) into REDCap using the 
memory aid as a tool or directly submitting information recorded on the paper 
memory aid.  Parents will be encouraged to submit information recorded on the 
memory aid into REDCap. 
• Obtain information on parent(s)/LAR(s) preferred method of contact by the study 
team to assist with obtaining follow-up information (e-mail or telephone)  
• Obtain medical history  
• Obtain demographic data & month/ day /year of prior influenza, DTaP and PCV13 
vaccines 
• Obtain concomitant medication use within 2 weeks of enrollment 
• Obtain temperature using the temporal artery thermometer to be dispensed to 
parent(s)/LAR(s) for use at home. Use temperature measurement as an opportunity 
to instruct the parent(s)/LAR(s) on use of temporal artery thermometer. 
• Dispense temporal artery thermometer to all parent(s)/LAR(s). Parent(s)/LAR(s) 
will get to keep the temporal artery thermometer dispensed.  
• Randomize study participant to simultaneous or sequential vaccine administration  
• Ensure participants receive corresponding Vaccine Information Sheets (VIS) during 
visit. 
• Administer assigned study products – Trained, licensed research staff will administer 
PCV13, DTaP, and IIV or PCV13 and DTaP  
• Administer other concomitant vaccines as needed for age according to ACIP 
recommendations (either research or clinic staff).  This is per usual clinical practice 
and is not considered a study procedure 
• Observe child in the clinic for at least 15 minutes after vaccination  
• Dispense paper memory aid to all parent(s)/LAR(s) to record temperatures, 
solicited adverse events, medical care utilization and antipyretic use.  
• Review use of REDCap for those preferring submitting memory aid information by 
internet and collect email address 
• Confirm date of next scheduled telephone and clinic study visit appointments. 
o Parent(s)/LAR(s) electing to use REDCap will only be called/contacted on 
Study Day 3 following Visit 1 if missing fever information or if out of range 
fever values and will only be called/contacted on Study Day 9 following Visit 1 
if missing information  
o All parent(s)/LAR(s) electing to use the paper memory aid only will be 
called/contacted on Study Day 3 following Visit 1.  
o All children will return for a visit on Visit 2 on Day 15. Remind parents using 
paper memory aid only to return memory aid at Visit 2. 
 
Visit 1A, Study Day 3 (window Days 3-6) Memory Aid Check - Phone Call/E-mail 
Follow-up 
• REDCap Follow-Up for Memory Aid Information 
o Review of REDCap information submitted for fever only on Day 1 and 
Day 2 for completeness and out of range values for fever.   
o If missing fever information or out of range fever values, contact 
parent(s)/LAR(s) to review the memory aid data for Day 1 and Day 2 and 
obtain any missing fever information or clarify any out of range fever values.  
o Instruct parent to enter any missing days of data in REDCap  

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o Record missing information regarding fever on paper case report form (CRF) 
o If missing days of information for solicited adverse events, medical care 
utilization, antipyretic use, occurrence of febrile seizure or occurrence of a 
serious event remind parent to complete information in REDCap, 
• Paper Memory Aid Completion 
o Contact parent(s)/LAR(s) to review and obtain Day 1 and Day 2 memory aid 
information for fever only (completeness and out of range values)  
o Record information regarding fever on paper CRF 
o Remind parent(s)/LAR(S) to bring the paper memory aid to Visit 2 
o Confirm date of next scheduled clinic visit appointments. 
 
Visit 1B, Study Day 9 (window Days 9-12) Memory Aid Check – Phone Call/E-mail 
Follow-up 
• REDCap Follow-Up for Memory Aid Information 
o Review of electronically submitted memory aid information (fever, 
solicited adverse events, medical care utilization, antipyretic use, 
occurrence of febrile seizure, or occurrence of a serious adverse event) 
for Days 1-8 for completeness 
o If missing information, contact parent(s)/LAR(s) to review the memory 
aid data for Days 1-8 and obtain any missing information 
o Instruct parent to enter missing days of data into REDCap 
o Record missing information on a paper CRF  
• Paper Memory Aid Completion 
o No scheduled follow-up for this visit 
 
Visit 2, Study Day 15 (window Days 15 – 22) Clinic Visit 
• Paper Memory Aid Completion for Visit 1 
o Collect paper memory aid.   
o Review of paper memory aid information (fever, solicited adverse events, 
medical care utilization, antipyretic use, occurrence of febrile seizure, or 
occurrence of a serious adverse event) for Days 1-8  
• Review and confirm continued study eligibility (Section 4.2) 
• Obtain temporal artery temperature. 
• Record any SAEs, febrile seizures occurring between day 9 after Visit 1 and Visit 2 
• Record concomitant medications  
• Ensure participants receive IIV Vaccine Information Sheets (VIS) during visit. 
• For subjects in the sequential study group, trained, licensed research staff will 
administer IIV. 
• Observe child in the clinic for at least 15 minutes after vaccination  
• Administer educational intervention and provide toothbrush to all study 
participants 
• No concomitant immunizations will be allowed or administered unless deemed a 
personal or public health priority by the health care provider caring for this 
patient or the study team. 
• Confirm preferred method of contact for follow-up (email or telephone) including 
continued preference for submitting memory aid information by REDCap or by 
mail. 
• Confirm subjects still have previously dispensed thermometer; if not, provide new 
thermometer for the parent to keep. Dispense new paper memory aid. Review 
instructions for use of thermometer and memory aid completion  

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• Review use of REDCap for those preferring to submit memory aid information by 
internet and verify email address 
• For those parent(s)/LAR(s) electing to use a paper memory aid, they will be provided 
survey regarding preferences for spacing of vaccinations. Give these 
parent(s)/LAR(s) a pre-addressed postage paid envelope to return the memory aid 
and survey. 
• Confirm date of next scheduled telephone appointments. 
o Parent(s)/LAR(s) electing to use REDCap will only be called/contacted on 
Day 3 following Visit 2 if missing fever information or if out of range fever 
values and will only be called/contacted on Day 9 if any memory aid 
information is missing. 
o Remind parents using REDCap that they will receive a parental perceptions 
survey on Day 9 to be completed using REDCap  
o Parent(s)/LAR(s) electing to use the paper memory aid only will be 
called/contacted on Day 3 following Visit 2.  
o Remind parents using paper memory aid only to complete the 
parental perceptions survey and mail in the memory aid on Day 9 
following Visit 2. 
 
Visit 2A, Study Day 3 Post Visit 2 (window Days 3-6) Memory Aid Check Phone 
Call/E-mail Follow-up 
• REDCap Follow-Up for Memory Aid Information 
o Review of REDCap information submitted for fever only on Day 1 and 
Day 2 following Visit 2 for completeness and out of range values for 
fever.   
o If missing fever information or out of range fever values, contact 
parent(s)/LAR(s) to review the memory aid data for Day 1 and Day 2 and 
obtain any missing fever information or clarify any out of range fever values.  
o Instruct parent to enter any missing days of data in REDCap  
o Record missing information regarding fever on paper case report form (CRF) 
o If missing days of information for solicited adverse events, medical care 
utilization, antipyretic use, occurrence of febrile seizure or occurrence of a 
serious event remind parent to complete information in REDCap, 
• Paper Memory Aid Completion 
o Contact parent(s)/LAR(s) to review and obtain Day 1 and Day 2 memory aid 
information for fever only (completeness and out of range values)  
o Record information regarding fever on paper CRF 
o Remind parent(s)/LAR(S) to use the pre-addressed postage paid envelope to 
mail in the paper memory aid and parental preference survey at Day 9 
following Visit 2 
 
Visit 2B, Study Day 9 Post Visit 2 (window Days 9-15) Memory Aid Check Phone 
Call/E-mail Follow-up 
• REDCap Follow-Up for Memory Aid and Parental Preference Information 
o Parent will receive parental preference survey on Day 9 after Visit 2 to 
complete through REDCap or verbally over the phone 
o Review of electronically submitted memory aid information (fever, 
solicited adverse events, medical care utilization, antipyretic use, 
occurrence of febrile seizure, or occurrence of a serious adverse event) 
for Days 1-8 and parental preference survey for completeness  

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o If missing information, contact parent(s)/LAR(s) to review the memory 
aid data for Days 1-8 and parental preference survey and obtain missing 
information 
o Instruct parent to enter missing days of data into REDCap 
o Record missing information on a paper CRF 
o Review medical record for occurrence of any SAEs or febrile seizures during 
the enrollment period  
o Complete end of study form once memory aid information and parental 
preference survey is completely entered in REDCap or has been obtained 
and medical record has been reviewed. 
• Paper Memory Aid Completion 
o No scheduled follow-up for this visit 
o If parent fails to send in paper memory aid or parental preference survey they 
can be contacted by phone or e-mail to remind them to return the memory aid 
and parental preference survey using pre-addressed postage paid envelope 
or complete verbally over the phone 
o Review medical record for occurrence of any SAEs or febrile seizures during the 
enrollment period 
o Complete end of study form once memory aid information and parental 
perceptions survey have been received and medical record has been 
reviewed. 
 
5.2 Parent/LAR Permission Process (Informed Consent) 
The consent 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 questions before and after permission is obtained.  Parent(s)/LAR(s) 
will be given as much time as needed after being approached about their child 
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 stressed that participation is voluntary and that parents can withdraw permission for 
their child 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. 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 child’s medical record per local requirements. Eligibility 
will also be assessed. 
 
5.3 Demographic Information, Medical History, Immunization History 
The participant’s age, race/ethnicity, day care attendance and the number of other 
children in the household will be obtained from parent/guardian report at the time of 
enrollment. The insurance payer status for the child will be obtained from the electronic 
health record (EHR). The participant’s medical history including: birthweight; history of 
prematurity; seizure disorder (including febrile seizure history and family history of febrile 
seizure in sibling or parent); significant medical conditions (cardiac disease, pulmonary 
disease including asthma or recurrent wheezing or chronic lung conditions, renal 
disease, diabetes, anemia, hemoglobinopathies) and concomitant medications taken 
within 2 weeks of enrollment will be obtained by review of the electronic health record 

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(EHR) and will be reviewed and confirmed by the parent/guardian at the time of 
enrollment.  Concomitant medications, history of intercurrent hospitalizations or febrile 
seizures will also be verified at Visit 2. 
 
Information on prior history of IIV receipt and on prior receipt of Diphtheria Tetanus 
Toxoid (DT), Diphtheria, Tetanus and acellular Pertussis vaccine (DTaP), and PCV13 
will be obtained at the time of study enrollment. The EHR and/or respective 
immunization registry will be reviewed for vaccination information. Research staff will 
document the vaccine, product brand, and date of administration of prior doses of IIV, 
DTaP, and PCV13 received.  If the information is not available in the EHR or 
immunization registry, a written record documenting prior receipt of these vaccines 
would be considered acceptable.  
Vaccines received as part of the study and concomitant immunization received during 
the study, will be documented by the research staff.  Documentation will include: product 
brand, lot number, site and date/time of vaccine administered during study participation.  
 
At the end of the study, the medical record will be reviewed to assess and record the 
occurrence of any serious adverse events or febrile seizures that occurred during the 
period of study enrollment. 
 
