Clinical Study of the Safety of Quadrivalent Live Attenuated Influenza Vaccine (LAIV4) in Children With Asthma of Varying Levels of Severity
Phase: PHASE4
Conditions: Asthma in Children, Vaccine Adverse Reaction, Vaccine Reaction, Asthma, Wheezing, Influenza
Sponsor: Vanderbilt University Medical Center

Protocol Title: Clinical Study of the Safety of Quadrivalent Live Attenuated Influenza 
Vaccine (LAIV4) in Children with Asthma of Varying Levels of Severity
Protocol Date: July 3, 2019
NCT03600428

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Clinical Study of the Safety of Quadrivalent Live Attenuated Influenza 
Vaccine (LAIV4) in Children with Asthma of Varying Levels of Severity 
 
Abbreviated Title: Safety of LAIV4 in Children with Asthma 
 
 
Centers for Disease Control and Prevention 
Clinical Immunization Safety Assessment (CISA) Project 
 
Lead Site Principal Investigator (PI): C. Buddy Creech, MD, MPH 
Lead Site Co-Investigator: Andrew G. Sokolow, MD 
Vanderbilt University Medical Center 
 
Contributing Site PI: Emmanuel B. Walter, MD, MPH 
Contributing Site Co-Investigator: Amy P. Stallings, MD 
Duke University Medical Center 
 
Contributing Site PI: Mary Staat, MD, MPH 
Contributing Site Co-Investigator: Carolyn Kercsmar, MD 
Cincinnati Children’s Hospital Medical Center 
 
Centers for Disease Control and Prevention (CDC) PI: Theresa Harrington, MD, MPH&TM 
CDC Co-Investigator: Karen R. Broder, MD 
 
Multicenter Principal Investigator: 
C. Buddy Creech, MD. MPH 
Vanderbilt Vaccine Research Program 
Vanderbilt University Medical Center 
 
Nashville, TN 37232 
 
 
 
 

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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 (U.S.) 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 
 
1 
BACKGROUND ................................................................................................................... 6 
2  STUDY OBJECTIVES ........................................................................................................... 11 
2.1  Study Objectives ................................................................................................................. 11 
2.1.1  Primary Objective ....................................................................................................... 11 
2.1.2 Secondary Objectives ................................................................................................... 11 
2.1.3   Exploratory Objectives ............................................................................................... 11 
2.2  Study Outcome Measures ................................................................................................... 12 
2.2.1 Primary Outcome Measure ........................................................................................... 12 
2.2.2  Secondary Outcome Measures .................................................................................... 12 
2.2.3  Exploratory Outcome Measures .................................................................................. 13 
3  ELIGIBILITY CRITERIA .................................................................................................... 15 
3.1  Inclusion Criteria ................................................................................................................ 15 
3.2  Exclusion Criteria ............................................................................................................... 15 
4   STUDY DESIGN AND PROCEDURES ............................................................................. 17 
4.1  Recruitment ........................................................................................................................ 17 
4.2  Enrollment and Randomization .......................................................................................... 17 
4.3  Study Visits and Procedures ............................................................................................... 18 
4.3.1  Visit 1 (Day 1) - Enrollment and Vaccination............................................................. 18 
4.3.2  Visit 2 [Day 4 (-1 through +2)] – Reminder [phone call, email, or text message] ...... 20 
4.3.3  Visit 3 [Day 8 (-1 through +3) – Contact [phone call(s), email(s), and/or text message(s)]
 
20 
4.3.4  Visit 4 [Day 15 + 5] – Contact [phone call(s), email(s), and/or text message(s)] ....... 20 
4.3.5  Visit 5 (Day 29 ± 3) – Contact [phone call(s), email(s), and/or text message(s)] ....... 21 
4.3.6  Visit 6 (Day 43 + 7) – Contact [phone call(s), email(s), and/or text message(s)] ....... 21 
4.4  Assignment of Asthma Severity ......................................................................................... 23 
4.4.1  Characterizing Asthma Severity .................................................................................. 23 
4.5  Baseline demographic and health data ............................................................................... 24 
4.6  Individual Peak Expiratory Flow Rate (PEFR) Evaluations .............................................. 24 
4.7  Vaccine Delivery ................................................................................................................ 24 
4.7.1  FluMist® Quadrivalent (Influenza Vaccine Live, Intranasal) ..................................... 24 
4.7.2  Fluzone® Quadrivalent Influenza Vaccine (suspension for intramuscular injection) . 25 
4.7.3  Seasonal Influenza Vaccine Single and 2-Dose Considerations for Participants aged 5-8 years
 
25 
4.8  Monitoring Vaccine Safety in the First 15 Days ................................................................ 26 
4.9  Extended follow-up for days 16-43 .................................................................................... 27 
4.10  Adverse Events and Serious Adverse Events ................................................................... 27 
5  RISKS....................................................................................................................................... 28 
5.1  Vaccines.............................................................................................................................. 28 
5.1.1  Inactivated Influenza Vaccine (IIV) ............................................................................ 28 
5.1.2  Live, attenuated influenza vaccine (LAIV) ................................................................. 28 
6  REPORTING OF ADVERSE EVENTS ............................................................................... 29 
7  STUDY WITHDRAWAL AND DISCONTINUATION ..................................................... 30 
7.1  Handling of Withdrawals .................................................................................................... 30 
7.2  Termination of Study .......................................................................................................... 30 

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8  STATISTICAL CONSIDERATIONS .................................................................................. 31 
8.1  Sample Size Calculations ................................................................................................... 31 
8.2  Analysis plan ...................................................................................................................... 31 
8.2.1  Primary Objective ....................................................................................................... 32 
8.2.2  Primary Outcome Measure .......................................................................................... 32 
8.2.3  Secondary Objectives and Secondary Outcome Measures (SOM) ............................. 33 
9  PRIVACY AND CONFIDENTIALITY ISSUES ................................................................ 35 
10  DATA HANDLING AND RECORDS RETENTION ....................................................... 36 
10.1  Data collection and data management .............................................................................. 36 
10.1.1  Vanderbilt Research Electronic Data Capture (REDCap) ......................................... 36 
10.1.2  Data cleaning and data quality assurance .................................................................. 37 
10.1.3  Role of the CDC Investigators in the Project ............................................................ 37 
11  ETHICS AND PROTECTION OF HUMAN SUBJECTS ............................................... 38 
11.1  Ethical Standard ................................................................................................................ 38 
11.2  Institutional Review Board ............................................................................................... 38 
11.3  Informed Consent Process ................................................................................................ 38 
11.3.1  Parental Permission ................................................................................................... 38 
11.3.2  Assent Process ........................................................................................................... 39 
12 REFERENCES .................................................................................................................... 40 
13 APPENDIX .......................................................................................................................... 42 
13.1 
Figure A1.  Childhood Asthma Control Test (c-ACT) ................................................. 42 
13.2 
Figure A2.  Asthma Control Test (ACT) ...................................................................... 43 
13.3 
Figure A2.  Preventative Omalizumab or Step-Up Therapy For Severe Fall Exacerbations 
(PROSE) Questionnaire ............................................................................................................. 44 
 
 
 
 

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LIST OF TABLES 
 
Table 1: Schedule of Events ....................................................................................................... 22 
Table 2: Asthma severity categories and prescription long-acting controller medications* 
for children with persistent asthma, aged 5-17 years .............................................................. 23 
 
 
 
 
 
LIST OF FIGURES 
 
Figure 1: Participant Flow Chart .............................................................................................. 18 
Figure 2: Influenza vaccine dosing algorithm for children aged 6 months through 8 years- 
Advisory Committee on Immunization Practices, United States, 2018. [Note: This 
recommendation is anticipated to be similar (using the July 1, 2019 cutoff) for the 2019-
2020 season]  ................................................................................................................................ 26 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1 BACKGROUND 
 
CDC’s Advisory Committee on Immunization Practices (ACIP) has long recommended annual influenza 
vaccination for all persons aged ≥6 months who do not have contraindications.  In June 2018, ACIP voted 
to reaffirm this core recommendation for the 2018-2019 influenza season.  Specifically, ACIP stated that: 
For the 2018-19 season, immunization providers may choose to administer any licensed, age-
appropriate, inactivated influenza vaccine (IIV), quadrivalent recombinant influenza vaccine (RIV4), or 
quadrivalent live attenuated influenza vaccine (LAIV4). LAIV4 is an option for those for whom it is 
otherwise appropriate1.  Influenza vaccination is particularly important for persons at high risk for 
medical complications attributed to severe influenza.1  It is anticipated that the recommendations will be 
similar for the 2019-20 season. ACIP designates persons with asthma to be at higher risk for severe 
influenza.1  
 
Asthma, a chronic, inflammatory disease of the pulmonary airways, can be life-threatening if not 
adequately managed.2 According to the U.S. National Health Interview Survey (NHIS), in 2016, 8.4 
million children <18 years (9.3%) had (current) asthma, with increased prevalence of asthma among 
older, compared with younger children [0-4 years (3.8%); 5-11 years (9.6%); 12-17 years (10.5%)].3 
Children in economically disadvantaged families were also more likely to have asthma (10.7%) than 
children in families that were not disadvantaged (6.7%).3 Furthermore, children with asthma are more 
likely to require hospitalization for influenza, and to experience asthma exacerbations after influenza 
illness.4,5 Despite this, NHIS data for the 2012-2013 influenza season revealed that influenza vaccination 
among children with asthma 2-17 years averaged almost 55%, up from 32% in 2004-2005, yet, this 
proportion still falls short of the Healthy People 2020 influenza vaccination goal of 80% for children with 
asthma (aged 6 months-17 years).6-8    
 
Live attenuated influenza vaccine (LAIV) is administered intranasally, and replication of the vaccine 
virus occurs primarily in nasopharyngeal epithelial cells. This replication can lead to symptoms of nasal 
congestion.9,10   Since 2013, all LAIV formulations used in the United States have been quadrivalent 
LAIV (LAIV4) (FluMist® Quadrivalent).  The Warnings and Precautions section of the FDA package 
insert for LAIV4 states that, “persons of any age with asthma may be at increased risk of wheezing 
following the administration (of LAIV)”.10  Similarly, ACIP considers asthma in persons aged ≥5 years a 
precaution for LAIV use.1  Because of the potential for increased risk of wheezing after LAIV, the use of 
LAIV in persons with asthma has been an area of vaccine safety research for many years; the safety issue 
remains unresolved. Broadening the LAIV recommendation to include persons with asthma could have 
several advantages: 1. Ease of program implementation, especially in busy clinic or school-based 
vaccination settings; 2. Ease of implementation and greater options for influenza pandemic preparedness; 
and 3. Greater options for children with needle phobia. A clinical study to assess the safety of LAIV4 in 
children with asthma could expand the evidence base and inform clinical decision-making and public 
health policy.  Below we present a summary of the safety data of LAIV in children and recent changes in 
ACIP recommendations for use of LAIV.  
 
