Safety and Immunogenicity of Adjuvanted Versus High-Dose Inactivated Influenza Vaccines in Older Adults
Phase: PHASE4
Conditions: Pain, Quality of Life, Injection Site Reaction, Side Effect of Drug, Adverse Drug Event
Sponsor: Duke University

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Safety and Immunogenicity of Adjuvanted versus High-Dose Inactivated Influenza Vaccines in 
Older Adults 
 
Short Title: FLUAD® vs. Fluzone® High-Dose Study 
 
 
 
Centers for Disease Control & Prevention  
Clinical Immunization Safety Assessment (CISA) Project  
 
 
Lead Site (Duke University) Principal Investigator: Ken Schmader, MD 
Lead Site Sub-principal Investigator: Emmanuel B. Walter, MD, MPH 
 
Contributing Site (Boston University) Principal Investigator: Elizabeth Barnett, MD 
Contributing Site Sub-principal Investigator: Christine Liu, MD 
Contributing Site Sub-principal Investigator: Heidi Auerbach, MD 
 
Contributing Site (Cincinnati Children’s Hospital Medical Center) Principal Investigator: 
Elizabeth Schlaudecker, MD 
Contributing Site Sub-principal Investigator: Mary Staat, MD 
 
Centers for Disease Control and Prevention (CDC) Principal Investigator: Theresa Harrington, 
MD, MPH&TM  
CDC Sub-principal Investigator: Karen R. Broder, MD 
 
 
 
 
 
NCT # NCT03183908 
 
Version Number: 5.0 
 
25 September 2018 
 
 
 

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STATEMENT OF COMPLIANCE 
• 
This trial will be conducted in compliance with the protocol, the International Conference 
on Harmonization (ICH) Guideline E6—Good Clinical Practice (GCP), and the applicable 
guidelines and regulatory requirements from the United States (US) Code of Federal 
Regulations (CFR), 45 CFR Part 46. 
• 
All study personnel with subject contact have completed Human Subjects Protection 
Training. 
 
 
 

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TABLE OF CONTENTS 
 
PROTOCOL SUMMARY ........................................................................................................... 5 
1 
BACKGROUND ................................................................................................................10 
1.1 
Background ...............................................................................................................10 
1.2 
Summary and Rationale ............................................................................................11 
2 
STUDY OBJECTIVES AND OUTCOME MEASURES ......................................................11 
2.1 
Study Objectives ........................................................................................................11 
2.1.1 
Primary Objectives: ................................................................................................11 
2.1.2 
Secondary Objectives ............................................................................................12 
2.1.3 
Exploratory Objectives: ..........................................................................................12 
2.2 
Study Outcome Measures .........................................................................................12 
2.2.1 
Primary Outcome Measures: .................................................................................12 
2.2.2 
Secondary Outcome Measures ..............................................................................13 
2.2.3 
Exploratory Outcome Measures .............................................................................13 
3 
STUDY DESIGN ...............................................................................................................14 
3.1 
Main study design ......................................................................................................14 
3.2 
Laboratory Studies ....................................................................................................14 
4 
STUDY ENROLLMENT AND WITHDRAWAL ..................................................................15 
4.1 
Subject Inclusion Criteria ...........................................................................................15 
4.2 
Subject Exclusion Criteria ..........................................................................................15 
4.3 
Recruitment ...............................................................................................................16 
4.4 
Reasons for and Handling of Withdrawals .................................................................18 
4.5 
Termination of Study..................................................................................................18 
5 
STUDY SCHEDULE, PROCEDURES, & EVLAUTIONS ..................................................18 
5.1 
Schedule of events and data collection ......................................................................18 
5.2.1 
Randomization .......................................................................................................22 
5.3 
Data Collection ..........................................................................................................23 
5.3.1 
Vaccine Supply, Storage, Administration, and Blinding ..........................................23 
5.4 
Reactogenicity and Safety Assessment .....................................................................24 
5.4.2 
Reporting of Adverse Events .................................................................................27 
5.4.3 
Safety Monitoring Plan ...........................................................................................28 
5.5 
Health-Related Quality of Life (HRQOL) ....................................................................28 
5.5.1 
Generic Measures of HRQOL ................................................................................28 
5.5.2 
Vaccination Specific Measure of HRQOL...............................................................30 
5.5.3 
Perceptions of the Vaccination Experience and Methods of Adverse Event 
Monitoring .........................................................................................................................30 
5.6 
Health Care Utilization ...............................................................................................30 
5.7 
Biospecimens Collection & Handling .........................................................................30 
5.7.1 
Serum ....................................................................................................................30 
6 
LABORATORY ANALYSES .............................................................................................31 