5.4 Temporal Artery Temperature Measurement and Fever Assessments 
Participants’ temperatures will be taken using a digital temporal artery thermometer that 
will be provided to each parent/LAR during enrollment to use for the study and keep for 
use following the study. The initial temperature will be recorded in the clinic and study 
staff will demonstrate proper use of the thermometer to the parent. Temperatures will be 
collected during both Visit 1 and Visit 2.  Thereafter, parent(s)/LAR(s) will measure and 
record the participant’s temperature at approximately the same time each day 
(preferably after 6:00 PM or right before participant goes to bed) beginning on Day 1 
(day of vaccination) and will do so through Day 8 following Visits 1 and 2.  In addition, 
parents will be instructed to take a temperature using a temporal artery thermometer if 
their child feels warm or feverish at any time from Days 1-8 after Visit 1 and 2 and to 
record the temperature on the memory aid.  Temperature measurements will be done for 
both the simultaneous and sequential groups in a similar fashion such that those 
children in the simultaneous group, who do not receive vaccinations at Visit 2, will also 
have temperatures measured.  If at any time a temperature ≥ 100.4°F (≥ 38°C) or ≤ 95°F 
(≤ 35°F) is recorded, a second measurement will be taken within 20 minutes.  The 
highest of those two temperature measurements will be recorded. If more than one 
temperature is taken on the same day (prior to bedtime), the highest temperature for that 
day should be recorded on either the paper memory aid or entered into REDCap. Any 
temperature measured after your child’s bedtime memory aid entry has been completed, 
should be considered for the next day’s memory aid entry. 
 
All temperatures will be measured using a temporal artery thermometer (Exergen 
Medical Scanner Model TAT-2000C)18,19.  Although parents may elect to use an 
alternate method for measuring temperatures, they will be required to measure temporal 
artery temperature measurements as specified above.  
 
For this study, temperatures will be documented using either the electronic memory aid 
through REDCap or the paper memory aid. The preferred method for documentation in 
this study is REDCap.  All parent(s)/LAR(s) will be encouraged to use the paper memory 

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aid as a tool to initially record temperatures and then enter information into REDCap. 
However, they can directly enter temperature information into REDCap if desired without 
using paper.  For parents electing to use REDCap, missing or out of range temperature 
data will be verified with the parent(s)/LARS on day 3 and missing data will be obtained 
on day 9 as needed following Visits 1 and 2. For parents electing to use paper memory 
aids only, temperature data will be verified on day 3 following Visits 1 and 2. 
Parents/LAR using the paper memory aid alone will submit the Visit 1 memory aid to 
study staff during Visit 2, and will mail the Visit 2 memory aid to the study team following 
the 8-day post-visit 2 period. The study team will review the paper memory aid at the 
time of receipt. 
 
For parent(s)/LAR(s) entering data into REDCap, if there are data discrepancies for 
temperatures entered directly into REDCap or obtained over the phone, the information 
provided by the parent in REDCap will be counted as the correct temperature 
information unless verified as otherwise by study staff. 
 
For parent(s)/LAR(s) using only the paper memory aid, if there are data discrepancies 
for temperatures recorded on the memory aid or obtained over the phone, the 
information provided by the parent on the memory aid will be counted as the correct 
temperature information unless verified as otherwise by study staff. 
5.5 Treatment Assignment Procedures 
This is an open-label, prospective, randomized study for young children who are to 
receive PCV13, DTaP and IIV vaccines.  The specific vaccines administered are based 
on availability from manufacturers prior to the 2017-2018 influenza season (see section 
5.5.3).  
 
5.5.1 Randomization 
Participants will be randomized (1:1) to receive either PCV13, DTaP and IIV 
simultaneously or sequentially (PCV13 and DTaP followed by IIV ~2 weeks later) using a 
permuted block randomization scheme stratified by study site (i.e. Duke University 
Medical Center and Kaiser Permanente Northern California). The first 10 children 
enrolled in the pilot at Duke University will be randomized in a block of 10 such that 5 
children will receive simultaneous vaccination and 5 will receive sequential vaccination.  
The project statistician at Duke University will generate permuted block 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. 
5.5.2 Blinding 
This study will be open label and study staff and subjects will not be blinded to treatment 
arm assignments. 
 
Vaccine (Supply, Storage, and Administration) and Educational Materials  
Vaccine Supply and Storage 
For consistency, the same formulations of DTaP, IIV and PCV13 vaccines will be used 
throughout this study to the extent feasible.  There are multiple products on the market 
for DTaP and IIV vaccines.  In the United States, only one PCV13 product (Wyeth 

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Pharmaceuticals, Inc) is licensed (package inserts, available at 
https://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm093833.htm) 
   
Because Duke and Kaiser Study clinics may not stock the same DTaP and IIV products 
in their routine supply, DTaP and IIV (single dose vials or prefilled syringes) will be 
purchased for this study using contract Task Order funds. DTaP and IIV will be 
maintained either at the respective primary research center or their affiliated clinic sites 
in a monitored medication refrigerator at 2-8°C in accordance with package insert 
guidelines.  Study supplied vaccines should be segregated from the clinic’s routine 
vaccine supply.  Study supplied vaccine may be transported between the primary 
research center and clinic sites using each site’s Standard Operating Procedure for 
Study Product Transport as long as the cold chain is maintained. 
• 
Infanrix® (GSK) will be purchased for use as the DTaP vaccine to be 
administered in this study. However, if there are vaccine supply issues at the 
time of the conduct of this study, Daptacel® (Sanofi) may be purchased and used 
in the place of Infanrix®.  
• 
2017-2018 Quadrivalent Fluzone® (Sanofi) will be purchased for use as the IIV 
administered in this study. If not available, an alternate US licensed IIV with an 
indication for this age group will be used. 
• 
PCV13 (Wyeth) will be used as in this study. This is the only US FDA licensed 
PCV13 product available.  Because both study sites routinely use the Wyeth 
PCV13 vaccine in their clinics, PCV13 will be supplied by the participant’s clinic 
site from their usual vaccine supply for use in the study and will not be 
purchased using contract Task Order funds. PCV13 will be maintained at the 
respective clinic sites in a monitored medication refrigerator at 2-8°C in 
accordance with package insert guidelines and clinic standard operating 
procedures. The cost of PCV13 will be billed to patient’s insurance.   
Vaccine Administration 
• 
To assure adherence to study randomization assignment, US licensed 
PCV13, DTaP, and IIV vaccines will be administered as study procedures. 
Young children meeting eligibility criteria for the study will either receive  
1) 
A single intramuscular (IM) 0.5 mL dose of PCV13 vaccine, 
a single IM 0.5 mL dose of DTaP vaccine and a single IM 
0.25 or 0.50 mL dose (depending upon IIV product used but 
used according to package insert directions) of IIV at Visit 1 
(simultaneous vaccination group) 
OR 
2) 
A single IM 0.5 mL dose of PCV13 vaccine and a single IM 
0.5 mL dose of DTaP at Visit 1, followed by a single IM 0.25 
or 0.50 mL dose (depending upon IIV product used but 
used according to package insert directions) of IIV vaccine 
~ 2 weeks  later (sequential vaccination group). 
 
• 
Following randomization assignment within the electronic data capture system, 
a licensed provider (RN, NP, PA, MD) from the study team will administer all 
vaccines. IIV and DTaP will be administered in the vastus lateralis muscle 
(anterolateral thigh).  PCV13 and other concomitantly administered vaccines 
will be administered in the other vastus lateralis muscle (anterolateral thigh). 

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Concomitant vaccines such as MMR, Varicella and MMRV vaccine may be 
administered in either thigh or in the deltoid area as well, consistent with ACIP  
General Best Practice Guidelines for Immunization 
https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html 
 
When more than one vaccine is given in the same limb, 1 inch or more should 
separate the injection sites, if possible, so that any local reactions can be 
differentiated. Concomitant vaccine administration will be allowed at Visit 1 but 
not Visit 2 unless deemed a personal or public health priority by the health care 
provider caring for this patient or the study team. Influenza vaccine may be 
administered outside of the study window in case of public health emergency 
or personal exposure.  
 
• 
Emergency management supplies will be available for initial treatment of an 
allergic reaction if needed. Children will be observed in the respective clinic 
area by study staff for 15 minutes post-vaccination.   
• 
The vaccine brand, manufacturer, lot number, expiration date, site of 
administration, and date/time of administration will be recorded on the case 
report form (CRF). Vaccination information will also be entered into the 
Immunization Registry and Medical Record. 
• 
 Receipt and disposition of study supplied DTaP and IIV will recorded on the 
study product accountability log. 
• 
 Following administration, used study syringes will be disposed of according 
to the respective clinic sites standard operating procedure.  
  
Educational Materials Provided to Parent(s)/LAR(s) at Visit 2 
 A brief educational intervention will be provided to all parent(s)/LAR(s).  
Parent(s)/LAR(s) will be provided educational materials regarding dental care for young 
children.  A handout posted on the American Academy of Pediatric Dentistry website 
regarding caries prevention in young children 
(http://www.mychildrensteeth.org/education/parent_fact_sheet_on_caries_bacteria/) will 
be given to parent(s)/LAR(s).   Parent(s)/LAR(s) will also be provided with a free small 
soft bristle toothbrush for their child.  
5.6 Solicited Systemic Adverse Events (Days 1-8 Following Visits 1 and 2) 
Temperature and other solicited systemic adverse events will be assessed and 
documented by parent(s)/LAR(s) after Visit 1 and Visit 2.  Beginning on the evening of 
Visit 1 and Visit 2 (Day 1), parent(s)/LAR(s) will measure and record their child’s 
temporal artery temperature using the study-supplied thermometer as described in more 
detail in Section 5.4.   
Parent(s)/LAR(s) will rate solicited systemic adverse events (other than fever) according 
to grading in Table 2 beginning on the evening of Study Visits 1 and 2 (Day 1) and for 
the next 7 days following the study visits (i.e. through Day 8).  Each of the following 
symptoms fussiness or irritability, change in eating habits and sleepiness, should be 
assessed each day.  For the day of vaccination, symptoms should be assessed from the 
time of vaccination until the time information is recorded.  For each subsequent day 
through Day 8 symptoms should be assessed from the time information is recorded on 
the previous day until the time it is recorded on the subsequent day. Grading for the child 
solicited systemic symptoms will be recorded on the study-supplied paper memory aid. 

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Parent(s)/LAR(s) will be instructed to notify child’s primary care provider promptly in 
addition to study staff using the 24-hour contact number provided in the memory aid in 
the event of any severe (Grade 3) temperature elevation or solicited systemic adverse 
event. Parent(s)/LAR(s) who at any time report severe solicited adverse events or 
express any concern about symptoms/unsolicited events to the study team will be 
encouraged to follow up with their child’s primary care provider. Study staff will assist 
with coordination of referral appointments as necessary. 
Table 2: Fever Assessment and Solicited Systemic Adverse Events 
 
None 
Mild (Grade 1) 
Moderate (Grade 
2) 
Severe (Grade 3) 
Temporal Artery 
Temperature  
°C 
°F 
 
≤ 37.9 
≤ 100.3 
 
≥ 38.0 - < 38.5 
≥ 100.4 - ≤ 101.3 
 
≥ 38.6 - < 39.5 
≥ 101.4 - < 103.1 
 
≥ 39.6 
≥ 103.2 
Fussiness or 
Irritability 
None 
Less playful than 
usual but not 
requiring more 
attention and able 
to console 
Requiring 
increased attention 
but able to console 
Unable to console 
Change in eating 
habits 
None 
Eating less than 
normal for 1 to 2 
feeds/meals 
Missed 1 or 2 
feeds/meals 
completely 
Refuses ≥3 feeds/ 
meals or refuses 
most feeds/meal 
Drowsiness or 
Sleepiness 
None 
Drowsiness but still 
interested in 
surroundings and 
did not miss feed or 
meal 
Not interested in 
surroundings or 
did not wake up for 
a feed or meal 
Sleeps most of the 
time or difficult to 
wake up 
*Cut off values for fever referenced from Fluzone Quadrivalent Package Insert 
(https://www.vaccineshoppe.com/image.cfm?pi=fluQIV&image_type=product_pdf) 
For this study, solicited adverse events will be documented using either the electronic 
memory aid through REDCap or the paper memory aid. The preferred method for 
documentation in this study is REDCap.  All parent(s)/LAR(s) will be encouraged to use 
the paper memory aid as a tool to initially record solicited adverse events and then enter 
information into REDCap. However, they can directly enter solicited adverse event 
information into REDCap if desired without using paper.  For parents electing to use 
REDCap, missing solicited adverse event data will be verified with the parent(s)/LARS 
on day 9 as needed following Visits 1 and 2. Parents/LAR using the paper memory aid 
alone will submit the Visit 1 memory aid to study staff during Visit 2, and will mail the 
study Visit 2 memory aid to the study team following the 8-day post-visit 2 period.  The 
study team will review the paper memory aid at the time of receipt.   
 