Review of Safety Evidence for LAIV in Children.  In 2014, after completing a review of available 
evidence, ACIP concluded that for healthy children aged 2-8 years, risks for harms assessed (including 
fever, wheezing, and serious adverse events) appeared to be similar for LAIV and IIV.11 However, for 

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children with chronic medical conditions placing them at higher risk for influenza complications, 
including asthma, data on the relative safety of LAIV and IIV were limited.11 Most studies suggested that 
LAIV was not associated with an increased risk of wheezing events after vaccination in children who are 
at least 2 years of age and that did not have a prior history of asthma and wheezing.12 However, data 
regarding LAIV safety in persons with a history of asthma or wheeze were less clear.12-14 One study of 
LAIV safety specified in the methods that children with severe asthma were included; no safety concerns 
were identified, but the small study (N=48) conducted in one season limited the ability to draw 
conclusions.13 There is even less information about the safety of LAIV4 in persons with asthma when 
compared with trivalent LAIV; LAIV4 has been the only live influenza vaccine product available in the 
United States since the 2013-14 influenza season.  
 
In an effort to further assess the safety of LAIV in participants with asthma, several clinical trials have been 
conducted over the past decade. These will be briefly summarized to provide a context for the proposed study. 
Redding et al. assessed the safety and tolerability of LAIV in children > 9 years of age with moderate to severe 
asthma.13 They enrolled 48 subjects (24 participants and 24 controls) into a randomized, double blind, placebo-
controlled study; spirometry was performed twice before vaccination to establish a baseline forced expiratory 
volume (FEV1) and once 2 to 5 days thereafter. The primary outcome was the percent change in percent-
predicted FEV1 before and after vaccination; a reduction of ≥15% was the prespecified endpoint. Peak flows, 
clinical asthma symptom scores and nighttime awakening scores were also measured daily from 7 days pre- to 
28 days post-vaccination. There was no difference in the primary outcome measure (percentage change in 
percent predicted FEV1) between the treatment and placebo groups (P = 0.78). Secondary outcomes did not 
differ between the two groups either; these included the number of participants with a decrease in FEV1, 
reductions in peak flows, use of beta-adrenergic rescue medications, asthma exacerbations and clinical asthma 
symptom scores before and after vaccination. The same proportion of participants in each group experienced 
post-vaccination symptoms within 10 days (92% and 91%, respectively; P = 1.0). No serious adverse events 
occurred. These data were reassuring for the safety of LAIV in asthmatic children but were of small sample 
size.13  
 
To further evaluate the safety of LAIV in children and adolescents, a larger randomized, double blind, 
placebo-controlled safety trial in healthy children age 12 months to 17 years was conducted by Bergen et 
al., in a large health maintenance organization.15 Children were randomized 2:1 to receive either LAIV or 
placebo. Children <9 years of age received a second dose of LAIV or placebo 28 to 42 days after the first 
dose. Enrolled children were followed for 42 days after each vaccination for all medically attended 
events. A total of 9689 evaluable children were enrolled in the study. Of the 4 pre-specified diagnostic 
categories (acute respiratory tract events, systemic bacterial infection, acute gastrointestinal tract events, 
and rare events potentially associated with wild-type influenza), none was associated with vaccine receipt. 
However, a significantly increased relative risk (4.06; 90% confidence interval, 1.29 to 17.86) of reactive 
airway disease was observed in children 18 to 35 months of age.15  
 
Given these concerns regarding the triggering of asthma by LAIV, Piedra et al. conducted an even larger 
open-label, non-randomized, community-based trial of LAIV in children 18 months to 18 years of age 
over a four-year period.16 In the four years of the study 18,780 doses of LAIV were administered to 
11,096 children. Medical records of all children were surveyed for serious adverse events (SAEs) and 
health care utilization was evaluated for medically attended acute respiratory illness and asthma. No 

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increased risk of asthma events for 0 to 14 days after vaccination was observed in children of any age 
group. In vaccine year 1, children who were 18 months to 4 years of age did have a significantly higher 
risk for asthma events 15 to 42 days after vaccination (RR 2.85; 95% CI: 1.01-8.03), but this was not seen 
in year 2. The authors concluded, “…although the possibility for a true increased risk for asthma was 
observed in one of the four years of the study in children who were 18 months to 4 years of age at 15 to 
42 days after vaccination, it is more likely that the association is a chance effect because of the 190 
comparisons made without adjustment for multiple comparisons.” They also concluded that LAIV was 
safe and not associated with an increase in asthma events in children who are younger than 5 years.16  
 
Utilizing the same population as Piedra, Gaglani et al. administered a single LAIV dose to healthy 
children aged 1.5-18 years with history of intermittent wheezing.17 As in the earlier study, they assessed 
the rates of medically attended acute respiratory illnesses, including acute asthma exacerbation, during 0-
14 and 0-42 days post-LAIV and also assessed the risk of new-onset asthma in LAIV recipients. During 
each of the 4 study years, a total of 454, 656, 656, and 430 children with intermittent wheezing who 
received LAIV, respectively, had no increased risk for medically attended acute respiratory illnesses, 
including asthma exacerbation. First-dose LAIV recipients, including those aged 1.5-4 years, and those 
receiving 2-4 consecutive annual doses had no increased risk. Children with parental report of intermittent 
wheezing and those with administrative database codes for asthma during the two prior years had no 
increased risk of wheezing. In addition, during the 4 years of the study, 2,952, 3,092, 2,953, and 2,478 
children without history of wheezing, respectively, had no increased risk of new-onset asthma. The 
authors concluded that “LAIV administration in children aged 1.5-18 years with a history of intermittent 
wheezing was safe, and was not associated with increased risk for medically-attended acute respiratory 
illnesses, including acute asthma exacerbation during any of the study years.”17  
 
Ashkenazi et al. compared the safety of LAIV and trivalent inactivated influenza vaccine (TIV) in young 
children with a history of recurrent respiratory tract infections.18 Children 6 to 71 months of age were 
randomized to receive 2 doses of LAIV (n = 1101) or TIV (n = 1086), 35 +/- 7 days apart before the start of the 
2002-2003 influenza season. They were followed for vaccine effectiveness and safety. Overall, 52.7% (95% 
confidence interval [CI] = 21.6%-72.2%) fewer cases of influenza caused by virus strains antigenically similar 
to vaccine were observed in LAIV than TIV recipients. Greater relative efficacy for LAIV was observed for the 
antigenically similar A(H1N1) (100.0%; 95% CI = 42.3%-100.0%) and B (68.0%; 95% CI = 37.3%-84.8%) 
strains but not for the antigenically similar A(H3N2) strains (-97.1%; 95% CI = -540.2% to 31.5%). Relative to 
TIV, LAIV reduced the number of respiratory tract infection healthcare provider visits by 8.9% (90% CI = 
1.5%-15.8%) and missed days of school, kindergarten, or day care by 16.2% (90% CI = 10.4%-21.6%). Rhinitis 
and rhinorrhea, otitis media, and decreased appetite were the only events that were reported more frequently in 
LAIV recipients (monitored for 11 consecutive days after vaccination). There was no difference between groups 
in the incidence of wheezing after vaccination (during the 42 days after vaccination). LAIV was well tolerated 
in these children and demonstrated superior relative efficacy compared with TIV in preventing influenza 
illness.18  
 
Given the concern about the safety of LAIV administration in patients with asthma, a large open-label study was 
conducted among 2,229 asthmatic children aged 6 to 17 years by Fleming et al. during the 2002-2003 
influenza season.4 Children receiving high-dose systemic corticosteroids were excluded from the study, 
but the study did not quantify the level of severity of the underlying asthma among study participants. 

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Nearly 70% of children were on inhaled corticosteroids.  No significant differences were reported between 
the LAIV and TIV vaccine recipients in the incidence of asthma exacerbations (during 42 days after 
vaccination), mean peak expiratory flow rates, asthma symptom scores, or nighttime awakening scores. 
Rhinorrhea and nasal congestion were commonly reported symptoms among recipients of LAIV during the 15 
days after study vaccination; injection site reactions were the most commonly reported symptoms among 
recipients of TIV. Overall, there was no evidence of a significant increase in adverse pulmonary outcomes 
for LAIV compared with TIV. LAIV had a significantly greater relative efficacy of 35% compared with 
TIV in this high-risk population.4 This well designed and conducted clinical trial serves as a model for the 
conduct of the proposed trial.  
 
More recently, the Centers for Disease Control and Prevention’s Vaccine Safety Datalink published a 
study assessing the safety of LAIV in persons with asthma.19  They assessed medically-attended 
respiratory events during the 14 days after LAIV (trivalent LAIV and monovalent 2009 H1N1 pandemic 
LAIV) compared with the 29 to 42 days after vaccination among persons 2 through 49 years over three 
influenza seasons (2008-2009; 2009-2010; 2010-2011).  Most patients had intermittent or mild persistent 
asthma. Medically-attended upper or lower respiratory events (outpatient or inpatient) were not 
significantly increased after LAIV. This was true for younger children 2-8 years as well as older children 
9-17 years.  
 
Summary of recent history of ACIP guidance for use of LAIV.  Based on influenza surveillance systems 
and published pre- and post-licensure clinical study data, ACIP recommendations for live attenuated 
influenza vaccine (LAIV) use in healthy children aged ≥2 years have changed over recent years. During 
2007-2008 through the 2013-2014 influenza seasons, ACIP recommended that either live attenuated 
influenza vaccine (LAIV) or IIV could be used for these children.9 In 2014, after completing an evidence 
review, ACIP concluded that data supported the superior efficacy for LAIV versus IIV in children aged 2-
8 years; in response ACIP recommended a preference for LAIV over IIV in this age group during the 
2014-15 influenza season.11 However, following this preferred recommendation, new data emerged 
suggesting that LAIV did not have superior efficacy over IIV.20 Therefore for the 2015-16 influenza 
season, ACIP removed the preference and recommended that either LAIV or IIV could be used in healthy 
children aged ≥2 years.20  Due to concerns regarding lack of effectiveness of quadrivalent LAIV 
(FluMist® Quadrivalent; LAIV4; MedImmune, Gaithersburg, MD) during the 2013-2014 and 2015-2016 
influenza seasons,  ACIP voted in June 2016 to recommend against use of LAIV4 in persons of any age 
during the 2016-2017 influenza season,21  and continued the recommendation against use of LAIV4 
during the 2017-2018 influenza season.1   The manufacturer (MedImmune/AstraZeneca) identified that a 
more immunogenic strain of post-pandemic A(H1N1) was needed to improve the immune response to 
LAIV4. The manufacturer changed the vaccine formulation and carried out clinical studies of viral 
shedding and antibody response to the new LAIV4 formulation in young children.  Results of these 
studies were presented at the February 2018 ACIP meeting.22  Based on results of these studies and 
additional investigations, the ACIP voted on February 21, 2018, to recommend inclusion of the updated 
quadrivalent formulation of LAIV (FluMist®; LAIV4) among vaccines eligible for use during the 2018-
2019 influenza season.22,23  On June 8, 2018, CDC published the updated recommendation for use of the 
Quadrivalent Live Attenuated Influenza Vaccine (LAIV4) during the 2018-2019 influenza season: “For 
the 2018–19 U.S. influenza season, providers may choose to administer any licensed, age-appropriate 
influenza vaccine (IIV, recombinant influenza vaccine [RIV], or LAIV4). LAIV4 is an option for those for 

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whom it is otherwise appropriate. No preference is expressed for any influenza vaccine product.”23  It is 
anticipated that the recommendations will be similar for the 2019-20 season. 
 
