Clinical trial NCT02967393
Conditions: Asthmatic
Sponsor: Vanderbilt University Medical Center
Start date: 2016-10-10; Completion date: 2017-02-01
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to note whether a larger safety study using quadrivalent live attenuated influenza vaccine (LAIV4) versus quadrivalent inactivated influenza vaccine (IIV4)(FLUARIX®), would be feasible in children with persistent asthma. Half of the patients in this study will receive the FLUARIX® influenza vaccine, while the other half will receive a cell cultured quadrivalent inactivated influenza vaccine (ccIIV4)(Flucelvax®) being used as a surrogate for LAIV4.

Detailed description:
The association of an increased risk in wheezing following receipt of a live-attenuated influenza vaccine in children at least 2 years of age with a prior history of asthma or wheeze remains unclear.

The Centers for Disease Control (CDC) and Prevention's Clinical Immunization Safety Assessment (CISA) planned to address a data safety gap regarding use of LAIV4 vaccine in children with asthma by conducting a 3-site randomized, non-inferiority prospective study. The main goal was to compare the safety of LAIV4 versus IIV4 in children 5-11 years with persistent asthma during the 2016-2017 influenza season. CDC and the CISA study sites developed a protocol and associated materials, and were poised to begin enrollment early during the 2016-2017 influenza season. However, after the June 22, 2016 Advisory Committee on Immunization Practices (ACIP) vote recommending against use of LAIV4 during the 2016-2017 influenza season, CDC and study investigators decided to defer implementing a study using LAIV4 during the 2016-2017 influenza season. Investigators will reconsider initiating this study during the 2017-2018 influenza season if ACIP votes to reinstate LAIV4 use or new data become available; ACIP makes recommendations annually.

The planned LAIV4 study had unique features in its design that previously had not been implemented in vaccine safety studies, including: 1) enrolling a substantial proportion of children with moderate-severe asthma 2) using digital peak flow meters and 3) collecting clinical data through multiple, complementary, measures for 42 days after vaccination. To capitalize on progress made during development of the study protocol and associated documents and procedures, CISA is proposing to carry out a study at the three sites to assess the feasibility of recruiting, enrolling, retaining, and collecting clinical data on children 5-11 years with persistent asthma of varied levels of severity in an influenza vaccine safety study. Findings from this proposed feasibility study will facilitate improving the LAIV4 study in the future if it goes forward through the CISA Project or in another venue. In 2016-2017 season, FDA approved a new influenza vaccine for use in persons aged 4 years and older, Flucelvax® Quadrivalent (ccIIV4); ACIP incorporated this vaccine into its recommendations for the 2016-2017 influenza season. Therefore ccIIV4 will be used in place of LAIV4 for this feasibility study. There is no evidence that Flucelvax® increases the risk of wheezing in asthmatic children. The feasibility study also offers an opportunity to gain some additional descriptive safety data for this new vaccine in asthmatic children.

Arms: arm 1: 0.5 mL intramuscular injection arm 2: 0.5 mL intramuscular injection
Interventions: intervention 1: ccIIV4 intervention 2: IIV4
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
1 
Feasibility study to assess the safety of quadrivalent, live attenuated influenza vaccine (LAIV4) 
versus quadrivalent inactivated influenza vaccine (IIV4) in children aged 5-11 years with persistent 
asthma of varied severity (cell culture quadrivalent IIV used as surrogate for LAIV4) 
 
 
Short Title: Influenza vaccine feasibility study in children with 
persistent asthma  
 
 
Centers for Disease Control & Prevention  
Clinical Immunization Safety Assessment (CISA) Project  
 
 
Lead Site Principal Investigator (PI): Kathryn M. Edwards, MD 
Lead Site Co-Investigator: Andrew G. Sokolow, MD 
 
Contributing Site PI: Emmanuel B. Walter, MD, MPH 
Contributing Site Co-Investigator: Amy P. Stallings, MD 
 
Contributing Site PI: Mary Staat, MD, MPH 
Contributing Site Co-Investigator: Carolyn Kercsmar, MD 
 
Centers for Disease Control and Prevention (CDC) PI: Theresa Harrington, MD, MPH&TM 
CDC Co-Investigator: Karen R. Broder, MD 
 
Multicenter Principal Investigator: 
Kathryn Edwards, MD 
Vanderbilt Vaccine Research Program 
 
Nashville, TN 37232 
Phone: 615-322-3078 
Fax: 615-322-2733 
Kathryn.Edwards@Vanderbilt.edu 
 
Protocol Version 1.0 
19 August 2016 
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 


CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
2 
regulatory requirements from the United States (US) Code of Federal Regulations (CFR), 45 CFR 
Part 46.      
                  
 
All study personnel with subject contact have completed Human Subjects Protection Training. 
 
 
 
 
 


CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
3 
Table of Contents 
 
1 
BACKGROUND ...................................................................................................................................... 5 
2 
FEASIBILITY STUDY OBJECTIVES .................................................................................................... 10 
2.1 
Study Objectives ........................................................................................................ 10 
Primary Objective ................................................................................................................. 10 
Secondary Objectives ........................................................................................................... 10 
2.2 
Study Outcome Measures ......................................................................................... 10 
Primary Outcome Measure .................................................................................................. 10 
Secondary outcome measures: ............................................................................................ 10 
3 
ELIGIBILITY CRITERIA ........................................................................................................................ 12 
3.1 
Inclusion Criteria ........................................................................................................ 12 
3.2 
Exclusion Criteria ....................................................................................................... 12 
3.3 
Characterizing Asthma Severity ............................................................................... 13 
4 
STUDY DESIGN AND PROCEDURES ................................................................................................. 15 
4.1 
Recruitment ................................................................................................................ 15 
Vanderbilt ............................................................................................................................. 15 
Cincinnati .............................................................................................................................. 15 
Duke 
16 
4.2 
Enrollment/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)] – Call/email ............................................................. 18 
4.3.3 
Visit 3 (Day 8 ± 2) – Call/email ................................................................................. 19 
4.3.4 
Visit 4 [Day 15 (- 1 through +2)] – Call/email .......................................................... 19 
4.3.5 
Visit 5 (Day 29 ± 2) – Call/email ............................................................................... 19 
4.3.6 
Visit 6 (Day 44 + 3) – Call/email ............................................................................... 19 
4.4 
Assignment of Severity ............................................................................................. 20 
4.5 
Baseline demographic data ...................................................................................... 20 
4.6 
Spirometry .................................................................................................................. 20 
4.7 
Individual Peak Expiratory Flow Rate (PEFR) Evaluations .................................... 20 
4.8 
Vaccine Delivery ......................................................................................................... 21 
Flucelvax® Quadrivalent ........................................................................................................ 21 
FLUARIX® Quadrivalent (Influenza Vaccine) Suspension for Intramuscular Injection .......... 21 
Seasonal Influenza Vaccine Dose 2 considerations for Subjects aged 5-8 years .................. 22 
4.9 
Monitoring Vaccine Safety in the First 15 Days ...................................................... 23 
4.10 
Extended follow-up for days 16-43 ........................................................................... 23 
5 
RISKS ................................................................................................................................................... 24 
5.1 
Vaccines ...................................................................................................................... 24 
5.2 
Inactivated Influenza Vaccine (IIV) ........................................................................... 24 
6 
REPORTING OF ADVERSE EVENTS .................................................................................................. 24 
7 
STUDY WITHDRAWAL/DISCONTINUATION ...................................................................................... 25 
7.1 
Handling of Withdrawals ........................................................................................... 25 
7.2 
Termination of Study ................................................................................................. 25 
8 
Statistical Analytic Plan ...................................................................................................................... 26 
Primary Objective ................................................................................................................. 26 
Primary Outcomes Measures ............................................................................................... 26 
Secondary Objectives ........................................................................................................... 26 


CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
4 
Secondary outcome measures ............................................................................................. 27 
9 
PRIVACY/CONFIDENTIALITY ISSUES ................................................................................................ 29 
10 
DATA HANDLING AND RECORDS RETENTION ................................................................................ 30 
10.1 
Data collection and management ............................................................................. 30 
Vanderbilt Research Electronic Data Capture (REDCap) ...................................................... 30 
Double data entry ................................................................................................................. 31 
Data cleaning and data quality assurance ............................................................................ 31 
Role of the CDC Investigators in the Project ........................................................................ 31 
11 
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................................................. 32 
11.1 
Ethical Standard ......................................................................................................... 32 
11.2 
Institutional Review Board ........................................................................................ 32 
11.3 
Informed Consent Process ....................................................................................... 32 
Informed Consent ................................................................................................................. 32 
Informed Consent/Assent Process ....................................................................................... 33 
12 
REFERENCES ...................................................................................................................................... 34 
APPENDIX .................................................................................................................................................... 36 
Figure A1. Asthma Control Chart for Children 5-11 years of age17 .................................... 36 
Figure A2. Daily Medication Steps for Persistent Asthma17 ............................................... 37 
Figure A3. Estimated Comparative Daily Dosages for Inhaled Corticosteroids23 ............ 38 
Schedule of Events ................................................................................................................. 40 
 
 
 
 


CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
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1 BACKGROUND 
 
Asthma, a chronic, inflammatory disease of the pulmonary airways, can be life-threatening if not adequately 
managed.1 According to the US National Health Interview Survey (NHIS), in 2012, 6.8 million children <18 
years (9.3%) had (current) asthma, with increased prevalence of asthma among older, compared with 
younger children [0-4 years (5.4%); 5-11 years (11.0%); 12-17 years (10.5%)].2 Children in economically 
disadvantaged families were also more likely to have asthma (13%) than children in families that were not 
disadvantaged (8%).2 Furthermore, children with asthma are more likely to require hospitalization for 
influenza, and to experience asthma exacerbations after influenza illness.3,4 Despite this, NHIS data for the 
2010-2011 influenza season revealed that influenza vaccination among children with asthma 2-17 years 
averaged almost 53%, up from 29% five years earlier, 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).5,6 The Advisory 
Committee on Immunization Practices (ACIP) designates asthma to be a ‘high-risk’ condition for which 
annual vaccination with the inactivated influenza vaccine (IIV) is recommended.7 In addition, due to the 
elevated morbidity and mortality associated with influenza virus infection (including pandemic influenza virus) 
in persons with asthma, the US Department of Health and Human Services’ Guidance on Allocating and 
Targeting Pandemic Influenza Vaccine notes that children with asthma are Tier 2 priority recipients (scale of 
Tier 1 highest to Tier 5 lowest) for receipt of pandemic influenza vaccine. 
 
Studies assessing the safety of live attenuated influenza vaccine (LAIV) in children with asthma 
Most studies conducted to date have suggested that LAIV is not associated with an increased risk of 
wheezing events after vaccination in children who are at least 2 years of age and that didn’t have a prior 
history of asthma or wheezing (Belshe).10  However, data regarding LAIV safety in persons with a history of 
asthma or wheeze are less clear, particularly among children with severe asthma.10-12  In an effort to address 
this important vaccine safety data gap, and to assess the safety of LAIV in subjects with asthma, several clinical 
trials have been conducted over the past decade. Redding and colleagues assessed the safety and tolerability of 
LAIV in children > 9 years of age with moderate to severe asthma.11 They enrolled 48 subjects into a randomized, 
double blind, placebo-controlled study and compared pre-study baseline to post-vaccination measurements of 
FEV1, peak flow, clinical asthma scores, and nighttime awakening scores. They found no difference in the primary 
outcome measure (% change in FEV1) or secondary outcomes (decrease in FEV1, reductions in peak flows, use 
of beta-adrenergic rescue medications, asthma exacerbations and clinical asthma symptom scores before and 
after vaccination) between the two groups. Bergen et al conducted a randomized, double blind, placebo-
controlled safety trial in 9689 healthy children age 12 months to 17 years 13 Enrolled children were followed 
for 42 days after each vaccination for all medically-attended events. 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.13  
 
Given these concerns regarding the possible triggering of asthma by LAIV, Piedra and colleagues conducted 
an open-label, non-randomized, community-based trial of LAIV in 11,906 children 18 months to 18 years of 
age over a four-year period; children were followed for 42 days post-vaccination.14 Investigators found no 
increase in asthma events during the 0 to 14 days after vaccination in children of any age group, and though 
they found a significantly increased risk for asthma events in children 18 months to 4 years during the 15 to 


CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
6 
42 days after vaccination (RR 2.85; 95% CI: 1.01-8.03), during the first year (only) of the study, after final 
analysis of all data, the authors concluded that LAIV was safe and not associated with an increase in asthma 
events in children who are younger than 5 years.14  
 
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.15 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.”15  
 
Finally, 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.3 Nearly 70% of children were on inhaled corticosteroids.  No significant differences were 
reported between the LAIV and trivalent inactivated influenza vaccine (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. 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.3  
 
ACIP recommendations for LAIV use in healthy children and children with asthma 
ACIP recommendations for LAIV use in healthy children aged ≥2 years have changed in recent years. During 
2007/08 through the 2013/14 influenza seasons, ACIP recommended that either live attenuated influenza 
vaccine (LAIV) or IIV could be used for these children.7 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.8 However, following this preferred recommendation, new data emerged suggesting that LAIV did not 
have superior efficacy over IIV.9 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.9   
 
In 2014, after completing a review of available evidence, ACIP also 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.8 However, for 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.8 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 didn’t have a prior history of asthma and wheezing.10 
However, data regarding LAIV safety in persons with a history of asthma or wheeze were less clear.10-12 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.11 There is even less information about the safety of quadrivalent LAIV (LAIV4) in persons with 
asthma when compared with trivalent LAIV.  
 
Since the 2013-14 influenza season, LAIV4 has been the only live influenza vaccine product available in the 
United States. ACIP recommendations specified that LAIV should not be used for, “Children aged 2 through 4 
years, who have asthma or who have had a wheezing episode noted in the medical record within the past 12 


CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
7 
months, or for whom parents report that a health care provider stated that they had wheezing or asthma 
within the last 12 months”.8 However, ACIP considered asthma in persons aged ≥5 years to be a “precaution” 
for the use of LAIV, leaving the vaccination decision to clinicians.9 Anecdotal experiences from front-line US 
pediatricians suggest that deciding whether or not to vaccinate children aged ≥5 years with asthma with 
LAIV4 may be difficult. Broadening the LAIV recommendation to include persons with asthma could have 
several advantages: ease of program implementation, especially in busy clinic or school-based vaccination 
settings; ease of implementation and greater options for influenza pandemic preparedness; and 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.  
 
ACIP interim guidance regarding use of LAIV4 for the 2016-2017 influenza season following the June 2016 
ACIP vote, and FDA information regarding FluMist® Quadrivalent (LAIV4) vaccine  
At the June 22, 2016 meeting, ACIP voted that “no live attenuated influenza vaccines (LAIV) should be used 
in any setting” during the 2016-2017 influenza season (http://www.cdc.gov/media/releases/2016/s0622-laiv-
flu.html). This interim recommendation resulted primarily from findings from two US-based observational 
studies. Data from the US Influenza Vaccine Effectiveness (VE) Network and from a US-based manufacturer 
(MedImmune) post-marketing study demonstrated that LAIV4 had lower vaccine effectiveness in youth 2-17 
years than IIV, and LAIV4 provided no statistically significant effectiveness against Influenza A (H1N1) during 
the 2015-2016 influenza season. According to the VE Network data, LAIV4 vaccine effectiveness against any 
influenza virus among children (2-17 years) was estimated at only 3 percent (95% confidence interval -49% - 
37%). In comparison, IIV had a VE estimate of 63 percent (95% confidence interval: 52% - 72%) against any 
influenza virus among children in this same age group.  
 