For parent(s)/LAR(s) entering data into REDCap, if there are data discrepancies for 
solicited adverse event entered directly into REDCap or obtained over the phone, the 
information provided by the parent in REDCap will be counted as the correct information 
unless verified as otherwise by study staff. 
 
For parent(s)/LAR(s) using only the paper memory aid, if there are data discrepancies 
for solicited adverse events recorded on the memory aid, the information on the memory 
aid should be taken as the correct adverse event information unless verified as 
otherwise by study staff. 

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5.7 Medical Care Utilization, Antipyretic Use, and Febrile Seizures (Days 1-8 
Following Visits 1 and 2) 
Parent(s)/LAR(s) will record medical care utilization, use of antipyretic medications, and 
febrile seizure occurrence (Table 3) beginning on the evening of Visit 1 and Visit 2 (Day 
1) and for the next 7 days following the study visits (through Day 8).  On the evening of 
Visit 1 and Visit 2, medical care utilization related to fever, use of antipyretic 
medications, and febrile seizure occurrence should be rated from the time of Visit 1 or 2 
until the information is recorded.  For each subsequent day through Day 8, these factors 
should be assessed from the time the information is recorded on one day to the time 
information is recorded on the next day.  
 
Table 3: Medical Care Utilization and Antipyretic Use 
 
 
 
Did you give your child fever or pain medicine? 
If yes, was it for fever? 
If yes, was it for pain?      
If yes, check type or types of medicine given 
      □ Acetaminophen (e.g. Tylenol) 
      □ Ibuprofen (e.g. Motrin, Advil) 
      □ Other    
 
Yes 
Yes 
Yes 
No 
No 
No 
Did your child receive medical attention? 
If yes, was it related to fever? 
 
If yes, check type or types of attention received 
      □ Telephone call for medical advice 
      □ Medical office visit including urgent care visit 
      □ Emergency department visit 
      □ Hospital admission 
 
If yes, provide reason for medical attention 
     _________________________________________ 
Yes 
Yes 
Yes  
No 
No 
No 
Did your child have a seizure? 
If yes, was it related to fever? 
Yes 
Yes 
No 
No 
 
For this study, medical care utilization, antipyretic use and the occurrence of febrile 
seizures will be documented using either the electronic memory aid through REDCap or 
the paper memory aid. The preferred method for documentation in this study is 
REDCap.  All parent(s)/LAR(s) will be encouraged to use the paper memory aid as a tool 
to initially record information and then enter information into REDCap; however, they can 
directly enter information into REDCap if desired without using paper.  For parents 
electing to use REDCap, missing data will be verified with the parent(s)/LARS on day 9 
as needed following Visits 1 and 2. Parents/LAR using the paper memory aid alone will 
submit the Visit 1 memory aid to study staff during Visit 2, and will mail the study Visit 2 
memory aid to the study team following the 8-day post-visit 2 period.  The study team 
will review the paper memory aid at the time of receipt. 
 
For parent(s)/LAR(s) entering data into REDCap, if there are data discrepancies for 
information entered directly into REDCap or obtained over the phone, then information 
provided by the parent in REDCap will be counted as the correct information unless 
verified as otherwise by study staff. 

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For parent(s)/LAR(s) using only the paper memory aid, if there are data discrepancies 
for information on the memory aid, the information on the memory aid should be taken 
as the correct information unless verified as otherwise by study staff. 
5.8 Additional Safety Assessments (Visit 1 Day 1 – Visit 2 Day 8) 
While completing the memory aid and during the in-person visit (Visit 2), 
parent(s)/LAR(s) will be prompted to report unsolicited serious adverse events (SAEs) 
and occurrence of febrile seizures. This will include asking: Has your child been seen for 
any medical visits? Has your child been evaluated in an emergency department or 
admitted to the hospital? If so, state reason why.” Parent(s)/LAR(s) who at any time 
express any concern about symptoms or serious unsolicited events will be encouraged 
to follow up with their child’s primary care provider. Study staff will assist with 
coordination of referral appointments as necessary. 
Medical records will be obtained and reviewed for any medical appointment/s other than 
for routine scheduled visits (preventive care visits or planned specialty care visits), 
febrile seizures, and serious adverse events (SAEs) from Visit 1 Day 1through Visit 2 
Day 8.  
IIV, PCV13 and DTaP administration for children are routinely recommended such that 
we do not anticipate having a significant issue with SAEs. However, we will monitor 
study participants for SAEs during the protocol-defined surveillance period from 
enrollment through 8 days following Visit 2. 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 scheduled hospital admission)  
• 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,  
 
Study site investigators will assess relatedness to study vaccine (related, possibly 
related, unlikely related, or not related) for SAEs and febrile seizure. A febrile 
seizure judged to be related to a non-study vaccine would not be considered related 
to, or probably related to vaccine.  SAEs will be reported to the CDC’s Immunization 
Safety Office within 48 hours of study staff awareness of the event, and the 
respective institutional review boards or human subject reviewing officials at DUHS, 
Kaiser and CDC per local IRB reporting requirements.  If indicated, SAEs will be 
reported through the CDC’s Vaccine Adverse Event Reporting System (VAERS) 
https://vaers.hhs.gov/index.   
Given that this study involves administering US-licensed vaccines that are included 
as part of routine clinical care, there will not be a designated data safety monitoring 
board for this study. If deemed necessary, we will designate an independent safety 
monitor with relevant expertise, in collaboration with the CDC. 

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5.9 Parental Perceptions  
At Visit 2, we will provide parent(s)/LAR(s) electing to use the paper memory aid with a 
paper survey to be completed 8 days after Visit 2 about their preferences regarding 
receiving influenza vaccine at the same time or separately from other routinely 
administered pediatric vaccines. Parents/LARs electing to use REDCap will receive the 
survey electronically at Day 9 following Visit 2 to be completed over the internet using 
REDCap.  We will collect information about the parent’s relationship to the child (mother, 
father, guardian). Parent(s)/LAR(s) using the paper survey will mail it to the study team 
and the data will be entered into REDCap by study staff upon receipt of the survey.  If 
survey information is not obtained in REDCap or sent by mail, the information may be 
obtained over the phone. 
 
6 STATISTICAL CONSIDERATIONS 
In collaboration with the CDC and Kaiser Permanente Northern California sites, the 
research team at Duke will oversee the statistical analysis. The first 10 children enrolled 
in the study are considered part of a pilot to assess study feasibility and make 
adjustments in study design if necessary.  As such we will measure some key feasibility 
benchmarks as noted in Table 4.  Children enrolled in the feasibility component of the 
study will be included in the main study. 
 
The main study is designed based on prior data14 suggesting that the proportion of 
children who have fever on day 1 and/or day 2 after the first and/or second visit in the 
sequential group will be approximately 18% and that the proportion of children with fever 
observed following simultaneous administration during the comparable time periods will 
be at least twice as high (36%).  
For analysis, data will reside on a secure Duke server maintained by Duke Health 
Technology Solutions (DHTS).  For the study, a database will be developed and a 
dataset for the study without personal identifiers will be made available to the CDC upon 
request. 
6.1 Sample Size and Power Estimation 
 
Allowing for a 10% drop out rate given an initial N=280, there should be approximately 
252 children enrolled into the study. If the true proportion of children who have fever on 
day 1 and/or day 2 after the first and/or second visit in the simultaneous group is 36% 
Table 4: Benchmarks for Pilot  
Benchmark 
Target 
Valid temperature obtained for D1 following Visit 1 
80% 
Valid temperature obtained for D2 following Visit 1 
80% 
Completion of Visit 2 
80% 
Valid temperature obtained for D1 following Visit 2 
80% 
Valid temperature obtained for D2 following Visit 2 
80% 
The thermometer was easy or very easy to use 
80% 
Reporting child’s information (temperature and side effects) to the study team was 
easy or very easy 
80% 

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and the true proportion in the sequential group is 18%, then there is 90% power to reject 
the null hypothesis of no difference with N=126 per group with a two-sided alpha 0.05 
level.  This is based upon using a Mantel-Haenszal statistic in a stratified analysis to 
control for sites. 
6.2 Analysis Plan 
 
6.2.1 Study Populations – There will be two study populations, the Intent-to-Treat (ITT) 
and Per Protocol populations.  The ITT Population includes any participant that 
was enrolled, randomized into the study, and received at least one study vaccine 
at Visit 1.  The Per Protocol Population is a subset of the ITT Population 
excluding those participants who do not provide valid temperature data on days 1 
and 2 following Visit 1 and Visit 2 and those with major protocol violations as 
determined by the study investigators. Statistical analyses will be performed for 
both study populations, or the ITT Population only if no participants are excluded 
from the Per Protocol Population.   
 
6.2.2 Primary Objective 1 – To compare the proportions of children with fever following 
simultaneous versus sequential vaccination with PCV13, DTaP, and IIV during 2 
visits. Children in the sequential vaccination group will receive PCV13 and DTaP 
at Visit 1 followed by IIV and health education at Visit 2.   Children in the 
simultaneous vaccination group will receive PCV13, DTaP, and IIV at Visit 1, 
followed by a health education visit without vaccination at Visit 2. Fever will be 
assessed on the visit day of, and the day after (days 1-2) each visit. 
 
Temperatures will be measured in children on the evening of, and for 7 subsequent 
evenings following Visit 1 and Visit 2.  For the primary objective we will compare the 
proportions of children with fever (Temperature ≥ 38.0°C or ≥ 100.4°F) on day 1 
and/or day 2 following Visit 1 and Visit 2 between the simultaneous and the sequential 
vaccination groups.   Fever on day 1 and/or day 2 after either visit will be counted as 
positive for this analysis. The proportions will be compared using a Mantel-Haenszal 
statistic in a stratified analysis by site to control for the randomization blocks at the 
two-sided alpha 0.05 level.  The relative risk and corresponding 95% confidence 
interval for the occurrence fever will also be calculated. 
 
6.2.3 Secondary Objective 1 – To compare the proportions of children with fever on 
day 1 and/or day 2 after Visit 1 and Visit 2 separately, in the simultaneous versus 
sequential vaccination group.  
 
For this secondary objective we will present the proportions of children with any fever on 
day 1 and/or day 2 following vaccination for Visit 1 and separately for Visit 2.  Fever on 
day 1 and/or day 2 after either visit will be counted as positive for this analysis. 
Proportions at each visit will be compared between the simultaneous and the sequential 
vaccination groups using a Mantel-Haenszal statistic in a stratified analysis by site to 
control for the randomization blocks. The relative risk and corresponding 95% 
confidence interval for the occurrence of any fever on day 1 and/or day 2 after Visit 1 
and/or Visit 2 will also be calculated. 
 
 

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6.2.4 Secondary Objective 2 – To compare the clinical importance of fever on day 1 
and/or day 2 after Visit 1 and Visit 2 (separately and combined) in the 
simultaneous versus sequential group. Clinical importance is assessed based on 
severity of fever, duration of fever, and medical care utilization for fever. 
 