In September 2015, CDC’s Immunization Safety Office-Clinical Immunization Safety Assessment 
(CISA) Project awarded 3 medical research centers a contract to conduct a clinical study to assess the 
safety of LAIV versus IIV in children 5-11 years diagnosed with persistent asthma.  This study intended 
to enroll participants during the 2016-2017 influenza season; however, these plans were postponed 
temporarily during the 2016-2017 and 2017-2018 influenza seasons due to the ACIP recommendation 
against use of LAIV.  ACIP’s vote in February 2018 to recommend use of LAIV4 and expressed no 
preference for use of LAIV or IIV in children during the 2018-19 influenza season.  This vote made it 
feasible for this CISA vaccine safety study to proceed, and it is anticipated that the recommendations will 
be similar for the 2019-20 season. 
 
 
 
 
 
 
 

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2  STUDY OBJECTIVES 
 
2.1  Study Objectives  
2.1.1  Primary Objective 
 
1. To compare proportions of participants with asthma exacerbations during the 42 days (until day 
43) after quadrivalent live attenuated influenza vaccine (LAIV4) versus quadrivalent inactivated 
influenza vaccine (IIV4) in children with asthma aged 5-17 years.  
 
The hypothesis for this primary objective is that the proportion of asthma exacerbations after LAIV4 is 
non-inferior to the proportion of asthma exacerbations after IIV4 (proportion of asthma exacerbations is 
NOT higher in the LAIV4 group vs. the IIV4 group). 
2.1.2 Secondary Objectives 
 
1. To compare proportions of participants with asthma exacerbations during the 14 days after 
LAIV4 versus IIV4  
2. To compare the proportions of participants with asthma symptoms and unscheduled albuterol use 
during the 14 days after receipt of LAIV4 or IIV4 
3. To compare the proportion of participants that experience a clinically significant decrease in Peak 
Expiratory Flow Rate (PEFR) from baseline during the 14 days after receipt of LAIV4 or IIV4 
2.1.3   Exploratory Objectives 
1. To compare proportions of participants with asthma exacerbations during the 14 days and 42 days 
after receipt of LAIV4 or IIV4, by asthma severity group 
2. To compare the proportions of participants with asthma symptoms and unscheduled albuterol use 
during the 14 days after receipt of LAIV4 or IIV4, by asthma severity group 
3. To compare the proportion of participants who experience a clinically significant decrease in 
PEFR from baseline during the 14 days after receipt of LAIV4 or IIV4, by asthma severity group 
4. To describe and compare changes in Peak Expiratory Flow Rate (PEFR) from baseline (pre-
vaccination) PEFR after vaccination over time during the 14 days after LAIV4 versus IIV4, by 
asthma severity group 
5. To compare change in Childhood Asthma Control Test (c-ACT) score (participants aged 5-11 
years) or Asthma Control Test (ACT) score (participants aged 12-17 years) from baseline through 
42 days after LAIV4 or IIV4, by asthma severity group  

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6. To compare asthma symptom days using Preventative Omalizumab or Step-up Therapy for 
Severe Fall Exacerbations (PROSE) from baseline during the 14 days after vaccination by asthma 
severity group 
7. To compare rates of medical utilization for asthma-related symptoms during the 14 and 42 days 
after LAIV4 or IIV4, by asthma severity group 
8. To describe and compare systemic reactogenicity events during the 14 days after receipt of 
LAIV4 or IIV4 by asthma severity group 
9. To describe and compare serious adverse events after LAIV4 vs. IIV4 during the 42 days after 
vaccination and assess relatedness to vaccine  
10. To describe and compare asthma symptoms and control among participants with and without a 
history of allergic rhinitis or hay fever, used as a proxy for allergic versus non-allergic asthma.  
 
2.2  Study Outcome Measures  
2.2.1 Primary Outcome Measure 
1. Comparison of the proportion of participants experiencing an asthma exacerbation during the 42 
days after LAIV4 vs. IIV4 (until day 43).  
 
According to the 2007 Expert Panel Report 3: Guidelines for the Diagnosis and Management of 
Asthma, asthma exacerbations, “are acute or subacute episodes of progressively worsening shortness 
of breath, cough, wheezing, and chest tightness (or some combination of these symptoms). 
Exacerbations are characterized by decreases in expiratory airflow that can be documented and 
quantified by simple  measures of lung function [spirometry or peak expiratory flow (PEF)]”.24   For 
this study, asthma exacerbation will be defined as:  any acute episode of progressively worsening 
shortness of breath (dyspnea), cough, wheezing, chest tightness, and/or respiratory distress during 
the 42 days (until day 43) after influenza vaccination for which the patient seeks unscheduled medical 
attention (e.g., healthcare provider office or Emergency Department visit or hospitalization) or 
receives a new prescription for systemic corticosteroids.   
2.2.2  Secondary Outcome Measures  
1. Comparison of the proportion of participants experiencing an asthma exacerbation during the 14 days 
after LAIV4 vs. IIV4. 
For the purposes of this outcome measure, the above definition of asthma exacerbation (section 
2.2.1) is modified to include the time period of 14 days after receipt of influenza vaccine (LAIV4 
or IIV4)  
 
2. Comparison of the proportion of participants with asthma symptoms and unscheduled albuterol use 
during the 14 days after receipt of LAIV4 or IIV4 (each is assessed separately). 
a. Cough 

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b. Wheezing 
c. Tightness in chest 
d. Nighttime awakening 
e. Unscheduled albuterol use 
 
3.   Comparison of the proportion of participants who experience a clinically significant decrease in peak 
flow measurement* from baseline during the 14 days after LAIV4 or IIV4.   
*For purposes of this measure, a clinically significant decrease in peak flow is defined as:  
a decrease of ≥20% in PEFR from baseline PEFR. 
2.2.3  Exploratory Outcome Measures 
1. a. Comparison of the proportion of asthma exacerbations by asthma severity group (Mild    
     vs. Moderate-Severe) during the 14 days after receipt of LAIV4 or IIV4 
 
       b. Comparison of the proportion of asthma exacerbations by asthma severity group (Mild  
          vs. Moderate-Severe) during the 42 days after receipt of LAIV4 or IIV4  
2. Comparison of the proportions of participants with asthma symptoms and unscheduled albuterol 
use by asthma severity group during the 14 days after receipt of LAIV4 or IIV4 (each symptom is 
assessed separately). 
a. Cough 
b. Wheezing 
c. Tightness in chest 
d. Nighttime awakening 
e. Unscheduled albuterol use 
3. Comparison of the proportion of participants that experience a clinically significant decrease in 
Peak Flow measurement any time during the 14 days after vaccination with LAIV4 or IIV4, by 
asthma severity group. For purposes of this measure, a clinically significant decrease in peak flow 
is defined as: a decrease of ≥20% in PEFR from baseline PEFR. 
 
4. A. Comparison of numerical changes in Peak Flow when compared to baseline during the 14 days  
after LAIV4 vs IIV4, by asthma severity group.  
 
  B. Description of changes in Peak Flow when compared to baseline during the 14 days after  
     LAIV4 vs IIV4, by asthma severity group  
 
5. Comparison of Change in Childhood Asthma Control Test (c-ACT) scores (participants aged 5-
11 years) or Asthma Control Test (ACT) scores (participants aged 12-17 years) from baseline 
during the 42 days after LAIV4 or IIV4, by asthma severity group  
 
6. Comparison of maximum number of asthma symptom days using Preventative Omalizumab or 
Step-up Therapy for Severe Fall Exacerbations (PROSE) from baseline during the 14 days after 
vaccination with LAIV4 or IIV4, by asthma severity group 

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7. Comparison of rates of medical utilization for asthma-related symptoms during the:  
a. 14 days after LAIV4 or IIV4 by asthma severity group 
b. 42 days after LAIV4 or IIV4 by asthma severity group  
 
8. Description and comparison of systemic reactogenicity events during the 14 days after receipt of 
LAIV4 or IIV4 by asthma severity group   
 
9. Description and comparison of serious adverse events during the 42 days after IIV4 or LAIV4 
and performance of a relatedness assessment 
 
10. Description and comparison of asthma symptoms and asthma control (PROSE, and c-ACT/ACT 
scores) among participants with and without a history of allergic rhinitis or hay fever, as a proxy 
for allergic versus non-allergic asthma 
 
 
 

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3  ELIGIBILITY CRITERIA 
 
3.1  Inclusion Criteria  
 
1. Children between 5-17 years of age, inclusive, at enrollment 
 
 
2. Participant must have a current diagnosis of persistent asthma1 
 
1 Physician diagnosis of asthma and current prescribed use of a long-acting controller 
medication. For purposes of this study, we have considered “controller” medications to be any 
single or combination use of long-acting medications used to prevent asthma exacerbations and 
to achieve long-term control of asthma (as compared to short-acting rescue medication).  (see 
Table 2, Section 4.4). 
 
 
3. Parent(s) or legal guardian(s) must provide written, informed consent and participant must 
provide assent as appropriate for age prior to initiation of study procedures and according to local 
IRB requirements 
 
 
4. Parent(s) or legal guardian(s) and participant must be willing and able to comply with planned 
study procedures and be available for all study visits 
 
5. Is in good health, other than their asthma, as determined by medical history  
 
6. English or Spanish literate2  
2 only English-speaking participants will be included at the Cincinnati and Duke sites  
 
7. Intention of being available for entire study period and complete all relevant study procedures, 
including follow-up using at least one of the following methods:  phone calls, text messages, or 
emails 
 
3.2  Exclusion Criteria 
 
1. Acute illness and/or a reported oral temperature of ≥ 100.4°F within 72 hours prior to enrollment 
(this may result in a temporary delay of vaccination) 
 
2. Use of antipyretic medication during the preceding 24 hours that might mask a fever (this may 
result in a temporary delay of vaccination) 
 
3. History of a severe allergic reaction (e.g., anaphylaxis) after a previous dose of any influenza 
vaccine or after any component of the influenza vaccine, including egg protein.   
 
4. Receipt of any licensed vaccine within 14 days (for inactivated vaccines) or 28 days (for live 
vaccines) prior to vaccination or planned receipt of any licensed vaccine within 42 days after 
vaccination  
 

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5. Receipt of current year’s (2018-2019 or 2019-2020 influenza season) licensed influenza vaccine 
for children 9-17 years (only).   
(Clarification:  Children aged 5-8 years are permitted to be enrolled if they have received zero or one 
dose of the 2018-2019 or 2019-2020 influenza season’s vaccine, and require two doses of the current 
year’s (2018-2019 or 2019-2020 influenza season) influenza vaccines.) (see Fig 2, section 4.7.3) 
 
6. Received an investigational agent (licensed or unlicensed vaccine, drug, biologic, device, blood 
product, or medication) in the 28 days prior to enrollment or planned receipt before 42 days after 
vaccination  
 
7. Have immunosuppression as a result of an underlying illness or treatment, or use of anticancer 
chemotherapy or radiation therapy within the preceding 36 months 
 
8. Have taken ≥20mg/day of prednisone or its equivalent, for 14 days or more within the past 28 
days 
 
9. Have known active neoplasm or a history of any hematologic malignancy  
 
10. Have had a previous exacerbation of their asthma symptoms requiring systemic steroids within 
the prior 28 days, or has had a life-threatening exacerbation of asthma in the past two years (e.g. 
hypoxic seizure, mechanical ventilation)  
 
11. Received influenza antiviral medication within 48 hours prior to study vaccination 
 
12. History of Guillain-Barré syndrome within 6 weeks of previous influenza vaccination 
 
 
 
 
13. Have any condition that, in the opinion of the investigator, would interfere with the evaluation of 
the responses or would place the participant at unacceptable risk of injury 
 
14. Has a positive urine or serum pregnancy test within 24 hours prior to vaccination in a post-
menarchal female, as LAIV is not recommended for use in pregnant females.1 
 
 
 
      
15. Currently taking aspirin or aspirin-containing products 
 
16. Any parent(s) or legal guardian(s) who is an immediate relative of study staff or is an employee 
supervised by study staff.   
 