The US Food and Drug Administration (FDA) reviewed the data presented to ACIP and continues to find that 
the benefits of FluMist® Quadrivalent outweigh any potential risks. FDA has stated that specific regulatory 
action is not warranted at this time; as a result, LAIV4 remains a licensed vaccine in the United States. The 
FDA noted that though the CDC VE Network data did not demonstrate statistically significant effectiveness 
for all influenza strains combined, three other observational studies (MedImmune study; study from Finland; 
study from the United Kingdom) did demonstrate statistically significant effectiveness of FluMist® 
Quadrivalent against all influenza strains combined, ranging from 46% to 58% effectiveness. The FDA 
indicates that this level of overall effectiveness is considered comparable to vaccine effectiveness against 
vaccine-similar strains for both FluMist® and inactivated influenza vaccines in prior seasons. Reasons for 
discordant results among the studies, particularly between the two U.S. studies, are not clear but may include 
limitations inherent in observational studies. The FDA continues to work with MedImmune to understand the 
factors that may be contributing to the lower than expected effectiveness of FluMist® Quadrivalent.  
 
Clinical Immunization Safety Assessment (CISA) Project Proposed Feasibility Study with Flucelvax® 
Quadrivalent during 2016-2017 Influenza Season 
The Centers for Disease Control and Prevention’s Clinical Immunization Safety Assessment (CISA) planned 
to address a data safety gap regarding use of LAIV4 vaccine in children with asthma by conducting a 3-site 
randomized, non-inferiority prospective study. The main goal was to compare the safety of LAIV4 versus IIV 
in children 5-11 years with persistent asthma during the 2016-2017 influenza season. CDC and the CISA 
study sites developed a protocol and associated materials, and were poised to begin enrollment early during 
the 2016-2017 influenza season.  However, after the June 22, 2016 ACIP vote recommending against use of 


CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
8 
LAIV4 during the 2016-2017 influenza season, CDC and study investigators decided to defer implementing a 
study using LAIV4 during the 2016-2017 influenza season. Investigators will reconsider initiating this study 
during the 2017-2018 influenza season if ACIP votes to reinstate LAIV4 use or new data become available; 
ACIP makes recommendations annually.  
 
The planned LAIV4 study had unique features in its design that previously had not been implemented in 
vaccine safety studies, including: 1) enrolling a substantial proportion of children with moderate-severe 
asthma 2) using digital peak flow meters and 3) collecting clinical data through multiple, complementary, 
measures for 42 days after vaccination. To capitalize on progress made during development of the study 
protocol and associated documents and procedures, CISA is proposing to carry out a study at the three sites 
to assess the feasibility of recruiting, enrolling, retaining, and collecting clinical data on children 5-11 years 
with persistent asthma of varied levels of severity in an influenza vaccine safety study. Findings from this 
proposed feasibility study will facilitate improving the LAIV4 study in the future if it goes forward through the 
CISA Project or in another venue.  In 2016-2017 season, FDA approved a new influenza vaccine for use in 
persons aged 4 years and older, Flucelvax® Quadrivalent (ccIIV4); ACIP incorporated this vaccine into its 
recommendations for the 2016-2017 influenza season. Therefore ccIIV4 will be used in place of LAIV4 for 
this feasibility study. The feasibility study also offers an opportunity to gain some additional descriptive safety 
data for this new vaccine in asthmatic children.  
 
On May 23, 2016, the quadrivalent formulation of Flucelvax® Quadrivalent (ccIIV4) was approved for use in 
persons 4 to <18 years of age under the accelerated approval of biological products regulations (21 CFR 
601.40-46). Flucelvax® Quadrivalent (ccIIV4) is a non-egg, cell culture-based [Madin Darby Canine Kidney 
cells (MDCK)], non-adjuvanted, inactivated influenza 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. According to the package insert, Flucelvax® Quadrivalent is antibiotic-, preservative-, and latex-free. 
ACIP considers Flucelvax® an appropriate option for vaccination in persons aged 4 years and older.  Federal 
funding was provided to develop this non-egg based cell culture technology to allow for rapid scale-up of 
influenza vaccination production as needed to fulfill the needs during an influenza pandemic. Flucelvax® is 
the only FDA-licensed formulation of a non-egg-based influenza vaccine approved for use in children and 
adolescents.  
 
The safety of Flucelvax® Quadrivalent in children was evaluated in a randomized, double-blind, controlled 
study conducted in the US. The safety population included a total of 2332 children 4 through 17 years of age; 
1161 children 4 through 8 years of age and 1171 children 9 through 17 years of age. In this study, subjects 
received Flucelvax® Quadrivalent or one of the two formulations of Flucelvax® (trivalent) influenza vaccine 
(Flucelvax® Quadrivalent n=1159, TIV1c, n=593 or TIV2c n= 580). Children 9 through 17 years of age 
received a single dose of Flucelvax® Quadrivalent or a trivalent Flucelvax® formulation. Children 4 through 8 
years of age received one or two doses (separated by 4 weeks) of Flucelvax® Quadrivalent or a Flucelvax®  
trivalent formulation based on determination of the subject’s prior influenza vaccination history. The mean 
age of subjects who received Flucelvax® Quadrivalent was 9.6 years of age.  In children ≥4 through <18 
years of age, for the quadrivalent formulation, the most common injection-site reaction was pain (59%) and 
tenderness for subjects ≥4 to <6 years of age (55%). Most of the solicited local adverse events (AEs) had 
their onset from 6 hours to 2 days after the vaccination and were mild to moderate in severity. The most 
common solicited systemic adverse events in children >4 years to < 18 years, that occurred at rates >10% 


CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
9 
were myalgia, headache, fatigue, sleepiness and irritability. Fevers ≥38.0 °C occurred in 3% of subjects; one 
subject who received ccIIV4 had a febrile convulsion.  In children 4 through 17 years of age, serious adverse 
events (SAEs) were collected throughout the study duration (until 6 months after last vaccination) and were 
reported by 0.5%, of the subjects who received Flucelvax® Quadrivalent. None of the SAEs were assessed 
as being related to study vaccine.   
 
 
 


CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
10 
 
2 FEASIBILITY STUDY OBJECTIVES 
 
 
Primary Objective 
 
To assess the feasibility of conducting a randomized prospective safety study of LAIV4 versus  IIV4 
during the 42 days after vaccination in children aged 5-11 years with persistent asthma of varied 
severity (ccIIV4 will be used as a surrogate for LAIV4)  
 
Secondary Objectives 
 
1. To compare proportions of local and systemic reactogenicity events during the 14 days after ccIIV4 
versus IIV4 in children with asthma aged 5-11 years.  
2. To describe the unsolicited and serious adverse events in children receiving ccIIV4 and IIV during the 
42 days. 
3. To compare proportions of asthma exacerbations during the 14 days after ccIIV4 versus IIV4 in 
children with asthma aged 5-11 years.  
4. To compare proportions of asthma exacerbations during the 42 days after ccIIV4 versus IIV4 in 
children with asthma aged 5-11 years.  
5. To explore differences between the ccIIV4 and IIV4 groups regarding clinical asthma symptoms after 
vaccination and changes in asthma control before and after vaccination in children with asthma of 
varied levels of severity. 
 