To evaluate the severity of fever, we will present the proportions of children with the 
highest level of fever defined as Grade 2 and/or 3 (≥ 38.6°C and/or ≥ 39.6°C) on day 1 
or day 2 following Visit 1, Visit 2 and Visit 1 and 2 combined by simultaneous and 
sequential vaccination groups.  
 
To evaluate the duration of fever, the following analysis will be performed:  The mean 
duration of any fever (in days)  will be  compared by simultaneous and sequential 
vaccination groups for children with fever that began on days 1 or 2 following Visit 1, 
Visit 2 and Visit 1 and 2 combined. Each consecutive day of fever on the memory aid will 
be counted per child per visit.  Thus, a child could contribute a maximum of 8 days per 
study visit, should a fever be reported at each day on the memory aid. 
 
Furthermore, we will present and compare the proportion of children with medical care 
utilization for fever (telephone contact, medical office visit, emergency department visit 
or hospital admission) on day 1 and/or day 2 following Visit 1, Visit 2 and Visit 1 and 2 
combined.   
   
Proportions will be compared between the simultaneous and the sequential vaccination 
groups using a Mantel-Haenszal statistic in a stratified analysis by center to control for 
the randomization blocks. The duration of fever will be compared between groups using 
a Mann-Whitney U/Wilcoxon rank-sum test. No adjustments will be made to the alpha 
level (two-sided alpha=0.05) for these secondary objectives. 
 
6.2.5 Exploratory Objectives 
 
For exploratory objective 1 the average peak temperature on day 1 and/or 2 following 
Visit 1, Visit 2 and Visit 1 and 2 combined will be presented by simultaneous and 
sequential vaccination groups. To evaluate the duration of fever,the number of fever 
degree-days on day 1 or 2 following Visit 1, Visit 2 and Visit 1 and 2 combined will be 
presented by simultaneous and sequential vaccination groups.  Comparisons will be 
made using a Mann-Whitney U/Wilcoxon rank-sum test. 
 
For exploratory objective 2 we will present the use of antipyretics for fever on day 1 
and/or day 2 after Visit 1 and Visit 2 (separately and combined) in the simultaneous 
versus sequential group in tables for presentation.  The proportion of children with 
antipyretic use on day 1 and/or day 2 following Visit 1, Visit 2 and Visit 1 and 2 combined 
will be compared using a Mantel-Haenszal statistic in a stratified analysis by site 
between the simultaneous and sequential vaccination groups. 
 
Exploratory objective 3 that evaluates the level of severity of fever at various time points, 
will be presented and compared using a Mantel-Haenszal statistic in a stratified analysis 
by site. 
 
Exploratory objectives 4 and 5 evaluate fever on days 3-8 and the clinical importance of 
fever on days 3-8, respectively.  We will present and compare the proportions in 

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objectives 4 and 5 using a Mantel-Haenszal statistic in a stratified analysis by site to 
control for the randomization blocks. We will adjust for MMR and MMRV receipt at Visit 1 
if necessary when analyzing the following outcome measures- EOM5.1, EOM5.2, and 
EOM 5.3 due to the possibility that a measles-containing vaccine may be administered 
at Visit 1 to infants in both the simultaneous and sequential group. Also for objective 5, 
we will present and compare the mean duration of any fever starting on days 3-8 using a 
Mann-Whitney U/Wilcoxon rank-sum test.  Other analysis to further evaluate the clinical 
importance of fever onset 3-8 days after Visit 1 and/or Visit 2 will be performed if 
necessary. 
 
Adverse event tables and listings will be prepared to assess Exploratory Objective 6 and 
7.  The group proportions of solicited systemic adverse events (excluding fever) 
occurring 1-8 days after Visit 1 and 2 will be compared as described above using a 
Mantel-Haenszal statistic in a stratified analysis.  The Mantel-Haenszal statistic will also 
be used for group proportions of febrile seizure, and serious adverse events determined 
to be related to vaccination.  If the cell sizes are too small (i.e., less than 5) then Fisher’s 
exact test will be used. 
 
Summary tables of acceptability will be produced to address Exploratory Objective 8.  
Likert scale questions will be compared between the study groups using an extended 
Mantel-Haenszal mean score statistic in a stratified analysis.   
 
No adjustments will be made to the alpha level (two-sided alpha=0.05) for these 
exploratory analyses. 
 
6.2.6 Sensitivity Analyses 
 
Sensitivity analyses will be performed under two conditions: 1) to exclude those who 
received antipyretics on day 1 and/or day 2 following Visit 1 and/or Visit 2; 2) to extend 
the risk window for fever to day 3 after Visit 1 and Visit 2.  These sensitivity analyses will 
be performed for the primary objective in both study populations (ITT and Per Protocol).  
The statistical comparison will be made using a Mantel-Haenszal statistic in a stratified 
analysis by center to control for the randomization blocks.  No adjustments will be made 
to the alpha level (two-sided alpha=0.05) for these sensitivity analyses. 
    
6.3 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 and Kaiser 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).20  Duke investigators have previously used 
the REDCap system for collection and analysis of large quantities of data. Participants 
will be given the option to fill out their reactogenicity diary either directly in the REDCap 
system or on paper. The preferred method of data capture for this study is REDCap.  

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Regardless of the method of data entry chosen, all parents(s)/LAR(s) will be encouraged 
to use the paper memory aid to initially record information. Parents(s)/LAR(s) who 
choose the paper form will receive phone calls or be contacted by e-mail on Day 3 
(Visits 1A, 2A) to collect the fever information recorded on their diary card, which will 
then be entered by study personnel onto a paper CRF. Participants who choose to enter 
the information directly into REDCap will receive phone calls or be contacted by e-mail 
as needed on Day 3 and/or Day 9 if they fail to enter their fever information for Days 1 
and 2 or if they are missing information for days 1-8 respectively. All study-related 
documents containing protected health information, e.g. enrollment logs, case report 
forms, memory aids (Appendices A-D) completed by study participants, will be 
maintained in secure research offices at Duke and Kaiser, which are accessible to 
research staff only.  
 
6.3.1 Research Electronic Data Capture (REDCap)  
Investigators within the NIH-funded Clinical and Translational Research Unit at 
Vanderbilt have developed REDCap (http://project-redcap.org/), to collect and manage 
data for diverse clinical and translational research studies. REDCap was designed 
around the concept of giving research teams an easy method to specify project needs 
and rapidly develop secure, web-based applications for collection, management and 
sharing of research data. REDCap accomplishes these key functions through use of a 
single study metadata table referenced by presentation-level operational modules. 
Based on this abstracted programming model, databases are developed in an efficient 
manner with little resource investment beyond the creation of a single data dictionary. 
The concept of metadata-driven application development is well established, and the 
critical factor for successful data collection lie1s in creating a simple workflow 
methodology allowing research teams to autonomously develop study-related metadata 
in an efficient manner. Of particular interest for this project, a subcomponent of REDCap, 
the REDCap Survey is designed for studies where data are collected directly from the 
research participant. This will be used with the web-based reaction forms that will be 
completed by the study subjects.  Both products include 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 into the REDCap database by parents or by members of the study 
team, from Duke and Kaiser 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, 

Fever after Simultaneous versus Sequential Vaccination in Young Children 
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36 
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 the lead and 
contributing sites with secured password-protected computers. Coded data without 
personal identifiers will be made available to the CDC and transferred using a secure 
transfer method.  
6.4 Role of the CDC Investigators in the Project 
This study is funded by a CDC contract with Duke University and Kaiser Permanente as 
Task Orders in the CISA Project Contract. The Duke University PI (Emmanuel “Chip” 
Walter) will oversee the study in partnership with the Kaiser Permanente PI (Nicola 
Klein).  CDC staff will collaborate with both sites to develop the protocol, conduct the 
study, ensure the study is aligned with US Department of Health and Human Services 
public health priorities, and analyze the data and disseminate the results. CDC may 
receive access to coded data not containing any directly identifying information. 
 
7    HUMAN SUBJECTS  
7.1 Human Subjects Involvement, Characteristics, and Design 
 
Duke and Kaiser investigators will be responsible for submitting the protocol, informed 
consent (Appendix A), memory aids (Appendix B), recruitment letters, flyers 
(Appendix C), and any written or verbally conveyed materials (Appendix D) 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. 
7.2 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.  Subjects will record solicited 
adverse reactogenicity events and any medical intervention sought on the day of and 7 
additional days following Visit 1 and Visit 2 on the memory aid (Appendix B).  Memory 
aid information will be reported to the study team during a telephone call or in the web-
based REDCap system. The research staff will assess temperature.   Medical records 
will be reviewed to assess for the occurrence of febrile seizures or serious adverse 
events during the entire study period. 

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7.3 Potential Risks and Benefits 
PCV13, DTaP and IIV are FDA licensed vaccines approved for use in children 12-16 
months of age. These vaccines are standard clinical practice and recommended by the 
CDC and ACIP.  Participants will be provided with the CDC Vaccine Information 
Statements (VIS) for PCV13, DTaP and IIV (http://www.cdc.gov/vaccines/hcp/vis/vis-
statements/dtap.html and http://www.cdc.gov/vaccines/hcp/vis/vis-
statements/pcv13.html).  
 
IIV risks include minor problems such as soreness, redness, swelling, or pain where the 
shot was given, hoarseness, sore, red or itchy eyes, cough, fever, aches, headache, 
itching, fatigue, all of which usually occur within 1-2 days of vaccination and are self-
limiting. Syncope (fainting) can occur in association with administration of injectable 
vaccines but is less likely in young children. More serious problems including a small 
increased risk of Guillain-Barré Syndrome estimated at 1 or 2 additional cases per 
million people vaccinated. This is much lower than the risk of severe complications from 
influenza infection, which can be prevented by IIV.  In addition, any medication can 
cause a severe allergic reaction, or anaphylaxis, which is estimated at ~1 in a million 
doses of IIV (http://www.cdc.gov/vaccines/hcp/vis/vis-statements/flu.html). 
 
DTaP risks include mild problems such as redness, swelling, and pain where the shot 
was given, redness or swelling where the shot was given, fever, chills, sore joints, 
headache, body aches, fatigue, nausea, vomiting, diarrhea, stomach ache, rash, and 
swollen glands, all of which usually occur within 1-2 days of vaccination and are self-
limiting. Moderate problems include higher severity of mild problems and swelling of the 
entire arm or leg in which the injection was given. Rarely, local injection site symptoms 
limit the ability to perform usual activities and require medical attention. 
 
PCV13 risks include mild problems such as drowsiness, temporary loss of appetite, 
redness, swelling, or tenderness where the shot was given, fever, increase in fussiness 
and irritability. Young children may be at increased risk for febrile seizure. 
 
Problems that could happen after any injected vaccine:  
• 
People sometimes faint after a medical procedure, including vaccination. Sitting 
or lying down for about 15 minutes can help prevent fainting, and injuries caused 
by a fall. Subjects should inform their doctor should they feel dizzy, or have vision 
changes or ringing in the ears. This is unlikely in small children.  
• 
Any medication can cause a severe allergic reaction. Such reactions from a 
vaccine are very rare, estimated at about 1 in a million doses, and 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. 
 