17. Previously enrolled in the study  
 
 
 

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4   STUDY DESIGN AND PROCEDURES 
 
4.1  Recruitment 
 
This is a prospective randomized, open label clinical trial in approximately 300 children aged 5-17 years, 
inclusive, with a physician diagnosis of persistent asthma.  The study will be conducted at three sites: 
Vanderbilt University Medical Center (Lead site), Cincinnati Children’s Hospital Medical Center 
(contributing site), and Duke University Medical Center (contributing site) during the 2018-2019 and 
2019-2020 influenza seasons. Participants will be randomized 1:1 to receive either a single intranasal 
dose of LAIV4 or an intramuscular injection of IIV4, stratifying by asthma severity (mild vs. moderate-
to-severe) and by age group (5-11 years vs. 12-17 years of age).  Vanderbilt will enroll approximately 100 
participants, Cincinnati will enroll approximately 110 participants, and Duke will enroll approximately 90 
participants.  All sites will begin enrolling when study vaccines become available.   Recruitment will 
occur at various clinics at the three study sites.  At all sites, study participants will be compensated for the 
initial clinic visit at enrollment, and for each study visit follow-up (excluding reminder-only 
communications), as outlined in Section 4.3.  A social security number will be requested for the parent, 
legal guardian, or child who receives monetary compensation for participating in this study.   A child may 
participate in this study even if their parent or legal guardian chooses not to provide a social security 
number; however, the study will not be able to provide compensation to the parent, legal guardian, or 
child if a social security number is not provided.  
 
4.2  Enrollment and Randomization 
 
Participants will be randomized (1:1) to receive either a single intranasal dose of licensed quadrivalent 
LAIV4 or an intramuscular injection of quadrivalent inactivated influenza vaccine (IIV4), stratifying by 
asthma severity (mild vs. moderate-to-severe) and age (5-11 vs. 12-17 years of age). Asthma severity 
level will be assessed at Visit 1 (see Table 2, section 4.4).  Randomization will be done separately for 
each site. Each site may have more than one clinic to recruit participants, and proportions of participants 
with mild or moderate-to-severe asthma can vary by clinics. Randomization will be accomplished using 
the REDCap System, hosted at Vanderbilt, or a back-up method if REDCap is temporarily unavailable. 
REDCap is a web-based system that is easily accessible to the other collaborating sites. This study will be 
open label and study staff and participants will not be blinded to treatment arm assignments.  
 
 
 

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Figure 1: Participant Flow Chart  
   
 
4.3  Study Visits and Procedures  
4.3.1  Visit 1 (Day 1) - Enrollment and Vaccination  
• 
Obtain parent(s) or legal guardian(s) permission by written informed consent prior to performing any 
study procedures. 
• 
Obtain child assent if applicable to site  
• 
May read script about study to participants aged 5 to 6 years if applicable to site  
• 
Medical history and medication history will be obtained, including a review of all current 
medications and medications taken within 28 days prior to enrollment. 
• 
A targeted physical exam may be performed by clinical study staff, based on information 
gathered during medical history 
• 
History of asthma and allergy disease  
• 
Temperature will be recorded prior to immunization; oral temperature must be <100.4◦ F without 
use of antipyretic medication prior to administration of vaccine. 

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• 
Sex, height, weight, and BMI (demographics) 
• 
Eligibility criteria will be reviewed to determine if child meets criteria for study.  
• 
A urine or serum pregnancy test will be collected on post-menarchal females.   
• 
For females, parent(s) or legal guardian(s) will be asked whether their child has had onset of 
menarche.  If the answer is “yes”, a urine or serum pregnancy test will be performed as part of 
eligibility assessment, and conducted within 24 hours before vaccination. Results of a positive 
pregnancy test would be communicated with the female being tested in accordance with local 
institutional practices. 
• 
 Asthma severity will be assessed according to Table 2, section 4.4.  
• 
Asthma control will be assessed with following tools:  
o Administration of the Childhood Asthma Control Test (c-ACT) or Asthma Control Test 
(ACT) score, as appropriate by age (Appendix, Fig. A1) 
o Clinical assessment to assess baseline asthma clinical symptoms [Preventative 
Omalizumab or Step-up Therapy for Severe Fall Exacerbations (PROSE) asthma 
symptom questionnaire] (Appendix Figure A2) 
• 
Patient and parent(s) or legal guardian(s) will be taught proper peak flow technique and will be 
provided with a digital peak flow meter by the study staff, even if they have another peak flow 
meter at home.  A baseline peak flow measurement (standing, three attempts) will be collected. 
The patient (and parent(s) or legal guardian(s)) will be requested to use this same peak flow meter 
every day at home beginning on the day of vaccination and for 14 days following vaccination, 
(days 1 through 15). (see section 4.6 below)  
• 
The child will be randomized to the respective treatment group (LAIV4 or IIV4) using the 
REDCap System. The Vaccine Information Sheet (VIS) for the respective vaccine administered 
will be provided to parent(s) or legal guardian(s) before the vaccine is administered 
(https://www.cdc.gov/vaccines/hcp/vis/current-vis.html). The VIS will be in the primary language 
of the parent(s) or legal guardian(s) consenting for the child to be enrolled in the study. 
• 
An assessment of the number of influenza vaccine doses needed will be performed for children 5-
8 years according to ACIP guidance.  See FIG. 2, section 4.7.3.   
• 
For children 5-8 years who are recommended to receive two doses of vaccine, study staff will 
document whether Dose #1 or Dose #2 will be given during the study.  Additional guidance will 
be provided to the parent if Dose #2 is needed during the influenza season per section 4.7.3 below 
(Seasonal Influenza Vaccine Single and 2-Dose Considerations for Participants aged 5-8 years) 
• 
The influenza vaccine will be administered according to the study randomization scheme. 
• 
Documentation of influenza vaccine Dose #1 or Dose #2 will be provided to the parent(s) or legal 
guardian(s). 
• 
Memory aid (daily symptom and peak flow diary on vaccination day, Day 1, and for the next 14 
days, through Day 15, and on day 43) will be reviewed with the parent and the parent will 
demonstrate ability to take temperature and will be instructed in the collection of post-vaccination 
asthma clinical symptoms and symptom scores, adverse event, fever and concomitant medication 
administration data for 14 days (until day 15) after vaccination  
• 
Parent(s) or legal guardian(s) will be given a thermometer to use for daily temperature recording  
• 
Study staff will record any immediate adverse events (AEs) after vaccination occurring while still 
in the clinic. They will observe the child for at least 20 minutes after vaccination. 

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Study staff will instruct the parents/legal guardians to follow up with their child’s healthcare 
provider if their child has a severe adverse event, worsening asthma symptoms or any other 
symptoms they find concerning  
• 
Study staff will educate parents/legal guardians to notify the study staff if the patient requires an 
additional unscheduled medical visit for management of asthma symptoms (medical services 
utilization), has a severe adverse event, or a new asthma control medication that has been 
prescribed.  
4.3.2  Visit 2 [Day 4 (-1 through +2)] – Reminder [phone call, email, or text message]  
• 
Reminder message to parent(s) or legal guardian(s) to complete memory aid.  
4.3.3  Visit 3 [Day 8 (-1 through +3) – Contact [phone call(s), email(s), and/or text message(s)] 
• 
Memory aid review for solicited symptoms 
• 
Unsolicited symptoms review 
• 
Obtain serious adverse event (SAE) information 
• 
Concomitant medications review 
• 
Medical services utilization review 
• 
Peak flow measurements 
• 
Parents/legal guardians will be instructed to follow up with their child’s healthcare provider if 
their child has a severe adverse event, worsening asthma symptoms, or any other symptoms they 
find concerning 
• 
Parents/legal guardians will be instructed to contact the study staff if the child has an unscheduled 
medical visit for management of asthma symptoms (medical services utilization), or has a new 
asthma medication prescribed, or experiences a severe adverse event 
4.3.4  Visit 4 [Day 15 + 5] – Contact [phone call(s), email(s), and/or text message(s)] 
• 
Memory aid review for solicited symptoms 
• 
Unsolicited symptoms review 
• 
Obtain serious adverse event (SAE) information 
• 
Concomitant medications review 
• 
Post-vaccination asthma clinical symptoms review and PROSE questionnaire 
• 
Medical services utilization review 
• 
Peak flow measurements 
• 
Study staff will instruct the parents/legal guardians to follow up with their child’s healthcare 
provider if their child has worsening asthma symptoms or any other symptoms they find 
concerning  
• 
Parents/legal guardians will be instructed to contact the study staff if the child has an unscheduled 
medical visit for management of asthma symptoms (medical services utilization) or has a new 
asthma medication prescribed.   

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4.3.5  Visit 5 (Day 29 ± 3) – Contact [phone call(s), email(s), and/or text message(s)] 
• 
Concomitant medications review 
• 
Unsolicited symptoms review 
• 
Medical services utilization review 
• 
Obtain serious adverse event (SAE) information 
• 
Study staff will instruct the parents/legal guardian to follow up with their child’s healthcare 
provider if their child has worsening asthma symptoms or any other symptoms they find 
concerning  
• 
Parents/legal guardians will be instructed to contact the study staff if the child has an unscheduled 
medical visit for management of asthma symptoms (medical services utilization) or has a new 
asthma medication prescribed. 
4.3.6  Visit 6 (Day 43 + 7) – Contact [phone call(s), email(s), and/or text message(s)] 
• 
Concomitant medications review 
• 
Unsolicited symptoms review 
• 
Medical services utilization review 
• 
Obtain serious adverse event (SAE) information 
• 
Post-vaccination asthma clinical symptoms review and symptom scores  
o Asthma control assessment (c-ACT/ACT, as appropriate by age) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 1: Schedule of Events 
Study Visit 
Enrollment 
Visit 1 
(Vaccination) 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Study Day  
1 
4 
8 
15 
29 
43 
Visit Window (Days) 
n/a 
3-6 
7-11 
15-20 
26-32 
43-50 
Type of Visit 
In –person 
Clinic 
Reminder 
only 
Contact 
Contact 
Contact 
Contact 
Obtain Informed Consent 
through parental permission  
X 
 
 
 
 
 
Obtain Assent (if applicable per 
site’s IRB requirement) 
X 
 
 
 
 
 
Review Eligibility Criteria  
X 
 
 
 
 
 
Document Prior Year Flu 
Vaccination and present year 
influenza vaccine status for 
children 5-8 years 
X 
 
 
 
 
 
Review Medical History  
X 
 
 
 
 
 
May perform targeted physical 
exam  
X 
 
 
 
 
 
Review Asthma History 
X 
 
 
 
 
 
Assess asthma clinical 
symptomsa (PROSE) 
X 
 
 
X 
 
 
Assess asthma controlb (c-
ACT/ACT) 
X 
 
 
 
 
X 
Asthma severity classificationc 
X 
 
 
 
 
 
Concomitant Medicationsd 
X 
 
X 
X 
X 
X 
Urine or serum pregnancy teste 
X 
 
 
 
 
 
Oral temperature 
X 
 
 
 
 
 
Sex, Height, Weight, BMI 
X 
 
 
 
 
 
Peak Flow Measurementf 
X 
 
X 
X 
 
 
Enrollment and Randomizationg 
X 
 
 
 
 
 
Study Vaccination 
X 
 
 
 
 
 
Post vaccination evaluation 
period (at least 20 minutes) 
X 
 
 
 
 
 
Distribute Memory Aid and 
other Materials 
X 
 
 
 
 
 
Memory Aid Review (solicited 
symptoms)  
 
 
X 
X 
 
 
SAE, unsolicited symptoms, and 
Medical Services Utilizationh 
X 
 
X 
X 
X 
X 
  a Asthma clinical symptoms assessed using the PROSE questionnaire. 
 b Asthma control assessed using the c-ACT or the ACT, as appropriate by age. 
c See section 4.4 in the protocol, for categories of asthma severity. 
d All current medications taken within 28 days prior to signing the informed consent form and through Day 43 (Visit 6).       
e Will be performed on all post-menarchal females within 24 hours before vaccination.  
fThe highest of 3 peak flow measurements will be recorded.   
g Participants will be randomized 1:1 to LAIV4 or IIV4; stratified by asthma severity and age stratum 
 hMedical services utilization to include visits to doctor, urgent care, emergency room, hospitalization. 