 
Primary Outcome Measure 
 
1. Assess the feasibility of conducting a randomized prospective safety study of LAIV4 versus IIV4 
during the 42 days after vaccination in children with asthma (ccIIV4 will substitute for LAIV4 in this 
feasibility study).  
a. Qualitative information about best practices and lessons learned  
b. Quantitative Benchmarks (Table A1 Appendix) 
Secondary outcome measures:  
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)]”.17 For the purpose of 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 after 
influenza vaccination for which the patient seeks unscheduled medical attention (e.g., healthcare 


CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
11 
provider office or Emergency Department visit or hospitalization) or receives a new prescription for 
systemic corticosteroids.   
 
1. Proportion of subjects with solicited local and systemic reactogenicity events for 14 days after 
vaccination between recipients of ccIIV4 and IIV4.  
 
2. Description of nature and frequency of unsolicited and serious adverse events in children receiving 
ccIIV4 and IIV during the 42 days after vaccination with ccIIV4 and IIV4.  
 
3. Proportions of asthma exacerbations in recipients of ccIIV4 and IIV4 during the 14 days post-
vaccination. 
 
4. Proportions of asthma exacerbations in recipients of ccIIV4 and IIV4 during the 42 days post-
vaccination. 
 
5. Proportions of clinical symptoms after vaccination and changes in measurement of asthma control, 
before and after vaccination in children with asthma of varied levels of severity, between recipients of 
ccIIV4 or IIV4. This will be assessed through four measures (see methods for schedule):  
A. Proportions of subjects with asthma symptoms as assessed on memory aid (e.g., wheezing, 
nighttime awakenings, cough) during days 1 through 15  
B. Change in Peak Expiratory Flow Rate (PEFR) after vaccination from baseline (pre-vaccination) 
PEFR  
C. Change in Childhood Asthma Control Test (cACT) scores after vaccination from baseline (pre-
vaccination) cACT 
D. Change in Pediatric Respiratory Outcome PROSE after vaccination from baseline (pre-
vaccination) PROSE 
E. Rates of medical utilization for asthma-related symptoms in recipients of ccIIV4 and IIV during the 
42 days post-vaccination.  
 


CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
12 
3 ELIGIBILITY CRITERIA 
 
 
1. Children between 5-11 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 daily controller medication 
 
 
3. Parent/legal guardian must provide written informed consent and subject must provide assent as 
appropriate for age prior to initiation of study procedures and according to local IRB requirement  
 
4. Parent/legal guardian and subject must be willing and able to comply with planned study procedures 
and be available for all study visits 
 
5. Children aged 5-8 years must have received at least 2 doses of seasonal trivalent or quadrivalent 
influenza vaccine prior to the current influenza season. Children 9-11 years must have received at 
least 1 dose of seasonal trivalent or quadrivalent influenza vaccine prior to the current influenza 
season.2 
2 Influenza vaccination history verification Figure 2 appendix 
 
 
6. Is in good health, other than their asthma, as determined by medical history and targeted physical 
examination based on medical history 
 
7. English or Spanish literate3  
3 only English speaking participants will be included at the Cincinnati site  
 
8. Intention of being available for entire study period and complete all relevant study procedures, 
including follow-up phone calls and collection of information 
 
 
 
 
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 (temporary 
deferral) 
 
3. History of a severe allergic reaction (e.g., anaphylaxis) to any component of study influenza vaccines 
or a known allergy to eggs 
 
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  
 
5. Receipt of current year’s licensed influenza vaccine  


CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
13 
 
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. Has immunosuppression as a result of an underlying illness or treatment, or use of anticancer 
chemotherapy or radiation therapy within the preceding 36 months 
 
8. Has taken ≥20mg/day of prednisone or its equivalent, for 14 days or more within the past 28 days 
 
9. Has known active neoplasm or a history of any hematologic malignancy  
 
10. Has 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. History of Guillian-Barré syndrome within 6 weeks of previous influenza vaccination 
 
 
 
 
12. Has 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 
 
13. Has any diagnosis, current or past, of schizophrenia, bipolar disease, or other major psychiatric 
disorder 
 
14. Currently taking aspirin or aspirin-containing products 
 
 
 
Prior to vaccination, it will be necessary to characterize asthma severity and control in each patient (see 
figures A1 through A3 in the appendix). This characterization will be based on the chart from the National 
Asthma Education and Prevention Program Expert Panel Report 3 that was issued in October 2007.17 For the 
purposes of the study, we will only recruit subjects with persistent asthma and within the full spectrum of 
severity. Subjects in well-controlled and not well-controlled categories will be enrolled; subjects with very 
poorly controlled asthma will be discussed with the physician prior to enrollment for their assessment as to 
whether these subjects can be safely enrolled, based on clinical judgment.




CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
15 
 
4 STUDY DESIGN AND PROCEDURES 
This is a prospective randomized, open label clinical trial in approximately 50 children aged 5-11 years 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). Subjects will be randomized 1:1 to receive either a single 
intramuscular dose of licensed Flucelvax® Quadrivalent (ccIIV4) or a single intramuscular dose of licensed 
Fluarix® Quadrivalent (IIV4), stratifying by asthma severity (mild vs. moderate/severe). 
 
 
Subject enrollment for this feasibility study will begin during September or October 2016.  Site-specific 
information is described below.  
Vanderbilt 
Vanderbilt will enroll approximately 20 participants. The Vanderbilt Pediatric Pulmonary Clinic will be the 
source for the majority of patients enrolled. There are additional Allergy and General Pediatric Clinics that 
have patients with asthma but if enrolled, these patients will be referred to the Pulmonary Clinic or to the 
Clinical Research Center at the Children’s Hospital where enrollment will occur. 
 
The Pediatric Pulmonary Clinic has the necessary space and infrastructure to provide support for this study. 
Ongoing clinical research is conducted there and the investigators can integrate research enrollment in the 
same area as they are providing clinical care. During the months prior to enrollment, the research staff will 
inquire about the study interest, will assess the ability of the families to assess clinical symptoms and to 
perform home respiratory testing, and will identify parental preferences for recording reaction data. Drs. 
Moore and Sokolow will facilitate introduction of the patients to the study staff, and the patients will be 
informed about the study. During August and September 2016, when recruitment and enrollment is expected 
to begin, Vanderbilt Vaccine Research Program (VVRP) study staff will be actively involved in recruitment. All 
qualifying patients for the study will be given information and contact numbers to discuss the study in the 
months prior to the study onset. The research team will provide follow up contact information to discuss 
questions or concerns.  
 
After informed consent, Vanderbilt study staff will target subjects with moderate or severe persistent asthma 
for the conduct of the study, which represents the majority of patients at this Vanderbilt clinic. Using the 
Severity and Control tables shown in the Appendix, subjects will be graded for each of these two parameters, 
severity and control, and these assessments will be recorded on the Case Report Form. Lists of children with 
an interest in the study will have been previously compiled prior to the availability of the vaccine. If the 
parents agree to participation, then the subjects will be seen in the outpatient clinic areas (e.g., Pediatric 
Pulmonary Clinic or Pediatric Clinical Research Center) at Vanderbilt Children’s Hospital. 
 
Cincinnati 
Cincinnati will enroll approximately 20 participants. The study population will be children with asthma who are 
patients at Cincinnati Children’s Hospital Medical Center (CCHMC) with primary recruitment from the 
Pulmonary Asthma and Pediatric Primary Care (PPC) Clinics at CCHMC. One of the ongoing quality 
management goals at CCHMC is to document the level of severity for all children cared for at CCHMC with 


CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
16 
asthma. Of those not categorized, Cincinnati will be able to categorize their asthma severity and control if 
they interested in the study. 
 