• 
The Advisory Committee on Immunization Practices (ACIP) does not make 
specific recommendations about simultaneous or sequential administration of 
PCV13, DTaP and IIV for young children.  However, based on the ACIP 
General Recommendations, PCV13, DTaP and IIV (all inactivated vaccines) 
may be administered to young children either simultaneously or 
sequentially.  The current General Best Practice Guidelines for Immunization 
(assessed at https://www.cdc.gov/vaccines/hcp/acip-recs/general-
recs/index.html 
 

Fever after Simultaneous versus Sequential Vaccination in Young Children 
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Simultaneous administration of vaccines is defined as administering more than one 
vaccine on the same clinic day, at different anatomic sites, and not combined in the 
same syringe. Experimental evidence and extensive clinical experience provide the 
scientific basis for administering vaccines simultaneously. Simultaneously administering 
all vaccines for which a person is eligible at the time of a visit increases the probability 
that a child, adolescent, or adult will be vaccinated fully by the appropriate age.    
Pneumococcal conjugate, Diphtheria toxoid, tetanus toxoid and acellular pertussis 
(DTaP), and quadrivalent inactivated influenza vaccine (IIV) can be administered 
simultaneously.   
 
There is the potential risk of loss of confidentiality about information obtained as part of 
this study. There is a potential risk of a short delay in influenza protection by delaying the 
receipt of influenza vaccine 2 weeks.  If parents are concerned that their child has an 
influenza-like illness (characterized by fever and irritability, cough, sore throat, or 
vomiting), they should seek care for their child with their child’s health care provider. If 
their child’s provider suspects or determines that their child has influenza, there are 
medications to treat influenza illness and their provider may opt to treat their child with 
one of these medications.   
 
7.4 Adequacy of Protection Against Risks 
 
7.4.1 Protections against Risk 
Subjects will be counseled on possible side effects following vaccination and followed 
closely during the 8 days post-vaccination for assessment of moderate to severe 
systemic reactogenicity.  Subjects with a prior history of any severe reaction following 
IIV, PCV13 or DTaP will be excluded from study enrollment.  
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. 
 
7.4.2 ClinicalTrials.gov Requirements 
The project is registered on ClinicalTrials.gov. (NCT03165981).  
 
7.5 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 LAR must sign and date the written informed consent form prior 
to initiation of any study procedure. 
 
7.5.1 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 routine childhood vaccinations in a manner that is consistent with ACIP 
recommendations.  Because this study is no more than minimal risk, the permission of 

Fever after Simultaneous versus Sequential Vaccination in Young Children 
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March 2, 2018 
39 
only one parent/LAR will be obtained.   Because the children are so young, 12 through 
16 months, they are not capable of providing assent. 
 
 
 

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40 
REFERENCES 
 
1. 
Zhou W, Pool V, Iskander JK, et al. Surveillance for safety after immunization: 
Vaccine Adverse Event Reporting System (VAERS)--United States, 1991-2001. MMWR 
Surveill Summ 2003;52:1-24. 
2. 
Launey Y, Nesseler N, Malledant Y, Seguin P. Clinical review: fever in septic ICU 
patients--friend or foe? Crit Care 2011;15:222. 
3. 
Kennedy A, Lavail K, Nowak G, Basket M, Landry S. Confidence about vaccines 
in the United States: understanding parents' perceptions. Health Aff (Millwood) 
2011;30:1151-9. 
4. 
Reid AY, Galic MA, Teskey GC, Pittman QJ. Febrile seizures: current views and 
investigations. Can J Neurol Sci 2009;36:679-86. 
5. 
Jones T, Jacobsen SJ. Childhood febrile seizures: overview and implications. Int 
J Med Sci 2007;4:110-4. 
6. 
Nakayama J, Hamano K, Iwasaki N, et al. Significant evidence for linkage of 
febrile seizures to chromosome 5q14-q15. Hum Mol Genet 2000;9:87-91. 
7. 
Duchwony M. Febrile Seizures in Childhood. In: Wyllie E, ed. Wyllie's Treatment 
of Epilepsy: Principles and Practice. 5th ed. Philadelphia, PA: Lippincott, Williams and 
Wilkin; 1993:647-53. 
8. 
Kelly HA, Skowronski DM, De Serres G, Effler PV. Adverse events associated 
with 2010 CSL and other inactivated influenza vaccines. Med J Aust 2011;195:318-20. 
9. 
Leroy Z, Broder K, Menschik D, Shimabukuro T, Martin D. Febrile seizures after 
2010-2011 influenza vaccine in young children, United States: a vaccine safety signal 
from the vaccine adverse event reporting system. Vaccine 2012;30:2020-3. 
10. 
Tse A, Tseng HF, Greene SK, Vellozzi C, Lee GM, Group VSDRCAIW. Signal 
identification and evaluation for risk of febrile seizures in children following trivalent 
inactivated influenza vaccine in the Vaccine Safety Datalink Project, 2010-2011. Vaccine 
2012;30:2024-31. 
11. 
Li R, Stewart B, McNeil MM, et al. Post licensure surveillance of influenza 
vaccines in the Vaccine Safety Datalink in the 2013-2014 and 2014-2015 seasons. 
Pharmacoepidemiol Drug Saf 2016. 
12. 
Duffy J, Weintraub E, Hambidge SJ, et al. Febrile Seizure Risk After Vaccination 
in Children 6 to 23 Months. Pediatrics 2016. 
13. 
Kawai AT, Martin D, Kulldorff M, et al. Febrile Seizures After 2010-2011 Trivalent 
Inactivated Influenza Vaccine. Pediatrics 2015;136:e848-55. 
14. 
Stockwell MS, Broder K, LaRussa P, et al. Risk of fever after pediatric trivalent 
inactivated influenza vaccine and 13-valent pneumococcal conjugate vaccine. JAMA 
Pediatr 2014;168:211-9. 
15. 
Englund JA, Walter EB, Fairchok MP, Monto AS, Neuzil KM. A comparison of 2 
influenza vaccine schedules in 6- to 23-month-old children. Pediatrics 2005;115:1039-
47. 
16. 
Steering Committee on Quality I, Management SoFSAAoP. Febrile seizures: 
clinical practice guideline for the long-term management of the child with simple febrile 
seizures. Pediatrics 2008;121:1281-6. 
17. 
Prymula R, Siegrist CA, Chlibek R, et al. Effect of prophylactic paracetamol 
administration at time of vaccination on febrile reactions and antibody responses in 
children: two open-label, randomised controlled trials. Lancet 2009;374:1339-50. 
18. 
Allegaert K, Casteels K, van Gorp I, Bogaert G. Tympanic, infrared skin, and 
temporal artery scan thermometers compared with rectal measurement in children: a 
real-life assessment. Curr Ther Res Clin Exp 2014;76:34-8. 

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19. 
Greenes DS, Fleisher GR. Accuracy of a noninvasive temporal artery 
thermometer for use in infants. Arch Pediatr Adolesc Med 2001;155:376-81. 
20. 
Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research 
electronic data capture (REDCap)--a metadata-driven methodology and workflow 
process for providing translational research informatics support. J Biomed Inform 
2009;42:377-81. 
 

CISA Fever SAP V1.0 
Page 1 of 17 
Revised: February 06, 2018 
 
Centers for Disease Control and Prevention  
Clinical Immunization Safety Assessment (CISA) Project  
 
 
A Prospective, Randomized, Open-label Clinical Trial to Assess Fever Following Simultaneous 
versus Sequential Administration of 13-valent Conjugate Pneumococcal Vaccine, Diphtheria 
Toxoid, Tetanus Toxoid, and Acellular Pertussis Vaccine and Inactivated Influenza Vaccine in 
Young Children 
 
Short Title: Fever after Simultaneous versus Sequential Vaccination in Young Children 
 
 
Final Statistical Analysis Plan 
 
Version 1.0 
 
February 06, 2018 
 
 
 
 
 
 

CISA Fever SAP V1.0 
Page 2 of 17 
Revised: February 06, 2018 
 
1 INTRODUCTION 
This document describes the statistical procedures that will be utilized for the CISA protocol 
Fever after Simultaneous versus Sequential Vaccination in Young Children.  This statistical 
analysis plan (SAP) describes the methods of statistical analysis.  The initial draft SAP 
(Version 0.1) was written prior to any data being analyzed in order to avoid bias.  Any 
subsequent changes that occur to the study protocol warranting changes to the analysis 
procedures will be documented in the SAP.  Table 1 below will be used for tracking changes 
to the SAP (both draft versions (0.X) and the final version (X.0). 
 
Table 1.  Statistical Analysis Plan Versions 
Version 
Date of Approval 
Major Changes from Prior Version 
0.1 
NA 
NA 
0.2 
NA 
Minor edits with the addition of linear regression analysis 
to address Secondary Objective b.2 average peak 
temperature.  See addition to Section 8.2. 
0.3 
NA 
Updates made to Secondary and Exploratory objectives 
based on CDC review.  See Version 2.0 of the protocol 
from October 12, 2017.   
0.4 
NA 
Minor edits and clarification based on call with CDC on 
December 13, 2017 and comments from an email on 
January 29, 2018. 
1.0 
February 6, 2018 
Final SAP 
  
2 PROTOCOL OBJECTIVES 
2.1 Primary 
a) PO 1: To compare the proportions of children with fever following simultaneous versus 
sequential vaccination with PCV13, DTaP, and IIV during 2 visits. Children in the 
sequential vaccination group will receive PCV13 and DTaP at Visit 1 followed by IIV and 
health education at Visit 2.   Children in the simultaneous vaccination group will receive 
PCV13, DTaP, and IIV at Visit 1, followed by a health education visit without vaccination 
at Visit 2. Fever will be assessed on the visit day of, and the day after (days 1-2) each 
visit. 
2.2 Secondary 
a) SO 1:  To compare the proportions of children with fever on day 1 and/or day 2 after Visit 
1 and Visit 2 separately, in the simultaneous versus sequential vaccination group. 
b) SO 2:  To compare the clinical importance of fever on day 1 and/or day 2 after Visit 1 
and Visit 2 (separately and combined) in the simultaneous versus sequential group. 
Clinical importance is assessed based on severity of fever, duration of fever, and 
medical care utilization for fever. 
 
 

CISA Fever SAP V1.0 
Page 3 of 17 
Revised: February 06, 2018 
 
2.3 Exploratory 
a) EO 1: To compare the height and duration of fever on day 1 and/or day 2 after Visit 1 and 
Visit 2 (separately and combined) in the simultaneous versus sequential group. 
b) EO 2: To compare the use of antipyretics for fever on day 1 and/or day 2 after Visit 1 and 
Visit 2 (separately and combined) in the simultaneous versus sequential group. 
c) EO 3: To describe and compare the level of severity of fever following Visit 1 and Visit 2 
(separately) in the simultaneous versus sequential group. 
d) EO 4: To compare the proportions of children with fever 3-8 days after Visit 1 and Visit 2 
(separately and combined) in the simultaneous versus sequential group. 
e) EO 5: To compare the clinical importance of fever occurring 3-8 days after Visit 1 and Visit 
2 (separately and combined) in the simultaneous versus sequential group. Clinical 
importance is assessed based on severity of fever, duration of fever, and medical care 
utilization for fever. 
f) EO 6: To describe and compare the occurrence of solicited systemic adverse events on 
day 1-8 after Visit 1 and Visit 2 in the simultaneous versus sequential group. 
g) EO 7: To describe and compare the occurrence of febrile seizure and/or serious adverse 
events during the period of enrollment (i.e. from Visit 1 through 8 days after Visit 2) in the 
simultaneous versus sequential group. 
h) EO 8: To describe and compare the perceptions among parents/ legally authorized 
representatives (LARs) of the simultaneous versus sequential schedule experience. 
3 STUDY ENDPOINTS 
3.1 Primary 
a) POM 1.1: Proportion of children with fever (temperature ≥ 38.0°C or ≥ 100.4°F) on day 1 
and/or day 2 following Visit 1 and/or Visit 2.  
3.2 Secondary 
a)  
1. SOM 1.1:  Proportion of children with fever (temperature ≥ 38.0°C or ≥ 100.4°F) 
on day 1 and/or day 2 following Visit 1. 
2. SOM 1.2: Proportion of children with fever (temperature ≥ 38.0°C or ≥ 100.4°F) on 
day 1 and/or day 2 following Visit 2. 
b)  
1. SOM 2.1: Proportions of children with moderate/severe fever (GRADE 2 and/or 3) 
on day 1 and/or day 2 following Visit 1, Visit 2, and Visit 1 and Visit 2 combined. 
2. SOM 2.2: Average number of consecutive days of fever (temperature ≥ 38.0°C or 
≥ 100.4°F) per subject for fever starting on day 1 or 2 following Visit 1, Visit 2 and 
Visit 1 and Visit 2 combined. Note: fever starting on day 1 or 2 could continue 
through day 8. 
3. SOM 2.3: Proportion of children with medical care utilization (telephone call, 
medical office visit, emergency department visit, or hospital admission) for fever 
on day 1 and/or day 2 following Visit 1, Visit 2 and Visit 1 and Visit 2 combined. 