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4.4  Assignment of Asthma Severity  
 
After the informed consent process, asthma severity will be assessed for each child according to the 
classification schema described on Table 2, section 4.4.1.    
4.4.1  Characterizing Asthma Severity 
Prior to randomization, it will be necessary to characterize asthma severity in each patient (see Table 2). 
For this study, we will only recruit participants with persistent asthma and will recruit within the full 
clinical spectrum of asthma severity described in Table 2 (mild, moderate, and severe).  For this study, we 
have created distinct categories of asthma severity levels, using existing literature and clinical judgement. 
Study staff should use these definitions at time of enrollment to identify if the children have mild-, 
moderate-, or severe-persistent asthma.  For the purposes of our study, the categories of asthma severity 
reflect the intensity of medical treatment needed to: 1) obtain optimal control of asthma, and 2) minimize 
impairment and risk resulting from asthma.  This categorization was adapted from the National Asthma 
Education and Prevention Program Expert Panel Report 3 that was issued in September 2011 and the 
associated Quick Reference Guide 
https://www.nhlbi.nih.gov/sites/default/files/media/docs/asthma_qrg_0_0.pdf)24  
 
Table 2: Asthma severity categories and prescription long-acting controller medications* 
for children with persistent asthma, aged 5-17 years 
Classification of  Asthma Severity 
Treatment of Persistent Asthma 
Mild Persistent 
Moderate Persistent 
Severe Persistent 
Low-dose ICS 
OR 
Montelukast 
OR 
Cromolyn sodium 
Low-dose ICS + Montelukast 
OR 
Low-dose ICS + LABA 
OR 
Medium-dose ICS 
 
 
Medium-dose ICS + Montelukast or 
LABA 
OR 
Any High-dose ICS 
OR 
Omalizumab/Xolair 
OR 
Mepolizumab/Nucala 
OR 
Chronic systemic steroids 
 
   *Controller medications include inhaled corticosteroids, oral corticosteroids, leukotriene receptor 
antagonists, long-acting beta agonists, and biologics. 
 
 
Abbreviations: LABA: long-acting beta-agonist; ICS: inhaled corticosteroids 

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4.5  Baseline demographic and health data  
 
All patients enrolled in the study will have baseline demographic and clinical data obtained from their 
parents/legal guardian at the time of enrollment and clarified with available medical records if necessary. 
These data will include age, gender, height, weight, BMI, allergy history, conditions for which the child 
takes prescribed or over-the-counter medications or supplements, and the list of medications or 
supplements.  If these data are not available from the clinic record, they will be obtained from the 
parent(s) or legal guardian(s).  
 
4.6  Individual Peak Expiratory Flow Rate (PEFR) Evaluations 
 
Participants will be trained on the “at home” performance of PEFR using a digital hand held device 
purchased by study funds and that participants will get to keep after completing the study. The device is 
easily learned, and it can provide an objective measure of control of asthma symptoms. Typically, a 
participant’s PEFR is measured while standing by the highest of 3 efforts. These measurements should be 
completed in the evening, before taking daily controller medication, to minimize variations that may be 
influenced by diurnal changes. Additionally, the PEFR maneuver should be attempted after completion of 
the two surveys that assess asthma control (c-ACT/ACT and PROSE) to avoid bias in the recording of 
daily symptoms. All efforts will be made to minimize variation in technique; training in proper digital 
peak flow meter use will be accomplished at study enrollment and reviewed at each study call.  
 
For this study, all sites will provide participants with a digital peak flow meter. This device has an 
automatic memory for peak flow measurements and each entry is marked with a time stamp; thus, 
participants will be instructed to record their daily PEFR data measurements on their memory aid until 
day 15.25,26  
 
4.7  Vaccine Delivery 
 
Only U.S.-licensed vaccines will be used in this study. These vaccines will be used according to the 
approved FDA package insert. The vaccines will be obtained from the study site pharmacies and will be 
administered by a licensed provider (RN, NP, PA, MD) from the study team. Both of the vaccines will be 
quadrivalent. The summaries from the package inserts of the two proposed vaccines are shown below.  
The influenza vaccines formulated for use during the 2018-2019 or 2019-2020 influenza season shall be 
used in this study for the respective season. Vaccines will be administered in a manner that is consistent 
with ACIP General Best Practice Guidelines for Immunization.27  
4.7.1  FluMist® Quadrivalent (Influenza Vaccine Live, Intranasal)  
FluMist® Quadrivalent is a vaccine indicated for active immunization for the prevention of influenza 
disease caused by influenza A subtype viruses and type B viruses contained in the vaccine. FluMist® 
Quadrivalent is approved for use in persons 2 through 49 years of age for intranasal administration by a 
healthcare provider.10   FluMist® Quadrivalent is not contraindicated for asthmatics, although persons of 
any age with asthma may be at increased risk of wheezing following the administration of this vaccine. In 

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the United States there is only one licensed formulation of live attenuated influenza vaccine (LAIV4; 
FluMist® Quadrivalent; AstraZeneca), and this will be used in all sites for the study.   
4.7.2  Fluzone® Quadrivalent Influenza Vaccine (suspension for intramuscular injection)  
Fluzone® Quadrivalent influenza vaccine (IIV4; Sanofi Pasteur) is a vaccine indicated for active 
immunization for the prevention of influenza disease caused by influenza A subtype viruses and type B 
viruses contained in the vaccine.28  Fluzone® Quadrivalent is approved for use in persons 6 months of age 
and older for intramuscular administration by a healthcare provider.  There is no precaution or 
contraindication against using Fluzone® Quadrivalent in persons with asthma.   In the event of lack of 
availability of Fluzone® Quadrivalent, another U.S.-licensed age-appropriate quadrivalent IIV product 
may be used according to the FDA package insert.29  
4.7.3  Seasonal Influenza Vaccine Single and 2-Dose Considerations for Participants aged 5-8 years 
Evidence from several studies indicates that children aged 6 months through 8 years require 2 doses of 
influenza vaccine (administered a minimum of 4 weeks apart) during their first season of vaccination for 
optimal protection.1   For children aged 5-8 years, the ACIP recommends 2 doses of seasonal influenza 
vaccine, administered at least 4 weeks apart, if they have not previously received 2 or more total doses of 
trivalent or quadrivalent influenza vaccine before July 1 of the current influenza season. For purposes of 
this study, July 1, 2018 would be used as the cutoff date for the 2018-2019 influenza season, and July 1, 
2019 would be used as the cutoff date for the 2019-2020 influenza season. The two doses need not to 
have been received during the same season or consecutive seasons. See Fig 2, (Influenza vaccine dosing 
algorithm for children aged 6 months through 8 years- Advisory Committee on Immunization Practices, 
United States, 2018.). 20  If a child needs two doses, it is acceptable for one dose to be LAIV4 and the 
other dose to be IIV3 or IIV4.  
 
Among participants 5 through 8 years otherwise eligible for enrollment into this study, Vanderbilt, 
Cincinnati, and Duke will assess during the pre-enrollment process and at the time of enrollment whether 
one or two doses of seasonal influenza vaccine is recommended for each of these potential study 
participants. For study participants in the 5-to-8year age category who are recommended to receive two 
doses of seasonal influenza vaccine during 2018-2019 or 2019-2020 influenza seasons, the following 
guidance will be used:   
• 
For those receiving dose #1 of influenza vaccine at Visit #1 during the study, the parent(s) or legal 
guardian(s) will be educated to seek the second dose from their usual healthcare provider; 
administration of the second dose will not be a study procedure. Study staff may facilitate, but will 
not be responsible for, making the appointment for the child to receive the second dose of the 
seasonal influenza vaccine at the healthcare provider office.  The parent(s) or legal guardian(s) must 
also be informed that the child would be eligible to receive Dose #2 beginning 4 weeks after Dose #1, 
but that the study will request that Dose #2 be administered after Day #43 to allow for the study to 
assess asthma symptoms during a complete 6-week timeframe after the vaccination. If during the 
study a parent(s) or legal guardian(s) changes their mind, and the child receives the second dose 
before day #43, the parent or legal guardian will be instructed to inform the study staff.  In addition, if 
there is widespread circulation of influenza virus in the local community at the time of enrollment (as 
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to postpone Dose #2 will be removed.  In 74% of influenza seasons from 1982–83 through 2015–16, 
peak influenza activity did not occur until January or later, and in 59% of seasons, the peak was in 
February or later.1  
• 
For children aged 5-8 years who have already received dose #1 during the 2018-2019 or 2019-2020 
influenza seasons before enrollment in this study, and who are recommended to receive Dose #2, 
study staff will ensure that at least 4 weeks have elapsed since Dose #1 before administering Dose #2 
during this study.  Study staff will document if Dose #1 or Dose #2 was administered during this 
study (at Visit #1) 
 
Figure 2: Influenza vaccine dosing algorithm for children aged 6 months through 8 years- 
Advisory Committee on Immunization Practices, United States, 2018. [Note: This 
recommendation is anticipated to be similar (using the July 1, 2019 cutoff) for the 2019-
2020 season]  
 
The seasonal influenza vaccine (quadrivalent live attenuated influenza vaccine or quadrivalent inactivated 
influenza vaccine) will be administered at baseline (Day 1 of study) according to the study randomization 
scheme.   
  4.8  Monitoring Vaccine Safety in the First 15 Days 
 
On the vaccination day and for the next 14 days post-vaccination (until day 15), all participants will be 
monitored daily by their parent(s) or legal guardian(s) and the information will be recorded using memory 
aids provided at the enrollment visit. Daily reactogenicity, including measurement of nighttime 
awakening, and unscheduled albuterol use and two validated questionnaires will be completed (c-
ACT/ACT and PROSE).  PROSE will be assessed at baseline (Day 1) and on Day 15. 
FIGURE 2. Influenza vaccine dosing algorithm for children aged 6 months through 8 years — 
Advisory Committee on Immunization Practices, United States, 2018.  
 
Source: Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on 
Immunization Practices-United States, 2018-19 Influenza Season MMWR Recomm Rep. 2018 Aug 24;67(3):1-20 

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In addition to the two questionnaires above, several predefined events that could occur after vaccine 
administration will also be recorded for 14 days after vaccination (through day 15). These will include 
fever (oral temperature ≥100.4°F), asthma symptoms, and other respiratory and systemic symptoms. 
Medication receipt, new prescriptions for asthma medications, and any previously unscheduled healthcare 
utilization (medical office visits, ED visits, hospitalizations) will also be documented on the reaction 
form. To ensure compliance with the reaction assessment, parents will be called, emailed through 
REDCap, or receive text messages on Days 4, 8 and 15 by the study staff.  
 