If influenza vaccine (ccIIV4 and IIV4) is available, Cincinnati would like to start enrollment in September 2016 
to maximize the number of weeks for enrollment. Using local and national data, we will determine the target 
weeks for enrollment to ensure this high-risk group of children with asthma are vaccinated for influenza well 
before the influenza season starts. The target enrollment period should be as soon as both vaccines are 
available and should end by the last week of November allowing for approximately 12-13 weeks for 
enrollment. 
 
Cincinnati will recruit approximately 20 children, 5-11 years of age, diagnosed with asthma of varying degrees 
of severity. The primary strategy for recruitment will be through the Pulmonary Asthma Clinic and the 
Pediatric Primary Care Center. Cincinnati will advertise at these two sites, as well as through the asthma 
registry and their database of past research participants who have agreed to be e-mailed for future studies. 
Any written communication provided to the potential subjects' parents/legal guardians about the study will be 
submitted to the IRB for their approval before study initiation. Recruitment letters introducing the study will be 
sent to parents of asthmatic children shortly ahead of the influenza vaccination season. To assist with 
recruitment, parents will then be called 2 to 3 weeks after sending the letter to screen for interest, eligibility 
and enrollment (September-November 2016).  Recruitment will also be coordinated with well child visits and 
clinic visits. Recruitment will be advertised by the use of flyers posted in pediatric/allergy/and pulmonary 
clinics. 
 
Interested parents may call or email the Cincinnati study line and study personnel will discuss the study by 
phone or email with the parent. Subjects will be screened using a phone screening tool (eligibility and brief 
medical history questions) from the parents. If potentially eligible and interested, an appointment will be 
scheduled. Parents will be informed that their decision to participate or not to participate in the study will not 
have any effect on their child as a patient. If parental permission is given for participation, the subjects will be 
seen in the Research Clinic (Schubert Center) at Cincinnati Children’s Hospital Medical Center. Cincinnati will 
enroll approximately 20 children with persistent asthma to include approximately 50% with mild, persistent 
asthma and 50% with moderate to severe asthma. 
Duke 
 
Duke will enroll approximately 10 children age 5-11 years with persistent asthma.  Duke study staff will obtain 
informed consent from parents/guardians of children with persistent asthma at clinical sites affiliated with 
Duke University in order to enroll, randomize and vaccinate approximately 10 children (5 with moderate to 
severe asthma and 5 with mild asthma). Children with persistent asthma will be enrolled at Duke 
Allergy/Immunology and Pulmonary Clinics located at Duke Children’s and WakeMed Children's Specialty 
Services in Raleigh, NC.  
 
Identification of children with persistent asthma will occur from providers at the clinic and through the use of 
the Duke patient data portal. With permission of their health care provider, recruitment letters introducing the 
study may also be sent to parents of asthmatic children. To assist with recruitment, parents will then be called 
10 days after sending the letter to schedule children for screening and enrollment. Recruitment will also be 


CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
17 
coordinated with clinic visits and or vaccination clinics. Recruitment will be advertised by the use of flyers 
posted in allergy/and pulmonary clinics.  
 
At all sites, study participants will be compensated for each clinic visit (including enrollment) and for each 
follow-up telephone/email contact. 
 
 
 
In total, the study will enroll approximately 50 children between 5-11 years of age, inclusive, who have 
persistent asthma of varying levels of severity (~20 from Vanderbilt, ~20 from Cincinnati and ~10 from Duke). 
The study will aim to enroll equal proportions of participants (50%) with mild and with moderate/severe 
asthma.  
 
Subjects will be randomized 1:1 to receive by intramuscular injection either a single dose of a licensed non-
egg, cell culture-based, quadrivalent inactivated influenza vaccine (ccIIV4-Flucelvax® Quadrivalent) or an 
egg-based formulation of inactivated influenza vaccine, stratifying by asthma severity (mild vs. 
moderate/severe). 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/severe asthma can vary by 
clinics, but the targeted proportions of asthma severity at site level will be 50% for each. Therefore, overall 
enrollment with randomization will recruit the same proportions of asthma severity participants in each arm. 
Randomization will be accomplished using the REDCap System, hosted at Vanderbilt. Since this is a web-
based system, it is easily accessible to the other collaborating sites as well.  
 
   


CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
18 
 
4.3.1 Visit 1 (Day 1) - Enrollment and Vaccination 
 
Informed consent/assent will be obtained 
 
Medical history and medication history will be obtained, including a review of all current medications 
and medications taken within 28 days of enrollment.   
 
History of asthma and allergy disease (asthma triggers, environmental, food and other documented 
allergies, allergy testing results, household pets, exposure to secondhand smoke in the home or 
daycare or where subject spends considerable time during the day) will be captured. 
 
Temperature will be recorded prior to immunization; oral temperature must be <100.4◦ F prior to 
administration of vaccine. 
 
Height and weight will be measured in order to calculate subject’s BMI 
 
Eligibility criteria will be reviewed to determine if child meets criteria for study 
 
Asthma severity and control will be assessed 
o Clinical assessment to assess baseline asthma clinical symptoms [Preventative Omalizumab 
or Step-up Therapy for Severe Fall Exacerbations (PROSE) asthma symptom questionnaire] 
o Administration of the Childhood Asthma Control Test (cACT) 
 
Patient and parent(s)/guardian will be taught proper peak flow technique and will be provided with a 
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/guardian) 
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, and on day 43 after vaccination (days 1 through 15 
and on day 43, respectively). (see section 4.7 below)  
 
The child will be randomized to the respective treatment group (ccIIV4 or IIV4) using the REDCap 
System. The Vaccine Information Sheet (VIS) for the respective vaccine administered will be provided 
to parents/guardians before the vaccine is administered. The VIS will be in the primary language of 
the parent/guardian consenting for the child to be enrolled in the study. 
 
The vaccine will be administered according to the study randomization scheme. 
 
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/guardian will be given a thermometer and a ruler to use for daily temperature and local 
reactions recording, respectively 
 
Study staff will record any immediate adverse events (AEs) after vaccination occurring while still in the 
clinic 
 
Study staff will educate the family to notify the study staff if the patient requires an additional 
unscheduled medical visit for management of asthma symptoms (medical services utilization) or a 
new asthma control medication that has been prescribed.  
4.3.2 Visit 2 [Day 4 (-1 through +2)] – Call/email 
 
 
Memory aid review for solicited symptoms 


CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
19 
 
Unsolicited symptoms review 
 
Concomitant medications review 
 
Post-vaccination asthma clinical symptoms review and symptom scores  
o Asthma control assessment (cACT) 
o PROSE 
 
Medical services utilization review 
 
Peak flow measurements 
 
Parent will be instructed to contact the study staff if the child utilizes medical services, has a new 
asthma medication prescribed. or experiences a serious adverse event 
4.3.3 Visit 3 (Day 8 ± 2) – Call/email 
 
 
Memory aid review for solicited symptoms 
 
Unsolicited symptoms review 
 
Concomitant medications review 
 
Post-vaccination asthma clinical symptoms review and symptom scores  
o Asthma control assessment (cACT) 
o PROSE 
 
Medical services utilization review 
 
Peak flow measurements 
 
Parent will be instructed to contact the study staff if the child utilizes medical services, has a new 
asthma medication prescribed, or experiences a serious adverse event 
4.3.4 Visit 4 [Day 15 (- 1 through +2)] – Call/email 
 
 
Memory aid review for solicited symptoms 
 
Unsolicited symptoms review 
 
Concomitant medications review 
 
Post-vaccination asthma clinical symptoms review and symptom scores  
o Asthma control assessment (cACT) 
o PROSE 
 
Medical services utilization review 
 
Peak flow measurements 
 
Parent will be instructed to contact the study staff if the child utilizes medical services, has a new 
asthma medication prescribed, or experiences a serious adverse event 
4.3.5 Visit 5 (Day 29 ± 2) – Call/email 
 
 
Concomitant medications review 
 
Medical services utilization review 
 
4.3.6 Visit 6 (Day 44 + 3) – Call/email 
 
 
Concomitant medications review 


CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
20 
 
Medical services utilization review 
 
Post-vaccination asthma clinical symptoms review and symptom scores  
o Asthma control assessment (cACT) 
o PROSE 
 
Peak flow measurement  
 
Administer parent/guardian satisfaction survey 
 
 
After informed consent, asthma severity will be classified as previously described. Using the Severity and 
Control tables shown in the Appendix, subjects will be assessed for severity, and these assessments will be 
recorded on the Case Report Form.  
 