CISA Fever SAP V1.0 
Page 4 of 17 
Revised: February 06, 2018 
 
3.3 Exploratory 
a)  
1. EOM 1.1: Average peak temperature of children with fever (temperature ≥ 38.0°C 
or ≥ 100.4°F) on day 1 and/or day 2 following Visit 1, Visit 2, and Visit 1 and Visit 
2 combined. 
2. EOM 1.2: Total number of fever degree-days (temperature ≥ 38.0°C or ≥ 
100.4°F) on day 1 and/or day 2 per subject following Visit 1, Visit 2, and Visit 1 
and Visit 2 combined. 
 
 
b) EOM 2.1: Proportion of children with antipyretic use for fever on day 1 and/or day 2 
following Visit 1, Visit 2 and Visit 1 and Visit 2 combined. 
 
c)  
1. EOM 3.1: Proportions of children with fever at different levels of severity (Grades 
1, 2, and 3) on day 1 and/or day 2 following Visit 1 and Visit 2. 
2. EOM 3.2: Proportions of children with fever at different levels of severity (Grades 
1, 2, and 3) on days 3-8 following Visit 1 and Visit 2. 
3. EOM 3.3: The proportion of children with fever at different levels of severity 
(Grades 1, 2,3 and all Grade) on days 1-8 following Visit 1 and Visit 2. 
 
d)  
1. EOM 4.1: Proportion of children with fever (temperature ≥ 38.0°C or ≥ 100.4°F) on 
at least one day on day 3-8 following Visit 1. 
2. EOM 4.2: Proportion of children with fever (temperature ≥ 38.0°C or ≥ 100.4°F) on 
at least one day on day 3-8 following Visit 2. 
3. EOM 4.3: Proportion of children with fever (temperature ≥ 38.0°C or ≥ 100.4°F) 
on at least one day on day 3-8 following Visit 1 and Visit 2 combined. 
 
e)  
1. EOM 5.1: Proportions of children with moderate/severe fever (GRADE 2 and/or 3) 
on at least one day during days 3-8 following Visit 1, Visit 2, and Visit 1 and Visit 2 
combined. 
2. EOM 5.2: Average number of consecutive days of fever (temperature ≥ 38.0°C or 
≥ 100.4°F) per subject for fever starting on 3-8 days following Visit 1, Visit 2, and 
Visit 1 and Visit 2 combined.  Note: fever starting on day 3-8 could continue through 
day 8. 
3. EOM 5.3 Proportion of children with medical care utilization (telephone call, 
medical office visit, emergency department visit, or hospital admission) for fever 
on 3-8 days following Visit 1, Visit 2, and Visit 1 and Visit 2 combined). 
 
f) EOM 6.1: The proportion of children with solicited systemic adverse events (excluding 
fever) at different levels of severity (Grades 1, 2, 3, and all Grades) on day 1-8 following 
Visit 1 and Visit 2. 
 
g) EOM 7.1: The proportion of children with febrile seizure and/or serious adverse events 
during the period of enrollment (i.e. from Visit 1 through 8 days after Visit 2). 
 

CISA Fever SAP V1.0 
Page 5 of 17 
Revised: February 06, 2018 
 
h) EOM 8.1: Proportion of parents reporting positive and negative perceptions about their 
vaccination schedule experience will be determined for each survey item. 
4 STUDY DESIGN 
4.1 Study Description 
This study is a prospective, randomized open-label clinical trial that will be conducted during 
the 2017-2018 influenza season.  During the 2017-2018 season, approximately 280 children 
will be enrolled at Duke University Medical Center and Kaiser Permanente Northern California. 
Young children aged 12-16 months will be enrolled over a period of approximately 7 months. 
Children will be followed for up to 37 days following enrollment. Eligible children will be 
randomized to receive simultaneous or sequentially administered US-licensed PCV13, US-
licensed DTaP vaccine, and US-licensed inactivated influenza vaccine (IIV). Children in the 
simultaneous group will receive PCV13, DTaP, and IIV vaccines at Visit 1, and then return for 
a health education visit without vaccination about 2 weeks later (Visit 2).  Children in the 
sequential group will receive both PCV13 and DTaP without IIV at Visit 1, and then will receive 
IIV and health education about 2 weeks later (Visit 2).  At Visit 1, children may also receive 
age- appropriate vaccines as recommended in the ACIP childhood immunization schedule.  
After Visit 1, non-study vaccines (U.S. licensed or investigational) are prohibited unless 
deemed a personal or public health priority by the health care provider caring for this patient 
or the study team. 
Parents will record the occurrence of fever, solicited adverse events, medical care utilization, 
and receipt of antipyretics over 8 days following Visit 1 and Visit 2. In addition, febrile seizures 
and serious adverse events will be recorded for the entire study period (from enrollment 
through 8 days following the Visit 2) and will be assessed through parental report and chart 
review.  
The first 10 children enrolled at Duke University Medical Center will be enrolled in a study pilot 
to quickly assess study feasibility benchmarks and make protocol adjustments if necessary.  
Data from pilot participants will also contribute to the analysis of primary, secondary and 
exploratory outcomes. 
4.2 Sample Size and Power 
Allowing for a 10% drop out rate given an initial N=280, there should be approximately 252 
children enrolled into the study. If the true proportion of children who have fever on day 1 
and/or day 2 after the first and/or second visit in the simultaneous group is 36% and the true 
proportion in the sequential group is 18%, then there is 90% power to reject the null hypothesis 
of no difference with N=126 per group with a two-sided alpha 0.05 level.  This is based upon 
using a Mantel-Haenszal statistic in a stratified analysis to control for sites. 
4.3 Randomization 
Participants will be randomized (1:1) to receive either PCV13, DTaP and IIV simultaneously 
or sequentially (PCV13 and DTaP followed by IIV ~2 weeks later) using a permuted block 
randomization scheme stratified by study site (i.e., Duke University Medical Center and Kaiser 
Permanente Northern California). The first 10 children enrolled in the pilot at Duke University 
will be randomized in a block of 10 such that 5 children will receive simultaneous vaccination 
and 5 will receive sequential vaccination.  The project statistician at Duke University will 
generate permuted block randomization schemes, which will be uploaded to REDCap. The 
randomization schedule will not be available to the study staff, so the next randomization 

CISA Fever SAP V1.0 
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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. This study will be open label and study staff and 
subjects will not be blinded to treatment arm assignments. 
5 PARAMETERS OF ANALYSIS 
5.1 Data Collection and Storage 
Data will be handled according to the Duke Vaccine and Trials Unit SOP (DVTU M010).  Data 
will be captured on paper CRFs and entered into the REDCap database. Diary data may be 
entered directly into REDCap, if the parent of the participant chooses to use this method.    
5.2 Analytic Issues 
There are two sites participating in the study and analysis of the primary objective will be 
stratified by site to account for this unit of randomization.  Secondary data objectives may be 
stratified by site when applicable.  There is one primary objective evaluated at the alpha 0.05 
level and no adjustments to the alpha level will be made for secondary and exploratory 
analyses.  
6 ANALYSIS POPULATIONS 
6.1 Intent-to-Treat (ITT) 
The ITT Population includes any participant that was enrolled, randomized into the study, and 
received at least one study vaccine at Visit 1.   
6.2 Per Protocol 
The Per Protocol Population is a subset of the ITT Population which excludes participants 
who do not provide valid temperature data on days 1 and 2 following Visit 1 and Visit 2 and/or 
participants with major protocol violations, as determined by the study investigators. The list 
of major protocol violations is located in Appendix 1.  
Statistical analyses will be performed for both study populations, or the ITT Population only if 
no participants are excluded from the Per Protocol Population.   
7 BASELINE DATA AND FLOW CHART 
7.1 Presentation of Baseline Data 
The following baseline data will be presented by site and vaccination group:  age, gender, 
gestational age, day care attendance, number of children living in the home, insurance payer 
status, ethnicity, race, receipt of first dose of influenza vaccine, receipt of inactivated influenza 
vaccine at Visit 1, and receipt of live vaccines at Visit 1.  Summary statistics (e.g., mean, 
median, standard deviation, interquartile range) will be presented for continuous variables.  
Categorical variables will be described with frequencies and percentages.   
7.2 Flow Chart 
The number of enrolled participants will be presented in a flow chart by site and vaccination 
group.  The number of visits completed and missed will be presented, along with a breakdown 
of the two analysis populations.   

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8 ANALYSIS OF STUDY OBJECTIVES 
8.1 Primary Objective 
The primary objective (PO 1) of the study is to compare the proportion of children with fever 
(temperature ≥ 38.0°C or ≥ 100.4°F) on day 1 and/or day 2 following Visit 1 and/or Visit 2.  
This information is captured on the memory aid form which is captured in the REDCap 
database.  Fever on day 1 and/or day 2 after either visit will be counted as positive (1) for this 
analysis and no fever reported will be negative (0). The proportions will be compared between 
the simultaneous versus the sequential group using a Mantel-Haenszal statistic in a stratified 
analysis by site to control for the randomization blocks at the two-sided alpha 0.05 level.  The 
relative risk and corresponding 95% confidence interval for the occurrence fever will also be 
calculated. 
8.2 Secondary Objectives 
There are two secondary objectives for this study.   
a) The first secondary objective (SO 1) is to compare the proportions of children with 
fever on day 1 and/or day 2 after Visit 1 and Visit 2 separately, in the simultaneous 
versus sequential vaccination group. Fever on day 1 and/or day 2 after either visit will 
be counted as positive (1) for this analysis and no fever reported will be negative (0). 
Proportions at each visit will be compared between the simultaneous and the 
sequential vaccination groups using a Mantel-Haenszal statistic in a stratified analysis 
by site to control for the randomization blocks. The relative risk and corresponding 
95% confidence interval for the occurrence of any fever on day 1 and/or day 2 after 
Visit 1 and Visit 2 separately will also be calculated. There are two separate statistical 
tests being performed at the alpha 0.05 level.  
 
b) The secondary objective (SO 2) is to compare the clinical importance of fever on day 
1 and/or day 2 after Visit 1 and Visit 2 (separately and combined) in the simultaneous 
versus sequential group. Clinical importance is assessed based on severity of fever, 
duration of fever, and medical care utilization for fever.  This information is captured 
on the memory aid form in the REDCap database.   
 
1. Severity of fever: To evaluate the severity of fever, we will present the 
proportions of children with the highest level of fever defined as Grade 2 and/or 
3 (≥ 38.6°C) on day 1 or day 2 following Visit 1, Visit 2 and Visit 1 and 2 
combined by simultaneous and sequential vaccination groups. 
 