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6.1 
Influenza Hemagglutination Inhibition (HAI) Assay ....................................................31 
7 
STATISTICAL CONSIDERATIONS ..................................................................................31 
7.1 
Analysis Plan .............................................................................................................32 
7.1.1 
Sample Size ..........................................................................................................32 
7.1.2 
Analysis Populations ..............................................................................................32 
7.1.3 
Primary Objective 1 ...............................................................................................33 
7.1.4 
Primary Objective 2 ...............................................................................................33 
7.1.5 
Primary Objective 3 ...............................................................................................33 
7.1.6 
Secondary Objective 1 ...........................................................................................34 
7.1.7 
Secondary Objective 2 ...........................................................................................34 
7.1.8 
Secondary Objective 3 ...........................................................................................35 
7.1.9 
Sensitivity Analyses ...............................................................................................35 
7.1.10 
Exploratory Objectives .......................................................................................36 
7.2 
Data Management .....................................................................................................36 
7.2.1 
Research Electronic Data Capture (REDCap) .......................................................36 
7.3 
Role of the CDC Investigators in the Project ..............................................................37 
8 
HUMAN SUBJECTS .........................................................................................................37 
8.1 
Human Subjects Involvement, Characteristics, and Design .......................................37 
8.2 
Sources of Material ....................................................................................................38 
8.3 
Potential Risks and Benefits ......................................................................................38 
8.4 
Adequacy of Protection Against Risks .......................................................................38 
8.4.1 
Protections against Risk ........................................................................................39 
8.4.2 
ClinicalTrials.gov Requirements ................................................................................39 
8.5 
Human Subjects ........................................................................................................39 
8.5.1 
Vulnerable Subjects Research ...............................................................................39 
REFERENCES .........................................................................................................................41 
APPENDIX ...............................................................................................................................43 
Appendix A:  Written Informed Consent ................................................................................44 
Appendix B:  Mini-Cog...........................................................................................................56 
Appendix C:  Rowland Universal Dementia Assessment Scale (RUDAS) .............................59 
Appendix D:  Treatment Administration Record/Immediate Reactogenicity Assessment Form
 ..............................................................................................................................................62 
Appendix E:  Patient Symptom Diary .....................................................................................65 
Appendix F:  FACES Pain Scale ...........................................................................................73 
Appendix G:  Immune-Mediated Conditions ..........................................................................75 
Appendix H:  Safety Monitoring Plan .....................................................................................77 
Appendix I:  LLFDI-CAT ........................................................................................................80 
Appendix J:  EQ-5D-5L and VAS ........................................................................................ 118 
Appendix K:  Vaccine Reaction Questionnaire .................................................................... 121 
Appendix L:  Perceptions of the Vaccination Experience ..................................................... 125 
Appendix M:  Recruitment Letter ......................................................................................... 132 
Appendix N:  Flyer ............................................................................................................... 133 
Appendix O:  Phone Script .................................................................................................. 135 
 
 