 
All patients enrolled in the study will have baseline demographic and clinical data available from their medical 
records or they will be obtained at the time of enrollment. These data will include age, gender, height and 
weight to determine the BMI; history of known asthma triggers, including exercise (i.e., exercise-induced 
bronchospasm), indoor/outdoor climate (e.g., cold, dry air; thunderstorms), allergies (environmental, food, 
medication, or other documented allergies); allergy testing results; other pertinent physician-diagnosed health 
conditions (e.g. gastroesophageal reflux disease); presence of household pets; daycare or school 
attendance; number of siblings/ persons in the household; and exposure to secondhand smoke in the home 
or other settings where the subject spends considerable time during the day. These details will be recorded in 
the Case Report Form for Visit 1. If these data are not available from the clinic record they will be obtained 
from the parents and entered into the REDCap case report form at the time of enrollment.  
 
 
Spirometry will not be performed as a study procedure.  All enrolled patients who have routine spirometry 
performed at baseline, as part of their clinical care, with a commercial spirometer will have that data recorded 
on the case report form. Recent joint statements issued by the American Thoracic Society (ATS) and the 
European Respiratory Society (ERS) to standardize endpoints for clinical trials suggested that the 
measurement of Forced Expiratory Volume in 1 second (FEV1) in an ambulatory clinic setting provides the 
best objective measure of airway obstruction, which is the hallmark of asthma exacerbation. The statement 
also cautioned that the safety of this testing has been widely established and that reproducibility is high. 
Additional information regarding pulmonary health can also be obtained from the Forced Vital Capacity (FVC) 
and the ratio of FEV1/FVC from the spirometry data obtained in the clinic in the patients with asthma.  For 
this study, spirometry data will be collected on all patients who have spirometry performed as standard of 
care (at any site) at enrollment and during any visit prompted by alterations in PEFR or home questionnaires 
to verify exacerbation.  
 
 
Subjects will be trained on the “at home” performance of PEFR using a hand held device purchased by study 
funds and that subjects will get to keep after completing the study. In addition, for all subjects who have 
spirometry performed at enrollment, it will be compared to the results obtained by the PEFR studies. 
Numerous longitudinal asthma studies have utilized the peak flow meter device to monitor control between 
study visits. The device is inexpensive, its use is easily learned, and it can provide an objective measure of 


CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
21 
control of asthma symptoms. While PEFR testing with a peak flow meter is inferior to the determination of 
FEV1 by spirometry as a measure of airway obstruction, it can be very helpful and additive to home 
questionnaires in monitoring control. Typically, a subject’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 asthma surveys to avoid bias in the recording of daily symptoms. All 
efforts will be made to minimize variation in technique; training in proper peak flow meter use will be 
accomplished at study enrollment and reviewed/reinforced at each study visit.  
 
For this study, all sites will provide participants with the same model of a digital peak flow meter. This device 
has an automatic memory of 240 data entries with a time stamp; thus, participants will be instructed to record 
their daily PEFR data measurements on their memory aid/REDCap until day 15 and again at day 43. The 
device can also be connected to a computer, and the values can be analyzed by using the Microlife Asthma 
analyzer software program.18,19  
 
 
Only US-licensed vaccines will be used in this study. The vaccines will be purchased from the study site 
pharmacies and will be administered by a vaccinator. Because ccIIV4 is quadrivalent, using quadrivalent IIV 
(IIV4) in the comparison group will be used. Preferably, all three sites will use the same vaccines, although if 
this is not possible, similar products will be chosen. The details from the package inserts of the two proposed 
vaccines are shown below.   
Flucelvax® Quadrivalent  
 
Flucelvax® 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. In the United States, 
Flucelvax® Quadrivalent is antibiotic-, preservative-, and latex-free. Flucelvax® is the only FDA-licensed 
formulation of non-egg, cell culture-based inactivated influenza vaccine (ccIIIV) approved for use in children 
and adolescents. The quadrivalent formulation of Flucelvax® (ccIIV4) was approved for use in persons 4 
years of age and older on May 23, 2016. Studies in children 4-17 years demonstrated non-inferior 
immunogenicity and comparable safety when compared to the Flucelvax® (trivalent) vaccine preparation. 
Data demonstrating a decrease in influenza disease after vaccination of this age group with Flucelvax® 
Quadrivalent are not available. Clinical benefit of Flucelvax® Quadrivalent for individuals 4 to <18 years of 
age is inferred from immunogenicity as a surrogate. It is our intention that half of the feasibility study subjects 
at the three CISA-contracted study sites will be randomized to receive Flucelvax® Quadrivalent vaccine. 
FLUARIX® Quadrivalent (Influenza Vaccine) Suspension for Intramuscular Injection 
 
FLUARIX® Quadrivalent is a vaccine indicated for active immunization for the prevention of disease caused 
by influenza A subtype viruses and type B viruses contained in the vaccine. FLUARIX® Quadrivalent is 
approved for use in persons 3 years of age and older for intramuscular injection only.  
 
There are multiple brands of inactivated influenza vaccine licensed and recommended for use in children 
aged 5-11 years, and ACIP does not state a preference.  For consistency, Fluarix® Quadrivalent inactivated 




CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
23 
the 2016-2017 influenza season. The quadrivalent seasonal inactivated influenza vaccine will be 
administered at baseline (Day 1 of study) according to the study randomization scheme.   
 
On the vaccination day and for the next 14 days post-vaccination, all subjects will be monitored daily by their 
parents and the information will be recorded using memory aids provided at the enrollment visit. Daily 
reactogenicity, including measurement of nighttime awakening, and two asthma scoring systems will be 
completed (cACT score and the PROSE score). 
 
In addition to the two symptom scores above, several predefined events that could occur after vaccine 
administration will also be recorded for 14 days after vaccination. These will include; fever (oral temperature 
≥100.4°F), runny nose/ nasal congestion, sore throat, cough, wheeze, vomiting, change in activity level, 
appetite change, irritability, abdominal pain/stomachache, headache, chills, and muscle aches. Local 
reactions after the intramuscular vaccination will also be captured and include: redness, swelling, and/or pain 
around the injection site. 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 or emailed 
through REDCap on Days 4, 8 and 15 by the study staff.  
 
On the day of vaccination and during the first 14 days after vaccination, if the subject 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 applicable. 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 PCP and inform study staff of this encounter.   
 
 
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. This will be accomplished by a telephone call 
or email through the REDCap system to the parents of the subjects, depending on their preference and their 
availability, at day 29 and at day 44 to determine the status of asthma control. On Day 29, subjects will be 
queried about concomitant medications and medical services utilization. On day 44, subjects will be queried 
about concomitant medications and medical services utilization, as defined above. The cACT score and 
PROSE score will also be completed at day 44. 
 
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 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 after vaccination and will 
include events that result in death, were life threatening, result in subject 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 subject and require medical or surgical intervention to prevent one of the outcomes listed 
above.   


CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
24 
5 RISKS 
 
 
All participants will receive the CDC VIS 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. 
 