2. Duration of fever:  To evaluate the duration of fever, the following analysis will 
be performed:  The mean duration of any fever (in days) will be compared by 
simultaneous and sequential vaccination groups for children with fever that 
began on days 1 or 2 following Visit 1, Visit 2 and Visit 1 and 2 combined. Each 
consecutive day of fever on the memory aid will be counted per child per visit.  
Thus, a child could contribute a maximum of 8 days per study visit, should a 
fever be reported at each day on the memory aid.  A child having fever on day 
1, no fever on day 2, and fever on day 3 only has 1 day of fever. 
 
3. Medical care utilization for fever:  We will present and compare the proportion 
of children with medical care utilization for fever (telephone contact, medical 

CISA Fever SAP V1.0 
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office visit, emergency department visit or hospital admission) on day 1 and/or 
day 2 following Visit 1, Visit 2 and Visit 1 and 2 combined. Medical utilization 
for fever will be counted as positive for this analysis if onset of fever on day 1 
and/or day 2 plus medical utilization on day 1, day 2 or day 3 after fever.  
Medical care related to fever will be determined by report on the diary.  
Proportions will be compared between the simultaneous and the sequential vaccination 
groups using a Mantel-Haenszal statistic (three tests) in a stratified analysis by site to 
control for the randomization blocks. The duration of fever will be compared between 
groups using a Mann-Whitney U/Wilcoxon rank-sum test (three tests).  
No adjustments will be made to the alpha level (two-sided alpha=0.05) for these secondary 
objectives. 
8.3 Exploratory Objectives 
There are eight exploratory objectives for this study.   
a) The first exploratory objective (EO 1) is to compare the height and duration of fever on 
day 1 and/or day 2 after Visit 1 and Visit 2 (separately and combined) in the 
simultaneous versus sequential group. The average peak temperature of each child 
with fever during the risk window of days 1 and 2 (temperature ≥ 38.0°C or ≥ 100.4°F) 
and the total number of fever degree-days (temperature ≥ 38.0°C or ≥ 100.4°F) 
following Visit 1, Visit 2 and Visit 1 and 2 combined will be presented by simultaneous 
and sequential vaccination groups.  These six comparisons will be made using a 
Mann-Whitney U/Wilcoxon rank-sum test. 
 
b) The second exploratory objective (EO 2) is to compare the use of antipyretics for fever 
on day 1 and/or day 2 after Visit 1 and Visit 2 (separately and combined) in the 
simultaneous versus sequential group.  The use of antipyretics for fever on day 1 
and/or day 2 after Visit 1 and Visit 2 (separately and combined) will be presented for 
the simultaneous versus sequential group in tables.  These three proportions of 
children with antipyretic use on day 1 and/or day 2 following Visit 1, Visit 2, and Visit 1 
and Visit 2 combined will be compared using a Mantel-Haenszal statistic in a stratified 
analysis by site between the simultaneous and sequential vaccination groups. 
 
c) The third exploratory objective (EO 3) is to describe and compare the level of severity 
of fever following Visit 1 and Visit 2 separately, in the simultaneous versus sequential 
group. Fever will also be assessed at different levels of severity (Grades 1, 2, and 3) 
on day 1 and/or day 2 and days 3-8 following Visit 1 and separately for Visit 2.  The 
grade levels are defined in Table 2.   
Table 2: Fever Grade Levels 
Temporal 
Artery 
Temperature 
None 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
°C 
°F 
≤ 37.9 
≤ 100.3 
≥ 38.0 - < 38.5 
≥ 100.4 - ≤ 101.3 
≥ 38.6 - < 39.5 
≥ 101.4 - < 103.1 
≥ 39.6 
≥ 103.2 
  

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There will be six (day 1 and/or day 2, days 3-8, and days 1-8 following Visit 1 and 
separately for Visit 2) statistical comparisons performed at the alpha 0.05 level. These 
group comparisons will be made using a Mantel-Haenszal statistic (row mean scores 
difference with standardized midranks scores [modified ridit scores]) in a stratified 
analysis by site to control for the randomization blocks. 
 
d) The fourth exploratory objective (EO 4) is to compare the proportions of children with 
fever on at least one day during days 3-8 after Visit 1 and Visit 2 (separately and 
combined) in the simultaneous versus sequential group. This information is captured 
on the memory aid form in the REDCap database. There will be three statistical 
comparisons performed at the alpha 0.05 level.  These group comparisons will be 
made using a Mantel-Haenszal statistic in a stratified analysis by site to control for the 
randomization blocks. 
 
e) The fifth exploratory objective (EO 5) is to compare the clinical importance of fever 
occurring on at least one day during days 3-8 after Visit 1 and Visit 2 (separately and 
combined) in the simultaneous versus sequential group. Clinical importance is 
assessed based on severity of fever, duration of fever, and medical care utilization for 
fever. This information is captured on the memory aid form in the REDCap database. 
 
1. Severity of fever:   To evaluate the severity of fever, the proportions of children 
with moderate/severe fever (GRADE 2 and/or 3 see Table 2 above) on at least 
one day during days 3-8 following Visit 1, Visit 2, and Visit 1 and Visit 2 
combined will be presented in a tabular format. This group comparison will be 
made using a Mantel-Haenszal statistic in a stratified analysis by site to control 
for the randomization blocks. 
 
2. Duration of fever:  To evaluate the duration of fever, the average number of 
consecutive days of fever (temperature ≥ 38.0°C or ≥ 100.4°F) per subject for 
fever starting on day 3-8 following Visit 1, Visit 2, and Visit 1 and Visit 2 
combined will be calculated. A fever starting on day 3-8 could continue through 
day 8. The mean duration of any fever will be presented in days for children 
with fever that began on days 3-8 after Visit 1 and Visit 2 (separately and 
combined). Each consecutive day of fever on the memory aid will be counted 
per child per visit.  Thus, a child could contribute a maximum of 6 days per 
study visit, should a fever be reported at each day on the memory aid.  The 
longest duration of any fever occurring for a child will be counted for that child.  
e.g.  If a child has fever on days 3 and 4, no fever on day 5, and fever occurring 
on days 6, 7, and 8 the duration of fever will be counted as 3 days for that child. 
 
There will be three statistical comparisons performed (mean duration of any 
fever starting on days 3-8 following Visit 1, Visit 2, and Visit 1 and Visit 2 
combined) at the alpha 0.05 level.  These group comparisons will be made 
using a Mann-Whitney U/Wilcoxon rank-sum test. 
 
3. Medical care utilization for fever: The proportion of children with medical care 
utilization determined by report on the diary (telephone call, medical office visit, 
emergency department visit, or hospital admission) for fever on at least one 

CISA Fever SAP V1.0 
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day during days 3-8 following Visit 1, Visit 2, and Visit 1 and Visit 2 combined, 
will be presented in tables or the simultaneous versus sequential group. There 
will be three statistical comparisons performed.  These group comparisons will 
be made using a Mantel-Haenszal statistic in a stratified analysis by site to 
control for the randomization blocks. 
 
f) The sixth exploratory objective (EO 6) is to describe and compare the occurrence of 
solicited systemic adverse events (excluding fever) on days 1-8 after Visit 1 and Visit 
2 in the simultaneous versus sequential group. Table 3 below lists the solicited adverse 
events to be collected. 
Table 3: Solicited Systemic Adverse Events 
 
None 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Fussiness or 
Irritability 
None 
Less playful than usual 
but not requiring more 
attention and able to 
console 
Requiring increased 
attention but able to 
console 
Unable to console 
Change in eating 
habits 
None 
Eating less than normal 
for 1 to 2 feeds/meals 
Missed 1 or 2 
feeds/meals 
completely 
Refuses ≥3 feeds/ 
meals or refuses 
most feeds/meal 
Drowsiness or 
Sleepiness 
None 
Drowsiness but still 
interested in 
surroundings and did 
not miss feed or meal 
Not interested in 
surroundings or did 
not wake up for a 
feed or meal 
Sleeps most of 
the time or 
difficult to wake 
up 
 
Listings of all solicited adverse events will be produced showing vaccination group, 
date of onset, date of resolution, and highest grade level.   The frequency and 
percentage of the highest grade level for participants will be presented by each of the 
three solicited adverse events.  There will be three statistical comparisons made using 
a Mantel-Haenszal statistic (row mean scores difference with standardized midranks 
scores [modified ridit scores]) in a stratified analysis by site to control for the 
randomization blocks. 
g) The seventh exploratory objective (EO 7) is to describe and compare the occurrence 
of febrile seizure and/or serious adverse events during the period of enrollment (i.e., 
from Visit 1 through 8 days after Visit 2) in the simultaneous versus sequential group. 
Listings of all febrile seizure and/or serious adverse events will be produced showing 
vaccination group, description, relatedness, date of onset, date of resolution, and SAE 
category.  The frequency of the occurrence of febrile seizure and/or serious adverse 
events by vaccination group will be compared using a Fisher’s Exact test because the 
expected number of events is very low (i.e., small cell counts).   
 
h) The eighth exploratory objective (EO 8) is to describe and compare the perceptions 
among parents/ legally authorized representatives (LARs) of the simultaneous versus 
sequential schedule experience.   Summary tables of acceptability will be produced by 
vaccination group.  Likert scale questions will be compared between the vaccination 
groups using a Mantel-Haenszal statistic (row mean scores difference with 
standardized midranks scrores [modified ridit scroes]) in a stratified analysis by site to 
control for the randomization blocks. 

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No adjustments will be made to the alpha level (two-sided alpha=0.05) for these exploratory 
analyses. 
8.4 Potential Adjustments to Exploratory Objectives 
a) It might be necessary to adjust for MMR and MMRV receipt at Visit 1 for the following 
outcome measures: EOM 3.2, EOM 3.3, EOM 4.1, EOM 4.3, EOM 5.1 and EOM 5.2.   This 
is due to the possibility that a measles-containing vaccine may be administered at Visit 1 
to infants in both the simultaneous and sequential group.  If there is an imbalance 
(detected by a Mantel-Haenszal statistic in a stratified analysis by site) between the 
vaccination groups in the percentages of MMR and/or MMRV receipt at Visit 1, the 
aforementioned exploratory outcome measures will be evaluated by subgroups of those 
with MMR and/or MMRV receipt at Visit 1 and those without MMR and/or MMRV receipt 
at Visit 1. 
9 SENSITIVITY ANALYSES  
Sensitivity analyses will be performed under three conditions:  
• 
to exclude those who received antipyretics on day 1 and/or day 2 following Visit 1 and/or 
Visit 2. 
• 
to extend the risk window for fever to day 3 after Visit 1 and Visit 2.   
• 
to compare the effect of the first versus second dose of current seasonal influenza vaccine 
These sensitivity analyses will be performed for the primary objective in both study populations 
(ITT and Per Protocol).  The statistical comparison will be made using a Mantel-Haenszal statistic 
in a stratified analysis by site to control for the randomization blocks.  No adjustments will be 
made to the alpha level (two-sided alpha=0.05) for these sensitivity analyses. 
 