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PROTOCOL SUMMARY 
 
Title:  
Safety and Immunogenicity of Adjuvanted versus High-Dose 
Inactivated Influenza Vaccines in Older Adults 
Phase: 
Phase IV 
Population: 
≥880 community-dwelling adults ≥65 years of age who intend 
to receive the inactivated influenza vaccine (IIV) during the 
2017-2018 (Year 1) or 2018-2019 (Year 2) influenza season.  
Approximately 20% of the participants will be ≥80 years old. 
Clinical Sites: 
Three: Duke University (Lead); Boston Medical Center 
(Contributing); Cincinnati Children’s Hospital (Contributing 
Subcontractor) 
Study Duration: 
24 months total 
• 
18 months to recruit/enroll over two influenza seasons 
• 
6 weeks participation for most subjects 
• 
Maximum of 6 months participation for a subset of 
approximately 100 participants at Duke during 2017-
2018 flu season 
• 
4.5 months to perform analysis and laboratory assays 
after the end of each flu season 
• 
A subset of 60 subjects from year 1 will be revaccinated 
with same influenza vaccine product during the year 2 
influenza season at Duke 
Participant Duration: 
• 
43 days for 780 participants 
• 
181 days for approximately 100 participants at Duke for 
longer term immunogenicity studies (Year 1 only) 
• 
Approximately 14 months for 60 participants in the 
repeat vaccination sub-study (at Duke only) 
Description of Study 
Procedures: 
This is a prospective, randomized, blinded clinical trial to 
assess the safety and immunogenicity of adjuvanted 
inactivated influenza vaccine (aIIV3) versus High-Dose 
inactivated influenza vaccine (IIV3-HD) in subjects aged ≥65 
years.  Participants aged 65 to 79 years will be randomized 
(1:1) to receive either aIIV3 or IIV3-HD using a permuted block 
randomization scheme stratified by Lead and Contributing 
Site(s) for at least 704 subjects.  A separate permuted block 
will be allocated for at least 176 subjects who are age 80 years 
or older, thus achieving an overall N≥880. 
Vaccine reactogenicity will be assessed for 8 days post-

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injection and compared between the two groups using identical 
paper diaries. Serious adverse events and events of clinical 
interest will be assessed through 42 days post-vaccination and 
compared between the two groups. 
Health-related quality of life will be assessed at baseline before 
vaccination, at day 3 and day 9 post-vaccination.  Perceptions 
of the vaccination study experience and adverse event 
monitoring experience will be assessed at days 9 and 29 post-
vaccination. 
 
Vaccine strain-specific serum hemagglutination inhibition 
antibody titers will be measured from blood samples collected 
pre- and 29 days post-immunization for all participants and for 
approximately 100 subjects at Duke on Day 181 (Year 1 only). 
 
Vaccine reactogenicity, serious adverse events (SAEs) and 
events of clinical interest, health related quality of life, and 
vaccine strain-specific serum hemagglutination inhibition 
antibody titers pre- and 29 days post-immunization will be 
measured in a subset of 60 subjects in a repeat vaccination 
sub-study (at Duke only).  Subjects in the second year of the 
repeat vaccination sub-study will be assigned to receive the 
same vaccination that they received the first year. 
Objectives: 
Primary Objectives: 
1. To compare the proportions of moderate/severe 
injection-site pain after aIIV3 and IIV3-HD in the full 
study population   
a. Hypothesis:  the proportion of subjects who 
have moderate/severe injection site pain within 
the first week post-vaccination will be non-
inferior for allV3 compared to IIV3-HD in the full 
study population  
2. To compare serious adverse events and events of 
clinical interest after aIIV3 and IIV3-HD in the full study 
population and by age-group 
3. To compare the seroconversion rate for the H3N2 
influenza A strain after aIIV3 and IIV3-HD in the full 
study population  

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a. Hypothesis: the seroconversion rate for the 
H3N2 influenza A strain in the full study 
population after aIIV3 will be non-inferior to IIV-
HD 
 
Secondary Objectives 
1. To compare the proportions of local and systemic 
reactions (other than moderate/severe injection site 
pain) after aIIV3 and IIV3-HD in the full study 
population and by age-group (65-79 years and ≥80 
years) 
2. To describe and compare changes in health-related 
quality of life after aIIV3 and IIV3-HD in the full study 
population and by age-group 
3. To compare serum hemagglutination inhibition (HAI) 
antibody titers after aIIV3 and IIV3-HD for each of the 
three influenza vaccine strains contained in the 
respective vaccine for that season in the full study 
population and by age (except for seroconversion for 
the H3N2 strain in the full study population) 
 