 
ACIP routinely recommends IIV for children with asthma7-9 and risks after IIV would 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 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 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. This happens very rarely. 
 
6 REPORTING OF ADVERSE EVENTS 
 
SAE and AE reporting will occur consistent with routine practice. Vaccine-associated SAEs will be medically 
attended per standard procedures, and reported to the Vaccine Adverse Event Reporting System (VAERS) in 
accordance with standard procedures, and information about such events will be included in the study data 
(https://VAERS.hhs.gov). SAEs will be reported promptly to the overseeing IRBs in accordance with 
institutional procedures. Any unanticipated problems resulting from study conduct related to participation will 
be promptly reported to the reviewing IRBs including the CDC, in accordance with institutional procedures.  
 
An 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/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 


CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
25 
jeopardize the patient or subject and require medical or surgical intervention to prevent one of the outcomes 
listed above. These will be reported to the IRBs. 
 
Participants who report severe solicited AEs or SAEs or express any concern about symptoms/unsolicited 
events will be encouraged to follow up with their pediatrician or primary care provider. Study staff will assist 
with coordination of referral appointments as necessary. 
 
 
7 STUDY WITHDRAWAL/DISCONTINUATION 
 
Subjects may voluntarily withdraw their consent for study participation at any time and for any reason, without 
penalty. 
 
A subject 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 subject, or would interfere with the subject'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. 
 
Subject withdrawal of consent. 
 
Subject lost to follow-up. 
 
Termination of this study. 
 
New information becomes available that makes further participation unsafe. 
 
Subjects may withdraw their consent for study participation at any time and for any reason, without penalty.  
 
 
Subjects who withdraw from the study before receiving vaccine will be replaced. Subjects who withdraw from 
the study after receiving vaccine 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. All SAE’s and AE’s 
that require VAERS reporting will be followed to adequate resolution or until considered stable.   
 
 
This study may be terminated for safety concerns of the PI, CDC, or participating IRBs.  
 
 
 


CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
26 
 
8 Statistical Analytic Plan  
 
This study aims to enroll approximately 50 participants (~20 from Vanderbilt, ~20 from Cincinnati and ~10 
from Duke).  Since sample-sizes were predetermined and since this is a feasibility study, no power 
calculations were conducted.  All analyses will be performed using R 3.2.3 (r-project.org), SAS version 9.4, or 
STATA version 14. 
  
Feasibility Analysis 
The proportion of children meeting the outlined feasibility benchmarks (Appendix, Table A1) will be 
determined.  
 
Descriptive Statistics  
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 ccIIV4 and IIV4 groups will be conducted using Pearson Chi-square and Wilcoxon tests 
appropriately.  
Primary Objective 
 
To assess the feasibility of conducting a randomized prospective safety study of LAIV4 versus IIV4 
during the 42 days after vaccination in children aged 5-11 years with persistent asthma of varied 
severity (ccIIV4 will be used as a surrogate for LAIV4)  
Primary Outcomes Measures 
1. Assess the proportions of those achieving Feasibility Benchmarks (Table A1 Appendix) 
 
2. Qualitatively describe best practices and lessons learned 
 
Secondary Objectives 
 
1. To compare proportions of local and systemic reactogenicity events during the 14 days after ccIIV4 
versus IIV4 in children with asthma aged 5-11 years.  
2. To describe the unsolicited and serious adverse events in children receiving ccIIV4 and IIV4 during 
the 42 days. 
3. To compare proportions of asthma exacerbations during the 14 days after ccIIV4 versus IIV4 in 
children with asthma aged 5-11 years.  
4. To compare proportions of asthma exacerbations during the 42 days after ccIIV4 versus IIV4 in 
children with asthma aged 5-11 years.  
5. To explore differences between the ccIIV4 and IIV4 groups regarding clinical asthma symptoms after 
vaccination and changes in asthma control before and after vaccination in children with asthma of 
varied levels of severity. 
 


CISA STUDY: Influenza Vaccine Feasibility Study in Children with Persistent Asthma  
 
 
27 
Secondary outcome measures 
1. Proportion of subjects with solicited local and systemic reactogenicity events for 14 days after 
vaccination between recipients of ccIIV4 and IIV4.  
2. The nature and frequency of the unsolicited and serious adverse events will be described in children 
receiving ccIIV4 and IIV4 during the 42 days.  
3. Proportions of asthma exacerbations in recipients of ccIIV4 and IIV4 during the 14 days post-
vaccination (until day 15). The asthma exacerbation proportion within 14 days post-vaccination will be 
calculated for children receiving ccIIV4 or IIV4 influenza vaccine. For this calculation a child with an 
asthma exacerbation (as defined earlier in the protocol) on one or more days during day 1-15 would 
be considered to have had an asthma exacerbation (dichotomous yes or no).  We will compare 
proportions in children receiving ccIIV4 vs. IIV4.   
4. Proportions of asthma exacerbations in recipients of ccIIV4 and IIV4 during the 42 days post-
vaccination (until day 43). The asthma exacerbation proportion within 42 days post-vaccination will be 
calculated for children receiving ccIIV4 or IIV4 influenza vaccine.  For this calculation a child with an 
asthma 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 will compare 
proportions in children receiving ccIIV4 vs. IIV4.   
5. Proportions of clinical symptoms after vaccination and changes in measurement of asthma control, 
before and after vaccination in children with asthma of varied levels of severity, between recipients of 
ccIIV4 or IIV4 will be assessed through five measures (see methods for schedule):  
A. Proportions of subjects with asthma symptoms as assessed on memory aid (e.g., wheezing, 
nighttime awakenings, cough) during days 1 through 15.  
Proportions of subjects with each asthma symptom (dichotomous yes or no) by treatment 
group, and asthma severity level will be calculated and a 95% confidence interval of the 
difference in proportions between the treatment groups will also be presented. 
B. Change in Peak Expiratory Flow Rate (PEFR) after vaccination from baseline (pre-vaccination) 
PEFR.  
Peak Expiratory Flow Rate (PEFR) evaluations are recorded once every day starting on day 1 
(baseline) through day 15; PEFR measurement will also be performed on day 43.  Proportion 
of subjects with clinically important change of >20% decrease in PEFR (dichotomous yes or 
no) will be calculated at baseline (day 1), during days 2 through 15 (observed >20% decrease 
on one or more days) and on day 43. Comparisons of proportions between days 2 through 15 
or day 43 with baseline will be conducted between the two treatment groups and 95% CIs of 
such proportion differences will be presented. Comparisons of mean/median between each 
day after vaccination with baseline will also be conducted between the two treatment groups 
and 95%CIs of such differences will be presented. 
 
Each subject will have repeated PEFR measurements (baseline, once a day for days 1-15 and 
once on the last study day 43), which naturally provides a longitudinal data set.  We plan to 
explore the change in PEFR after vaccination for up to 43 days between ccIIV4 and IIV4 
groups through a full likelihood longitudinal analysis such as a mixed effects model. We may 
adjust for covariates listed below while accommodating multiple random subject effects.  We 
may apply restricted cubic splines for some continuous covariates to relax the linearity 


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assumption.  Estimates of average treatment effects along with 95%CIs will be reported for 
day 15 and day 43. 
C. Change in Childhood Asthma Control Test (cACT) scores after vaccination from baseline (pre-
vaccination) cACT 
The cACT scores are recorded at baseline, days 4, 8, 15 and 43; lower scores indicate poorer 
asthma control for the interval.  Proportions of subjects with cACT scores <20 (dichotomous 
yes or no) will be calculated at baseline (day 1), on days 4, 8, 15, and 43.  Comparisons of 
proportions between days 4, 8, 15 or day 43 with baseline will be conducted between the two 
treatment groups and 95%CIs of such proportion differences will be presented. Comparisons 
of mean/median between day 4, 8, 15, or 43 with baseline will also be conducted between the 
two treatment groups and 95%CIs of such differences will be presented. 
 