On the day of vaccination and during the first 14 days (until day 15) after vaccination, if the participant 
reports an increase in their symptoms and an increase in the need for medications for their asthma, the 
family will be instructed to contact the study staff, so medical records can later be collected, if needed. If 
at any point a study participant is experiencing symptoms of any asthma exacerbation, the participant or 
their parent will be instructed to contact their primary care provider (PCP) and inform study staff of this 
encounter.   
 
4.9  Extended follow-up for days 16-43 
 
After the initial 15-day follow up after vaccination, there will be an extended surveillance period for 
safety assessment from day 16 after vaccination for a total of 42 days (Day 43). This will be 
accomplished by a telephone call, text messaging, or email through the REDCap system to the parents of 
the participants, depending on their preference and their availability, at day 29 and at day 44 to determine 
the status of asthma control. On Day 29, participants will be queried about concomitant medications, 
unsolicited symptoms, serious adverse events, and medical services utilization. On day 44, participants 
will be queried about concomitant medications, unsolicited symptoms, serious adverse events, and 
medical services utilization, as defined above. The c-ACT/ACT score will also be completed at day 44. 
 
During the extended follow up period, parents/legal guardian will be instructed to contact the study staff 
if the participant has an unscheduled medical visit for management of asthma symptoms or a new asthma 
medication prescribed. 
 
4.10  Adverse Events and Serious Adverse Events 
 
Adverse events (AEs) will be recorded on the memory aid and will include the need for new prescription 
or nonprescription medications for the control of asthma, an unscheduled healthcare provider visit or 
consultation within 42 days (until day 43) after vaccination, any other clinically significant event 
occurring at any point during the study period. Serious AEs (SAEs) will also be monitored through 42 
days (until day 43) after vaccination and will include events that result in death, were life threatening, 
result in participant hospitalization or prolongation of existing hospitalization, result in persistent or 
significant disability or incapacity. Additionally, important medical events that may not have resulted in 
death, were not life threatening, or did not require hospitalization might be considered SAEs when, 
according to appropriate medical judgment, they jeopardize the patient or participant and require medical 
or surgical intervention to prevent one of the outcomes listed above.  Medical records will be requested 
and reviewed to evaluate SAE and assess relatedness of SAEs to receipt of LAIV4 or IIV4 

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5  RISKS 
 
5.1  Vaccines 
 
All participants will receive the CDC Vaccine Information Statements (VIS) 
(https://www.cdc.gov/vaccines/hcp/vis/current-vis.html) before vaccination. With any medicine, 
including vaccines, there is a chance of reactions. These are usually mild and go away on their own, but 
serious reactions are also possible. Any medication or vaccine can cause a severe allergic reaction, 
including anaphylaxis. Such reactions from a vaccine are very rare, estimated at about 1 in a million 
doses, and would happen within a few minutes to a few hours after the vaccination. As with any 
medicine, there is a very small chance of a vaccine causing a serious injury or death. 
5.1.1  Inactivated Influenza Vaccine (IIV) 
ACIP routinely recommends IIV for children with asthma9,11,20 and risks after IIV would be expected to 
be no higher than those encountered through usual care. Most people who get a flu shot do not have any 
problems with it. Minor problems following a flu shot may include:  soreness, redness, or swelling where 
the shot was given, hoarseness, sore, red or itchy eyes, cough, fever, aches, headache, itching, fatigue. If 
these problems occur, they usually begin soon after the shot and last 1 or 2 days.  More serious problems 
following a flu shot can include the following: There may be a small increased risk of Guillain-Barré 
Syndrome (GBS) after inactivated flu vaccine. This risk has been estimated at 1 or 2 additional cases per 
million people vaccinated, primarily in adults.  This is much lower than the risk of severe complications 
from flu, which can be prevented by flu vaccine. Problems could happen after any injected vaccine: 
People sometimes faint after a medical procedure, including vaccination. Sitting or lying down for about 
15 minutes after vaccination can help prevent fainting and injuries caused by a fall. Some people get 
severe pain in the shoulder and have difficulty moving the arm where a shot was given. 
5.1.2  Live, attenuated influenza vaccine (LAIV) 
ACIP considers use of LAIV as a precaution for children aged ≥5 years with asthma.1 In addition to the 
usual risks as described in the VIS (https://www.cdc.gov/vaccines/hcp/vis/current-vis.html), children with 
asthma might experience higher rates of asthma exacerbations after LAIV than with IIV.9,11,20 Most 
people who get LAIV do not have any problems with it. Reactions to LAIV may resemble a very mild 
case of flu. Some of the most common symptoms that have been reported following LAIV in children and 
adolescents 2-17 years of age are runny nose, nasal congestion, sore throat, cough, fever, headache, 
muscle aches, wheezing, abdominal pain, vomiting, or diarrhea .10  
 
There is also the potential risk of loss of confidentiality about the information obtained as part of this 
study (see section 9). 
 
 

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6  REPORTING OF ADVERSE EVENTS 
 
Parent(s) or legal guardian(s) who at any time express any concern about symptoms or serious unsolicited 
events will be encouraged to follow up with their child’s health care provider. 
Serious adverse events (SAEs) will be reported to CDC and all participating IRBs according to 
institutional requirements. 
If indicated, adverse events will be reported to CDC’s Vaccine Adverse Event Reporting System 
(VAERS). The National Childhood Vaccine Injury Act requires healthcare providers to report: 
• 
Any adverse event listed by the vaccine manufacturer as a contraindication to further doses of the 
vaccine; or 
• 
Any adverse event listed in the VAERS Table of Reportable Events Following Vaccination 
(https://vaers.hhs.gov/docs/VAERS_Table_of_Reportable_Events_Following_Vaccination.pdf) 
[link accessed 5/2/2019) that occurs within the specified time period after vaccination. 
In addition, CDC encourages reporting of any clinically significant adverse event that occurs in a patient 
following a vaccination, even if there is uncertainty regarding if a vaccine caused the event. 
 
As noted in section 4.10, a SAE is an AE meeting one or more of the following criteria 
• 
Life-threatening illness  
• 
Death  
• 
Hospitalization - An event requiring inpatient hospitalization 
• 
Prolongation of existing hospitalization 
• 
Persistent or significant disability or incapacity 
 
Additionally, important medical events that may not have resulted in death, were not life threatening, or 
did not require hospitalization might be considered SAEs when, according to appropriate medical 
judgment, they jeopardize the patient or participant and require medical or surgical intervention to prevent 
one of the outcomes listed above.  These will be reported to the IRBs. SAEs will be assessed for 
relatedness to vaccine: related or not related.  
 
Participants who report severe solicited AEs or SAEs or express any concern about symptoms, and/or 
unsolicited events will be encouraged to follow up with their pediatrician or primary care provider. Severe 
solicited or unsolicited adverse events are those that prevent daily activity and/or require a doctor’s office 
visit or a missed day of school or daycare.  
 
 
 

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7  STUDY WITHDRAWAL AND DISCONTINUATION 
 
Participants may voluntarily withdraw their consent for study participation at any time and for any reason, 
without penalty. 
 
A participant may withdraw or be withdrawn from this study for any of the following reasons: 
• 
Medical disease or condition, or any new clinical findings for which continued participation, in 
the opinion of the site principal investigator or appropriate sub-investigator, would compromise 
the safety of the participant, or would interfere with the participant's successful completion of this 
study, or would interfere with the evaluation of responses. 
• 
As deemed necessary by the site principal investigator or appropriate sub-investigator for 
noncompliance or other reasons. 
• 
Participant withdrawal of consent. 
• 
Participant lost to follow-up. 
• 
Termination of this study. 
• 
New information becomes available that makes further participation unsafe. 
 
Participants may withdraw their consent for study participation at any time and for any reason, without 
penalty.  
 
7.1  Handling of Withdrawals 
 
Participants who withdraw from the study before randomization will be replaced. Participants who 
withdraw from the study after randomization will not be replaced. Every attempt should be made to 
collect all data specified by the protocol relative to study vaccine received up to the time of withdrawal. 
Data collected before withdrawal will still be used for analysis. 
  
7.2  Termination of Study  
 
This study may be terminated for safety concerns of the PI, CDC, or participating IRBs.  
 
 

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8  STATISTICAL CONSIDERATIONS 
 
8.1  Sample Size Calculations 
 
This study aims to enroll approximately 300 participants (at least 100 from Vanderbilt, at least 110 from 
Cincinnati, and at least 90 from Duke). We assume that the proportion of asthma exacerbations in 42 days 
(until day 43) after vaccination is 12% after LAIV4 and IIV4.4 We also assume that ~10% of the children 
may drop out, yielding a total sample of at least 270 (135 LAIV4 and 135 IIV4).   
 
We expect the proportion of asthma exacerbation in LAIV4 (experimental group) will be at least as high 
as IIV group (control group).  The power estimate is shown below, given delta of 10% and one-sided 
alpha is set at 5% level. 
     
Proportion of asthma 
exacerbation in control 
IIV4 group (pc) 
Proportion of asthma 
exacerbation in LAIV4 
experimental group (pe) 
Estimated power to reject 
H0: pe – pc>=10% 
12% 
12% 
81.1% 
 
The null hypothesis will be rejected (and delta margin non-inferiority claimed) when the upper bound of 
the 95% one-sided confidence interval for the PE-PC is less than 10%.  IBM SPSS SamplePower 
software version 3.0.1 was used for the power calculation which was not adjusted for stratifying by site. 
 
8.2  Analysis plan 
  
Descriptive analyses will be summarized for continuous variables with mean, standard deviation, median, 
and interquartile range. Categorical variables will be summarized with frequencies and percentages. 
Explanatory figures will be generated to evaluate the data distribution.  Comparisons of demographic 
characteristics between LAIV4 and IIV4 groups will be conducted using Pearson Chi-square and 
Wilcoxon tests appropriately.  
 
We will prepare three datasets for analyses populations for main analysis of the primary and secondary 
objectives.  These are defined below. 
 
Intent-to-Treat (ITT) Population:  
 
The ITT Population includes any participant that was enrolled, randomized into the study, and received a 
study vaccine at Visit 1.   
 
Per Protocol Population for 43 Days:  
 
The Per Protocol Population for 43 days is a subset of the ITT Population.  This is defined as all 
participants who were randomized, vaccinated, completed study procedures through day 43, had no 
protocol violations that are likely to affect the objectives, and did not receive a second dose of influenza 
vaccine before day 43.   

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Per Protocol Population for 15 Days   
 
The Per Protocol Population for 15 days is a subset of the ITT Population.  This is defined as all 
participants who were randomized, vaccinated, completed study procedures through day 15, and have no 
protocol violations that are likely to affect the objectives.  
 
The Per Protocol population for 43 days is the primary analysis population for the Primary Objective. 
Statistical analyses for the Primary Objective will be performed for the ITT population and the Per 
Protocol for 43 days, or the ITT Population only if no participants are excluded from the Per Protocol 
Population.  The Per Protocol population for 15 days is the primary analysis population for the Secondary 
Objectives. Statistical analyses for the Secondary Objectives will be performed for the ITT population 
and Per Protocol population for 15 days, or the ITT Population only if no participants are excluded from 
the Per Protocol Population.  The list of major protocol violations for analysis will be provided in the 
Statistical Analysis Plan (SAP).  
 