 

CISA Fever SAP V1.0 
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Appendix 1 
Major Protocol Violations 
 
Study Title: A Prospective, Randomized, Open-label Clinical Trial to Assess Fever Following 
Simultaneous versus Sequential Administration of 13-valent Conjugate Pneumococcal Vaccine, 
Diphtheria Toxoid, Tetanus Toxoid, and Acellular Pertussis Vaccine and Inactivated Influenza 
Vaccine in Young Children 
Short Title: Fever after Simultaneous versus Sequential Vaccination in Young Children 
Sponsor: Centers for Disease Control and Prevention Clinical Immunization Safety Assessment 
(CISA) Project  
Lead Site Principal Investigator: Emmanuel B. Walter, MD, MPH 
Contributing Site Principal Investigator: Nicola Klein, MD 
Centers for Disease Control and Prevention (CDC) Principal Investigator: Karen R. Broder, 
MD  
CDC Sub-principal Investigator: Patricia Wodi, MD 
NCT #: 03165981  
Purpose: To define major protocol violations that will be used to establish the Per Protocol 
Population for the Fever after Simultaneous versus Sequential Vaccination in Young Children 
study 
Background: Per the protocol analysis plan there will be two study populations, the Intent-to-
Treat (ITT) and Per Protocol populations.  The ITT Population includes any participant that was 
enrolled, randomized into the study, and received at least one study vaccine at Visit 1.  The Per 
Protocol Population is a subset of the ITT Population excluding those participants who do not 
provide valid temperature data on days 1 and 2 following Visit 1 and Visit 2 and those with major 
protocol violations as determined by the study investigators. Statistical analyses will be performed 
for both study populations, or the ITT Population only if no participants are excluded from the Per 
Protocol Population.  
This document stands to serve as a general guideline for the study investigators to a priori define 
major protocol violations.  Participants with major protocol violations will not be included in the 
Per Protocol Population. 
 
 
 
 
 
 
 

CISA Fever SAP V1.0 
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Major Protocol Violations Defined: 
 
1) Inclusion/Exclusion Criteria Violations 
 
Did Not Meet Study Inclusion Criteria 
At 
Study 
Entry  
Visit 1 
During 
Period 
of 
Enrollment1 
1. 12 through 16 months of age (i.e. from the 1-year birthday until the day 
before 17 months of age) at the time of vaccination  
 
X 
X 
2. Stable health as determined by investigator's clinical examination and 
assessment of child's medical history 
 
X 
 
3. Has received all immunizations recommended by Advisory Committee for 
Immunization Practices (ACIP) during the first year of life with the exception of 
rotavirus and influenza vaccines.* 
*Immunizations recommended during the first year of life include: 3 
doses of DTaP, 3 doses of PCV13, 2- 3 doses of inactivated polio virus 
vaccine, 3 doses of Hepatitis B vaccine, and 2 or 3 doses of Hib vaccine 
such that the primary Hib series is complete depending upon the brand 
used. 
(https://www.cdc.gov/vaccines/schedules/hcp/imz/child-
adolescent.html). 
X 
X 
4. The parent(s)/ legally authorized representative(s) LAR(s) intend for the 
child to receive DTaP and PCV13 in addition to this season's IIV 
 
X 
 
5. The parent(s)/LAR(s) must be willing and capable of providing permission 
for their child to participate through the written informed consent process 
 
X 
 
6. The parent(s)/LAR(s) must be able to comply with the requirements of the 
protocol (e.g., completion of the memory aid (either electronic or paper 
diary), return for follow-up visits, respects intervals between the visits and 
have telephone access. 
 
X 
 
7. The parent(s)/LAR(s) must be English speaking 
 
X 
 
8. The parent(s)/LAR(s) must agree to sign a medical release for the child 
so that study personnel may obtain medical information about the child's 
health (if needed) 
 
X 
 
Met Exclusion Criteria 
 
 
1. History of any seizure (including febrile seizure) in the child or a febrile 
seizure in a first degree relative* 
*First degree relatives include biological parents or siblings 
X 
X 
2. Has already completed influenza vaccination during the current season 
per ACIP recommendations* 
*Children needing two doses of influenza vaccine per ACIP 
recommendations and who are receiving a second dose of 
X 
X 

CISA Fever SAP V1.0 
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Revised: February 06, 2018 
 
influenza vaccine may be enrolled; however, an attempt will be 
made to preferentially enroll children needing two doses at the 
time of receipt of their first dose of influenza vaccine 
3. Receipt of more than 3 previous doses of DTaP  
X 
X 
4. Received the 3rd dose of DTaP within 6 months of Visit 1 
X 
X 
5. Receipt of more than 3 previous doses of PCV13 
X 
X 
6. Received the 3rd dose of PCV13 within 8 weeks of Visit 1 
X 
X 
7. History of a severe allergic reaction (e.g. anaphylaxis) to a previous dose 
of any influenza, diphtheria toxoid-, tetanus toxoid-, or pertussis-
containing vaccine, or pneumococcal vaccine 
X 
 
8. History of a severe allergic reaction (e.g., anaphylaxis) to any component 
(including egg protein) of any of the three vaccines used in this study.  
X 
  
9. History of Guillain-Barré syndrome within 6 weeks following a prior dose 
of influenza, DTaP, or tetanus toxoid containing vaccine 
X 
 
10. History of a progressive neurologic disorder 
X 
 
11. History of encephalopathy within 7 days of a previous pertussis-
containing vaccine 
X 
 
12. History of collapse within 3 days after a prior dose of DTaP 
X 
 
13. Received any other licensed vaccines within 14 days (for inactivated 
vaccines) or 28 days (for live vaccines) prior to Visit 1* 
*Concomitant vaccine administration for ACIP recommended 
vaccines are allowed to be administered on the first vaccination 
day in this study but at no other time in this study period unless 
deemed a personal or public health priority by the health care 
provider caring for this patient or the study team. 
X 
X 
14. Received an experimental/investigational agent (vaccine, drug, biologic, 
device, blood product, or medication) within 28 days prior to Visit 1, or 
expects to receive an experimental/investigational agent during the study 
period (up to 8 days after visit 2)  
X 
X 
15. A moderate to severe acute illness within 72 hours of Visit 1* 
*All vaccines can be administered to persons with a minor 
illness such as diarrhea, mild upper respiratory infection without 
fever. 
X 
X 
16. A reported temperature greater than or equal to 100.4°F (38.0°C) within 
72 hours prior enrollment or a temperature (measured by temporal artery 
thermometer) greater than or equal to 100.4°F (38.0°C) at the time of 
enrollment*  
*This may result in a temporary delay of vaccination 
X 
X 
17. Receipt of an antipyretic medication (acetaminophen or ibuprofen) within 
24 hours prior to enrollment* 
*This may result in a temporary delay of vaccination 
X 
X 
18. Parent(s)/LAR is planning to administer a prophylactic antipyretic or 
medication on the day of, and/or within 7 days following Visit 1 or Visit 2* 
*This exclusion does not apply if the caretaker indicates he/she 
might administer antipyretics or analgesics after vaccination to 
reduce fever or pain 
X 
 
19. Long term (at least 14 consecutive days) oral corticosteroids (prednisone 
2 mg/kg/day or equivalent other glucocorticoid), any parenteral steroids, 
high-dose inhaled steroids (>800 mcg/day of beclomethasone 
X 
X 

CISA Fever SAP V1.0 
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Revised: February 06, 2018 
 
dipropionate or equivalent) or other immune-modifying drugs or 
immunosuppressants within the preceding 6 months prior to Visit 1*  
*Topical and nasal steroids are allowed 
20. Any confirmed or suspected immunosuppressive or immunodeficient 
condition, based on medical history and or their provider's routine 
physical examination*  
*No laboratory testing required 
X 
X 
21. Has an active neoplastic disease, a history of any hematologic 
malignancy, current bleeding disorder, or taking anticoagulants. 
X 
X 
22. Unable to receive an intramuscular injection in the thigh* 
* For example – a broken bone or cast for treatment of broken 
bone in a lower extremity, congenital anomaly in lower extremity 
precluding administration in the affected extremity or if deemed 
inappropriate by the study investigator 
X 
 
23. Any condition deemed by the investigator to place the child at increased 
risk as a result of their participation in the study 
X 
 
24. Any child or grandchild of a study investigator or study team member  
X 
X 
1If study team during the period of enrollment subsequent to Visit 1 becomes aware subject 
did not meet inclusion criteria or met exclusion meets the definition of a major violation 
 
Met Study Exclusion Criteria 
At Visit 2 
After Visit 2 
During 
Period 
of 
Enrollment2 
1. Has already completed influenza vaccination during the current season 
per ACIP recommendations 
 
X 
X 
2. History of a severe allergic reaction (e.g. anaphylaxis) to a previous dose 
of any influenza vaccine. 
X 
 
3. History of a severe allergic reaction (e.g., anaphylaxis) to any component  
(including egg protein) of the influenza vaccine used in this study 
X 
 
4. History of Guillain-Barré syndrome within 6 weeks following a prior dose 
of any influenza vaccine 
X 
 
5. Received an experimental/investigational agent (vaccine, drug, biologic, 
device, blood product, or medication) after randomization or expects to 
receive an experimental/investigational agent during the remaining study 
period (up to 8 days after visit 2)  
X 
X 
6. A moderate to severe acute illness within 24 hours of Visit 2* 
* This may result in a temporary delay of Visit 2 and/or 
vaccination.  All vaccines can be administered to persons with 
a minor illness such as diarrhea, mild upper respiratory infection 
without fever. 
X 
X 
7. A reported temperature greater than or equal to 100.4°F (38.0°C) within 
24 hours prior to Visit 2 or a temperature (measured by temporal artery 
thermometer) greater than or equal to 100.4°F (38.0°C) at the time of Visit 
2*  
*This may result in a temporary delay of Visit 2 and/or 
vaccination 
X 
X 

CISA Fever SAP V1.0 
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Revised: February 06, 2018 
 
8. Receipt of an antipyretic medication (acetaminophen or ibuprofen) within 
24 hours prior to Visit 2* 
*This may result in a temporary delay of Visit 2 and/or 
vaccination 
X 
X 
9. Parent(s)/LAR is planning to administer a prophylactic antipyretic or 
medication on the day of, and/or within 7 days following Visit 2* 
*This exclusion does not apply if the caretaker indicates he/she 
might administer antipyretics or analgesics after Visit 2 to 
reduce fever or pain 
X 
 
10. Unable to receive an intramuscular injection in the thigh* 
* For example – a broken bone or cast for treatment of broken 
bone in a lower extremity, congenital anomaly in lower extremity 
precluding administration in the affected extremity or if deemed 
inappropriate by the study investigator 
X 
 
11. Any condition deemed by the investigator to place the child at increased 
risk as a result of their participation in the study 
X 
 
2If study team during the period of enrollment subsequent to Visit 2 becomes aware subject 
met exclusion meets the definition of a major violation 
 
Procedural Violations 
Visit 1 
• Written informed consent not obtained 
• Study eligibility not reviewed  
• Temperature using the temporal artery thermometer not obtained 
• Assigned study products administered prior to randomization  
• Assigned study products not administered according to respective package insert 
specifications 
• Study products received were not according to randomization assignment 
• Study products not administered in thighs 
 
Visit 2 
• 
Visit 2 not done 
• 
Study eligibility not reviewed  
• 
Temperature using the temporal artery thermometer not obtained 
• 
Assigned study product (IIV if in sequential group) not administered according to package 
insert specifications 
• 
Study products received were not according to randomization assignment 
• 
Concomitant vaccine/s administered 
• 
Study product not administered in thighs 
 
Interval Between Visits 1 and 2 
• 
The protocol notes that the maximal interval between Visit 1 (Day 1) and Visit 2 (Day 15 
(+7)) is 21 days.  If Visit 2 occurs between Day 15 and Day 25, it will not be considered a 
major Protocol Violation. 

CISA Fever SAP V1.0 
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Parental assessments 
• 
Parents did not measure temperature using temporal artery method 
 
Other Major Protocol Violations 
• 
Vaccines administered during any point during study period but not at Visit 1 or Visit 2 
o Emergency response 
o For other reason  
 
• 
Use of immunosuppressive steroid dose (i.e. ≥14 days of daily receipt of 20 mg or 2 mg/kg 
body weight of prednisone or equivalent.) or other immune-modifying drugs or 
immunosuppressants from Visit 1 through 8 days after Visit 2