Similar full likelihood longitudinal analysis (stated in 8.2.4, 2, B) may be conducted using cACT 
measurements as the outcome.  
D. Change in Pediatric Respiratory Outcome PROSE after vaccination from baseline (pre-
vaccination) PROSE 
The PROSE score are recorded at baseline, days 4, 8, 15 and 43. Comparisons of 
mean/median between day 4, 8, 15, or 43 with baseline will be conducted between the two 
treatment groups and 95%CIs of such differences will be presented. 
 
Similar full likelihood longitudinal analysis (stated in 8.2.4, 2, B) may be conducted using 
PROSE measurements as the outcome.  
E. Rates of medical utilization for asthma-related symptoms in recipients of ccIIV4 and IIV4 during 
the 42 days post-vaccination (until day 43).  
 
The rate of medical utilization for asthma-related symptoms is defined as the number of 
unscheduled medical visits divided by the length of follow-up time in days.  We will report rate 
differences between the two treatment groups at day 15 and day 43 along with 95%CIs.  
Covariates of interest are based on previous studies and epidemiological plausibility. The 
covariates listed below are for model consideration though they are not limited.    
Main exposure: treatment group 
Baseline measurement: PEFR, cACT, PROSE, asthma severity level such as severity status 
(mild, moderate or severe), control status (well-controlled or not well-controlled), and age, gender, 
race, daytime and nighttime asthma scores, nighttime awakening, BMI/BMI percentile 
Other covariates may include days from immunization, community pollen levels near to the time of 
ccIIV4 or IIV4 vaccination, exposure to second-hand smoke, and the frequency of smog 
alert/ozone alert days over the study interval in the communities where the children reside.   
 


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9 PRIVACY/CONFIDENTIALITY ISSUES 
 
Subject confidentiality is strictly held in trust by the site principal investigators, other study personnel, the 
sponsor, and their agents.  Subjects 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 subject’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 subject; or (4) study results which may be published. If a written 
contract for the conduct of this study which includes confidentiality provisions inconsistent with this statement 
is executed, that contract’s confidentiality provisions shall apply rather than this statement. 
 
 
 


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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 for at least 2 years after study completion, but potentially longer based on local institutional 
requirements.  
 
 
The amount of data that will be collected for the proposed feasibility study will be limited in quantity, but a 
large, multisite study based on this feasibility study would be substantial and would 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 reaction forms, 
and short customized questionnaires to collect information from study subjects. This system will be used by 
Vanderbilt, Cincinnati and Duke for data management.  All electronic linkages will fulfill regulations for 
protection of human subjects and requirements to minimize the risk of breach of confidentiality. After initial 
set-up, the work load required for electronic data collection will be substantially reduced (description of 
REDCap resources below).22 The Vanderbilt, Cincinnati and Duke investigators have previously used the 
REDCAP system for collection and analysis of large quantities of data. Participants’ parents/guardians will be 
given the option to fill out their reactogenicity diary either directly in the REDCap system or on paper. 
Participants who choose the paper form will receive a phone call on day 3-6, 7-9, 14-17, 27-31, and 44-47 
post-vaccination to collect the information recorded on their memory aid, which will then be entered by study 
personnel onto REDCap. All study-related documents containing protected health information, e.g. enrollment 
logs, case report forms, memory aids completed by study participants, will be maintained in secure research 
offices at Vanderbilt, Cincinnati and Duke, respectively, which are accessible to research staff only.  
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.22 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. Of particular interest for this project, a subcomponent of 
REDCap, the REDCap Survey is designed for studies where data are collected directly from the research 
participant. This will be used with the web-based reaction forms that will be completed by the study subjects’ 
parents/guardians.  Both products include secure institutional data hosting and include 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 


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31 
from study participants, to link the baseline data, sample collection date, and laboratory results in an 
automated database family, to perform data cleaning and data quality assurance efficiently, and to design an 
analytical dataset for the analysis of the project data.  
Double data entry  
Double data entry for each record is a means of ensuring quality data collection by later comparing the 
records. We will create two identical REDCap databases to store our data, each site can designate two data 
entry persons to enter each database.  Or if there is only one data entry person, then at least 7 days lagging 
time between entering same participants’ info into these two databases will be required to reduce/remove 
memory residual, in other words, same participants’ info can’t be entered into both databases within 7 days.  
For example, participants 1-10 and 11-20 can be entered into database 1 and 2 this week respectively, and 
next week they can be switched and entered into the other database respectively. From previous experience, 
seven days waiting period is long enough to minimize memory residual effect. 
 
Both the leading site and the collaborating sites will use REDCap to collect subjects’ information and all sites 
will do double data entry. CDC can use REDCap as a means of monitoring the study.  Data will be entered 
into REDCap in a timely manner by experienced data entry personnel.  Periodic data enrollment audits will be 
conducted through the recruitment period to ensure that we are not missing appropriate children and help 
monitor study progress. Comparisons of double data entry will be conducted and a list of discrepancies 
between two databases will be generated for each site on a regular basis.   
Data cleaning and data quality assurance 
In order to perform data cleaning and data quality assurance efficiently, double data entry will be performed 
with numerous built-in filters and checks for consistency of the data including range and limit checks, 
branching logic and pull down menus to limit choices for categorical variables to a pre-specified list will be 
implemented and performed automatically to minimize data entry error. The data will be randomly sampled 
and checked against source records on a regular basis. The data and related analytical datasets will also be 
stored 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.   
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 (Kathryn 
Edwards and Andrew Sokolow) will oversee the overall study and direct activities at Vanderbilt University.  
Duke University (Emmanuel (Chip) Walter and Amy Stallings) will contribute subjects and direct activities at 
Duke, and Mary Staat and Carolyn Kercsmar will contribute subjects and direct activities at Cincinnati. CDC 
personnel will collaborate with both 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/PROTECTION OF HUMAN SUBJECTS 
 
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. 
 
Prior to enrollment of subjects into this trial, the approved protocol and informed consent form will be 
reviewed and approved by the appropriate IRB.  
 
Informed Consent 
The site principal investigator will choose subjects in accordance with the eligibility criteria detailed in Section 
3.  Before any study procedures are performed, subjects must sign an informed consent form that complies 
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, subjects’ 
parent(s)/legal guardian(s) will receive a comprehensive explanation of the proposed study procedures and 
study interventions/products, 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.  Subjects’ parent(s)/legal 
guardian(s) will also receive a detailed explanation of the proposed use and disclosure of their protected 
health information.  Subjects’ parent(s)/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. 
Informed consent forms describing in detail the study interventions/products, study procedures, risks and 
possible benefits are given to subjects. Informed consent forms will be IRB-approved and subjects 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 subjects and their parent(s)/legal 
guardian(s) and answer any questions that may arise. The subject’s parent(s)/legal guardian(s) must sign the 
informed consent form, and written documentation of the informed consent process is required prior to 
starting any study procedures/interventions being done specifically for the trial, including administering study 
product. Subjects will be given a copy of all informed consent forms that they sign. 


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By signing the informed consent form, parents/guardians give permission on behalf of their children and 
agree to complete all evaluations required by the trial, unless the subject withdraws voluntarily, or is 
withdrawn or terminated from the trial for any reason. 
The rights and welfare of subjects will be protected by emphasizing to subjects that the quality of their 
medical care will not be adversely affected if they decline to participate in or withdraw from this trial. 
Informed Consent/Assent Process  
Assent will be obtained from all children following local IRB policies and standard practices for obtaining and 
documenting assent.  
 
 


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    APPENDIX 
 
 
 


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