In the ITT and Per Protocol populations, participants will be analyzed according to randomization 
assignment, rather than treatment group.  If applicable, sensitivity analyses on primary and secondary 
objectives will be done on datasets defined by treatment group.  For example, if a participant was 
assigned to LAIV4 and inadvertently received IIV4 that participant would be reassigned to the IIV4 
treatment group in the sensitivity analyses. 
 
Adjustments for enrollment site and/or other covariates for study objectives will be described in the 
comprehensive Statistical Analysis Plan (SAP). The analysis methods for the exploratory objectives, as 
well as sensitivity analyses, will be also be detailed in the SAP.  
 
All analyses will be performed using R 3.5.0 (r-project.org), SAS version 9.4, or STATA version 15, or 
updated software from these programs.  
8.2.1  Primary Objective  
1. To compare proportions of asthma exacerbations during the 42 days (until day 43) after LAIV4 
versus IIV4 in children with asthma aged 5-17 years.  
 
The hypothesis for this primary objective is that the proportion of asthma exacerbations after LAIV4 is 
non-inferior to the proportion of asthma exacerbations after IIV4 (proportion of asthma exacerbations is 
NOT higher in the LAIV4 group vs. the IIV4 group). 
8.2.2  Primary Outcome Measure 
1. Proportions of asthma exacerbations in recipients of LAIV4 and IIV4 during the 42 days post-
vaccination (until day 43).  
 
The asthma exacerbation proportion within 42 days (until day 43) post-vaccination will be calculated for 
children receiving LAIV4 or IIV4 influenza vaccine.  For this calculation a child with an asthma 

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exacerbation (as defined earlier in the protocol) on one or more days during day 1-43 would be 
considered to have had an asthma exacerbation (dichotomous yes or no).  We propose a one-sided test for 
non-inferiority of asthma exacerbation in children receiving LAIV4 vs. children receiving IIV4.  More 
precisely, we hope to reject the null hypothesis H0 indicating a higher proportion of children with asthma 
exacerbation (above an acceptable margin DELTA=10%) in the experimental (LAIV4) group as 
compared to the control (IIV4) group. Namely, PE is the true probability of event (asthma exacerbation) 
in the experimental group, PC is the true probability of event in the control group, and DELTA indicates 
maximum clinically acceptable absolute increase in the probability of event in the experimental group 
over probability of event in the control group. We hope to reject: H0:  PE >= PC + DELTA in favor of 
alternative hypothesis H1: PE < PC + DELTA.  The null hypothesis H0 will be rejected (and DELTA 
margin non-inferiority claimed) when the upper limit of the 95% one-sided confidence interval for the 
PE-PC is less than DELTA. More explicitly, if pe is the estimated event proportion in the experimental 
group; pc is the estimated event proportion in the control group; ne is the number of children in the 
experimental group; and nc if the number of children in the control group, then H0 is rejected if 
(1
)
(1
)
(
)
(0.95)
pe
pe
pc
pc
pe
pc
z
DELTA
ne
nc


−
−
−
+
+
<






 
8.2.3  Secondary Objectives and Secondary Outcome Measures (SOM)  
1. The first secondary objective (SO 1) is to compare the proportion of participants with asthma 
exacerbations during the 14 days (until day 15) after receipt of LAIV4 or IIV4.  
 
Outcome measure:  Comparison of the proportion of participants experiencing an 
asthma exacerbation during the 14 days after LAIV4 vs. IIV4. 
 
The analysis is similar to primary objective 1 using a one-sided non-inferiority test with 
the alpha level set at 0.05 and non-inferiority margin of 10% though asthma exacerbation 
proportions during the 14 days post-vaccination is the outcome. 
 
2. The second secondary objective (SO 2) is to compare the proportion of participants with asthma 
symptoms and unscheduled albuterol use during the 14 days after receipt of LAIV4 or IIV4.   
 
Outcome measures:   
 
SOM 2a: Proportions of participants with asthma symptoms of cough after LAIV4 vs. 
IIV4 during the 14 days post-vaccination. 
 
SOM 2b: Proportions of participants with asthma symptoms of wheezing after LAIV4 vs. 
IIV4 during the 14 days post-vaccination. 
 
SOM 2c: Proportions of participants with asthma symptoms of tightness in chest after 
LAIV4 vs. IIV4 during the 14 days post-vaccination. 
 

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SOM 2d: Proportions of participants with asthma symptoms of nighttime awakening after 
LAIV4 vs. IIV4 during the 14 days post-vaccination. 
 
SOM 2e: Proportions of participants with unscheduled albuterol use to treat asthma 
symptoms after LAIV4 vs. IIV4 during the 14 days post-vaccination. 
Proportions of participants with each asthma symptom (yes or no) along with 
unscheduled albuterol use to treat asthma symptoms (yes or no) will be compared 
between two treatment groups using Chi-square tests.  Proportions and difference of 
proportions between two treatment groups will be reported along with their 95% CIs.  No 
adjustments will be made to the alpha level (two-sided alpha=0.05) for this secondary 
objective. 
 
3. The third secondary objective (SO 3) is to compare the proportion of participants who experience a 
clinically significant decrease in Peak Expiratory Flow Rate (PEFR) from baseline during the 14 days 
after receipt of LAIV4 or IIV4. 
 
Outcome measure:  Proportions of participants that experience a clinically significant 
decrease in peak flow measurement from baseline (≥ 20% in PEFR from baseline) after 
LAIV4 vs. IIV4 during the 14 days post-vaccination 
 
Proportions of participants with a clinically significant (≥ 20%) decrease in PEFR from 
baseline (yes or no) will be compared between two treatment groups using a Chi-square test.  
Proportions and difference of proportions by two treatment groups will be reported along 
with their 95% CIs.   No adjustments will be made to the alpha level (two-sided alpha=0.05) 
for this secondary objective. 
 
 

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9  PRIVACY AND CONFIDENTIALITY ISSUES  
 
Participant confidentiality is strictly held in trust by the site principal investigators, other study personnel, 
the sponsor, and their agents.  Participants will have code numbers and will not be identified by name.  
 
The study protocol, documentation, data, and all other information generated will be held in strict 
confidence.  No information concerning this study or the data will be released to any unauthorized third 
party without prior written approval of the sponsor. 
All information provided by the sponsor and all data and information generated by the participating as 
part of this study (other than a participant’s medical records) will be kept confidential by the site principal 
investigators and other study personnel to the extent permitted by law. This information and data will not 
be used by the site principal investigator or other study personnel for any purpose other than conducting 
this study.  These restrictions do not apply to: (1) information which becomes publicly available through 
no fault of the site principal investigator or other study personnel; (2) information which is necessary to 
disclose in confidence to an IRB solely for the evaluation of this study; (3) information which is 
necessary to disclose in order to provide appropriate medical care to a study participant; or (4) study 
results which may be published.  
A Certificate of Confidentiality from the Centers for Disease Control and Prevention (CDC) covers this 
study.  Under this Certificate, the researchers may not disclose or use information or documents that may 
identify participants in any legal, administrative, legislative, or other action, unless the participant has 
consented for this use or the information is required to be reported by federal, state or local law such as 
child abuse or some infectious diseases. 
 
 

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10  DATA HANDLING AND RECORDS RETENTION 
 
Study records and reports, including, but not limited to, electronic case report forms (eCRFs), source 
documents, informed consent forms, laboratory test results, and medication inventory records, shall be 
retained locally by each site in accordance with institutional record keeping requirements.  Across all 
sites, records will be retained for a minimum of 3 years after the study is closed, as is required under 45 
CFR 46.115(b). 
 
10.1  Data collection and 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 REDCap platform, will be used to design study forms, including 
the memory aid forms, and short customized questionnaires to collect information from study 
participants. This system will be used by Vanderbilt, Cincinnati and Duke for data management.  All 
electronic linkages will fulfill regulations for protection of human participants and requirements to 
minimize the risk of breach of confidentiality. After initial set-up, the workload required for electronic 
data collection will be substantially reduced (description of REDCap resources below).30 The Vanderbilt, 
Cincinnati and Duke investigators have previously used the REDCap system for collection and analysis 
of large quantities of data. Participants’ parent(s) or legal guardian(s) will fill out their paper memory aid 
and will be contacted via phone calls, emails, and/or a text messages according to the visit schedule in 
section 4.3.  The data will be entered by study personnel onto REDCap. All study-related documents 
containing protected health information, e.g. enrollment logs, case report forms, will be maintained in 
secure research offices at Vanderbilt, Cincinnati and Duke, respectively, which are accessible to research 
staff only.  
10.1.1  Vanderbilt Research Electronic Data Capture (REDCap)  
Investigators within the NIH-funded Clinical and Translational Research Unit at Vanderbilt have 
developed REDCap, to collect and manage data for diverse clinical and translational research studies.30 
REDCap was designed around the concept of giving research teams an easy method to specify project 
needs and rapidly develop secure, web-based applications for collection, management and sharing of 
research data. REDCap accomplishes these key functions through use of a single study metadata table 
referenced by presentation-level operational modules. Based on this abstracted programming model, 
databases are developed in an efficient manner with little resource investment beyond the creation of a 
single data dictionary. The concept of metadata-driven application development is well established, and 
the critical factor for successful data collection lies in creating a simple workflow methodology allowing 
research teams to autonomously develop study-related metadata in an efficient manner.  REDCap 
includes secure institutional data hosting and full audit-trails in compliance with HIPAA security 
requirements. The REDCap Consortium is comprised of 647 active institutions, including CCHMC and 
Duke Health Technology Solutions. 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 

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link the baseline data, in an automated database family, to perform data cleaning and data quality 
assurance efficiently, and to design analytical datasets for the analysis of the project data.  
 
Periodic data enrollment audits will be conducted through the recruitment period to help monitor study 
progress.  
10.1.2  Data cleaning and data quality assurance 
To maximize data cleaning and data quality assurance, built-in filters and checks for consistency of the 
data including range and limit checks and branching logic and pull-down menus to limit choices for 
categorical variables to a pre-specified list will be 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 in the Department of Biostatistics with secured password-
protected computers at Vanderbilt University. Data cleaning check and error reports will be generated on 
a regular basis for all sites.   
10.1.3  Role of the CDC Investigators in the Project 
This study is funded by a CDC contract with Vanderbilt University, Cincinnati Children’s Hospital 
Medical Center and Duke University as Task Orders in the CISA Project Contract. Vanderbilt University 
(C. Buddy Creech and Andrew Sokolow) will oversee the overall study and direct activities at Vanderbilt 
University.  Duke University (Emmanuel (Chip) Walter and Amy Stallings) will contribute participants 
and direct activities at Duke, and Mary Staat and Carolyn Kercsmar will contribute participants and direct 
activities at Cincinnati. CDC personnel will collaborate with the three study sites to develop the protocol, 
conduct the study, ensure the study is aligned with CDC public health priorities, and analyze the data and 
disseminate the results. CDC may receive access to coded data. 
 
 
 

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11  ETHICS AND PROTECTION OF HUMAN SUBJECTS 
 
11.1  Ethical Standard 
The site principal investigators will ensure that this trial is conducted in full conformity with principles of 
the Belmont Report:  Ethical Principles and Guidelines for the Protection of Human Subjects of Research 
of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral 
Research (April 18, 1979) and codified in 45 CFR 46 and ICH E6; 62 Federal Regulations 25691 (1997), 
if applicable.  The site principal investigator’s Institution will hold a current Federal Wide Assurance 
(FWA) issued by the Office of Human Research Protection (OHRP) for federally funded research. 
11.2  Institutional Review Board 
Prior to enrollment of participants into this trial, the approved protocol and informed consent-parental 
permission documents will be reviewed and approved by the appropriate IRB.  
11.3  Informed Consent Process 
11.3.1  Parental Permission  
The site principal investigator or designee will choose participants in accordance with the eligibility 
criteria detailed in Section 3.  Before any study procedures are performed, the investigators must obtain 
and document the permission of the child’s parent(s) or legal guardian(s), in accordance with the 
requirements of 45 CFR 46 and the local IRB. 
Informed consent is a process that is initiated prior to an individual agreeing to participate in a trial and 
continuing throughout the individual’s trial participation.  Before any study procedures are performed, 
participants’ parent(s) or legal guardian(s) will receive a comprehensive explanation of the proposed 
study procedures and study intervention, study products (influenza vaccines), including the nature and 
risks of the trial, alternate therapies, any known AEs, and the other elements that are part of obtaining 
proper informed consent.  Participants’ parent(s) or legal guardian(s) will also receive a detailed 
explanation of the proposed use and disclosure of their protected health information.  Participants’ 
parent(s) or legal guardian(s) will be allowed sufficient time to consider participation in the study, after 
having the nature and risks of the study explained to them, and have the opportunity to discuss the trial 
with their family, friends or legally authorized representative or think about it prior to agreeing to 
participate. 
Parental permission forms describe in detail the study intervention, study products, study procedures, 
risks and possible benefits that are given to participants. Parental permission forms will be IRB-approved 
and the participant’s parent(s) or legal guardian(s) will be asked to read and review the appropriate 
document.  Upon reviewing the appropriate document, the site principal investigator (or designee) will 
explain the research study to participants and their parent(s) or legal guardian(s) and answer any questions 
that may arise.  If the participant’s parent(s) or legal guardian(s) agrees, he, she, or they will be asked to 
sign the parental permission document.  Written documentation of parental permission is required prior to 

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starting any study procedures or interventions being done specifically for the trial, including 
administering study product (seasonal influenza vaccine). The parent(s) or legal guardian(s) will be given 
a copy of all parental permission forms that they sign. 
By signing the parental permission form, parent(s) or legal guardian(s) give permission on behalf of their 
children to participate in all aspects of the study. 
The rights and welfare of participants will be protected by emphasizing to participants that the quality of 
their medical care will not be adversely affected if they decline to participate in or withdraw from this 
trial. 
11.3.2  Assent Process  
This study includes children aged 5 through 17 years. Assent will be obtained following local IRB 
policies and standard practice for obtaining and documenting assent.  During the consent/assent process, 
study staff will discuss the study with both the parent and child. For children who require assent based on 
local IRB policies, study staff will actively solicit the assent (affirmative agreement) of the child.  A 
child’s failure to object will not will not be sufficient to demonstrate assent. 
 
Vanderbilt 
Cincinnati  
Duke 
5 and 6 year olds: a simple 
script will be read describing the 
study. Assent will not be 
obtained 
 
 
7-17 year olds: written assent 
will be obtained using an assent 
form. The assent process 
includes reading the assent form 
and engaging the parent and 
participant in a discussion about 
the study.   
 
 
 
5 year olds: assent will not be 
obtained 
 
 
 
6-10 year olds: verbal assent 
will be included as part of 
obtaining parental permission. A 
verbal assent script will be used 
to describe the study to the child 
 
 
 
11-17 year olds: written assent 
will be obtained using an assent 
form 
5 year olds: assent will not be 
obtained 
 
 
 
6-11 year olds: verbal assent 
will be included as part of 
obtaining parental permission. A 
verbal assent script will be used 
to describe the study to the child  
 
 
 
12-17 year olds: written assent 
will be included as part of 
obtaining parental permission.  
They will be asked for written 
assent during the informed 
consent discussion process with 
the parent and child. 
 
 
 
 

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12     REFERENCES   
 
1. 
Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and Control of Seasonal Influenza with 
Vaccines: Recommendations of the Advisory Committee on Immunization Practices - United 
States, 2017-18 Influenza Season. MMWR Recommendations and reports : Morbidity and 
mortality weekly report Recommendations and reports / Centers for Disease Control. 
2017;66(2):1-20. 
2. 
Association AL. Asthma & Children Fact Sheet. http://www.lung.org/lung-health-and-
diseases/lung-disease-lookup/asthma/learn-about-asthma/asthma-children-facts-sheet.html. 
Accessed February 15, 2016. 
3. 
National Health Interview Survey 2016 asthma data for children under age 18 years. 
https://ftp.cdc.gov/pub/Health_Statistics/NCHS/NHIS/SHS/2016_SHS_Table_C-1.pdf. Published 
2016. Accessed June 25, 2018. 
4. 
Fleming DM, Crovari P, Wahn U, et al. Comparison of the efficacy and safety of live attenuated 
cold-adapted influenza vaccine, trivalent, with trivalent inactivated influenza virus vaccine in 
children and adolescents with asthma. Pediatr Infect Dis J. 2006;25(10):860-869. 
5. 
Jain S, Kamimoto L, Bramley AM, et al. Hospitalized patients with 2009 H1N1 influenza in the 
United States, April-June 2009. N Engl J Med. 2009;361(20):1935-1944. 
6. 
CDC. Influenza vaccination coverage among persons with asthma--United States, 2005-06 
influenza season. MMWR Morb Mortal Wkly Rep. 2008;57(24):653-657. 
7. 
CDC. Vaccination coverage among persons with asthma -- United States, 2010-2011 influenza 
season. MMWR Morb Mortal Wkly Rep. 2013;62(48):973-978. 
8. 
Simon AE, Ahrens KA, Akinbami LJ. Influenza Vaccination Among US Children With Asthma, 
2005-2013. Academic pediatrics. 2016;16(1):68-74. 
9. 
Fiore AE, Uyeki TM, Broder K, et al. Prevention and control of influenza with vaccines: 
recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR 
Recommendations and reports : Morbidity and mortality weekly report Recommendations and 
reports / Centers for Disease Control. 2010;59(Rr-8):1-62. 
10. 
FluMist® Quadrivalent Package Insert. 
https://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM294
307.pdf. Accessed June 25, 2018. 
11. 
Grohskopf LA, Olsen SJ, Sokolow LZ, et al. Prevention and control of seasonal influenza with 
vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP) -- 
United States, 2014-15 influenza season. MMWR Morb Mortal Wkly Rep. 2014;63(32):691-697. 
12. 
Belshe RB, Edwards KM, Vesikari T, et al. Live attenuated versus inactivated influenza vaccine 
in infants and young children. N Engl J Med. 2007;356(7):685-696. 
13. 
Redding G, Walker RE, Hessel C, et al. Safety and tolerability of cold-adapted influenza virus 
vaccine in children and adolescents with asthma. Pediatr Infect Dis J. 2002;21(1):44-48. 
14. 
Turner PJ, Southern J, Andrews NJ, Miller E, Erlewyn-Lajeunesse M. Safety of live attenuated 
influenza vaccine in atopic children with egg allergy. J Allergy Clin Immunol. 2015;136(2):376-
381. 
15. 
Bergen R, Black S, Shinefield H, et al. Safety of cold-adapted live attenuated influenza vaccine in 
a large cohort of children and adolescents. Pediatr Infect Dis J. 2004;23(2):138-144. 
16. 
Piedra PA, Gaglani MJ, Riggs M, et al. Live attenuated influenza vaccine, trivalent, is safe in 
healthy children 18 months to 4 years, 5 to 9 years, and 10 to 18 years of age in a community-
based, nonrandomized, open-label trial. Pediatrics. 2005;116(3):e397-407. 
17. 
Gaglani MJ, Piedra PA, Riggs M, Herschler G, Fewlass C, Glezen WP. Safety of the intranasal, 
trivalent, live attenuated influenza vaccine (LAIV) in children with intermittent wheezing in an 
open-label field trial. Pediatr Infect Dis J. 2008;27(5):444-452. 

CISA Protocol LAIV-Asthma 
 
Version 5.0 
03July 2019  
 
 
41 
 
18. 
Ashkenazi S, Vertruyen A, Aristegui J, et al. Superior relative efficacy of live attenuated 
influenza vaccine compared with inactivated influenza vaccine in young children with recurrent 
respiratory tract infections. Pediatr Infect Dis J. 2006;25(10):870-879. 
19. 
Duffy J, Lewis M, Harrington T, et al. Live attenuated influenza vaccine use and safety in 
children and adults with asthma. Annals of allergy, asthma & immunology : official publication of 
the American College of Allergy, Asthma, & Immunology. 2017;118(4):439-444. 
20. 
Grohskopf LA, Sokolow LZ, Olsen SJ, Bresee JS, Broder KR, Karron RA. Prevention and 
Control of Influenza with Vaccines: Recommendations of the Advisory Committee on 
Immunization Practices, United States, 2015-16 Influenza Season. MMWR Morb Mortal Wkly 
Rep. 2015;64(30):818-825. 
21. 
ACIP votes down use of LAIV for 2016-2017 flu season. 
https://www.cdc.gov/media/releases/2016/s0622-laiv-flu.html. Published 2016. Accessed June 
25, 2018. 
22. 
ACIP Presentation Slides: February 2018 Meeting. 
https://www.cdc.gov/vaccines/acip/meetings/slides-2018-02.html. Published 2018. Accessed June 
25, 2018. 
23. 
Grohskopf LA, Sokolow LZ, Fry AM, Walter EB, Jernigan DB. Update: ACIP 
Recommendations for the Use of Quadrivalent Live Attenuated Influenza Vaccine (LAIV4) - 
United States, 2018-19 Influenza Season. MMWR Morb Mortal Wkly Rep. 2018;67(22):643-645. 
24. 
NHLBI. Asthma Care Quick Reference: Diagnosing and Managing Asthma 
https://www.nhlbi.nih.gov/files/docs/guidelines/asthma_qrg.pdf. Published 2012. Accessed June 
25, 2018. 
25. 
Eigen H, Bieler H, Grant D, et al. Spirometric pulmonary function in healthy preschool children. 
American journal of respiratory and critical care medicine. 2001;163(3 Pt 1):619-623. 
26. 
Wang X, Dockery DW, Wypij D, Fay ME, Ferris BG, Jr. Pulmonary function between 6 and 18 
years of age. Pediatric pulmonology. 1993;15(2):75-88. 
27. 
Best Practices Guidance of the Advisory Committee on Immunization Practices (ACIP). 
https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html. Accessed June 25, 2018. 
28. 
Fluzone® Quadrivalent Package Insert. 
https://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM356
094.pdf. Accessed June 25, 2018. 
29. 
Vaccines Licensed for Use in the United States. 
https://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm093833.htm. 
Accessed June 25, 2018. 
30. 
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(2):377-381. 
 
 

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13     APPENDIX 
 
13.1 Figure A1.  Childhood Asthma Control Test (c-ACT) 
 
 
 

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13.2 Figure A2.  Asthma Control Test (ACT) 
  

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13.3 Figure A2.  Preventative Omalizumab or Step-Up Therapy For Severe Fall Exacerbations 
(PROSE) Questionnaire 
 

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