Exploratory Objectives: 
1. To describe how the reactogenicity events affect 
health-related quality of life after IIV3 and IIV3-HD in 
the full study population and by age-group 
2. To describe and compare participant perceptions of the 
vaccination experience  
3. To describe participant perceptions of methods of 
adverse event monitoring in older adults receiving 
influenza vaccines. 
4. To describe injection site pain immediately after 
vaccination after aIIV3 and IIV3-HD  
5. To describe and compare the proportions of immediate 
adverse events after aIIV3 and IIV3-HD and unsolicited 
adverse events in the full study population and by age-
group (65-79 years and ≥80 years) 
6. To describe factors (e.g., statin use) associated with 
reactogenicity to aIIV3 and IIV3-HD 
7. To describe the safety of aIIV3 and IIV3-HD after 
repeat administration of the same product over 2 
consecutive influenza seasons in a subset of subjects   
8. To describe the relationship between reactogenicity 
and immunogenicity for aIIV3 and IIV3-HD 
9. To explore factors (e.g., statin use) associated with 
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10. To describe the immunogenicity of aIIV3 and IIV3-HD 
after repeat administration of the same product over 2 
consecutive influenza seasons in a subset of subjects  
11. To assess changes in serum hemagglutination 
inhibition at 1 month after aIIV3 and IIV3-HD 
vaccination and at 6 months after vaccination in a 
subset of subjects 
Outcome Measures: 
Primary:  
1. Comparison of the proportion of subjects reporting 
moderate/severe injection site pain within the first week 
post-vaccination in both treatment groups. 
2. The frequency and descriptions of serious adverse 
events and adverse events of clinical interest observed 
in the two treatment cohorts 
3. H3N2 HAI seroconversion:  The proportion of subjects 
achieving H3N2 seroconversion at day 29 (an HAI titer 
> 1:40 at day 29 if the baseline titer is < 1:10 or a 
minimum four-fold rise in HAI titer if the baseline titer is 
> 1:10) in the respective season’s vaccine  
 
Secondary 
1. Comparison of local and systemic reactions within the 
first week post-vaccination in both treatment groups. 
2. Change in scores on the Late Life Function & Disability 
Instrument (Year 1 only), EuroQOL 5 dimensions-5 
level (EQ-5D-5L) and EuroQOL visual analogue scale 
(EQ VAS) pre-vaccination and post-vaccination will be 
compared between the vaccination groups and age 
groups. 
3. HAI titers: 
a. The proportion of subjects achieving 
seroconversion at day 29 (an HAI titer > 1:40 at 
day 29 if the baseline titer is < 1:10 or a 
minimum four-fold rise in HAI titer if the baseline 
titer is > 1:10) for H1N1 and influenza B and 
H3N2 (by age group only) in the respective 
season’s vaccine  
b. Proportion of subjects with a seroprotective HAI 
titer (≥ 1:40) pre- and post-immunization at day 
29 for each IIV antigen in the respective 
season’s vaccine The geometric mean HAI titer 
(GMT) for each IIV antigen in the respective 
season’s vaccine 
c. The geometric mean HAI titer (GMT) for each IIV 
antigen in the respective season’s vaccine 
 

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Exploratory: 
1. Associations between moderate/severe local and 
systemic reactogenicity events and quality of life 
outcomes in the full study population and by age group  
2. Comparison between vaccination groups of proportion 
of participants with negative and positive perceptions of 
the vaccination experience based on responses to the 
Perceptions of Vaccination Experience questionnaire 
3. Proportion of participants with difficulty performing 
adverse event monitoring based on responses to 
questions to the Perceptions of Vaccination Experience 
questionnaire 
4. Mean injection site pain scores immediately after 
vaccination in both vaccination groups using the Faces 
Pain Scale 
5. Compare the frequency and descriptions of immediate 
reactogenicity and immediate serious adverse events 
and adverse events of clinical interest between 
vaccination groups. 
6. Associations between reactogenicity and demographic, 
co-morbidity and medication factors from subjects’ 
medical histories, including statin use 
7. Compare changes in local and systemic reactions in 
subjects who receive vaccine in both study years 
8. Associations between HAI titers and moderate/severe 
local and systemic reactogenicity events. 
9. Associations between HAI titers and demographic, co-
morbidity and medication factors in subjects’ medical 
histories including statin use 
10. Comparison of seroprotection and seroconversion as 
defined by HAI titers and geometric mean HAI titers in 
subjects who receive vaccine in both study years 
11. Comparison of seroprotection and seroconversion as 
defined by HAI titers and geometric mean HAI titers 
between 1 month and 6 months in the same subjects 
(Year 1 only) 
 
Estimated Time to Complete 
Enrollment: 
Approximately 6 months for enrollment during each of two 
consecutive flu seasons, for an overall duration of 18 months  

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1 BACKGROUND  
1.1 Background 
The Advisory Committee on Immunization Practices (ACIP) has long recommended influenza 
vaccination for older persons ≥65 years to prevent influenza and its complications1.  In addition 
to standard inactivated influenza vaccine (IIV), several new licensed influenza vaccines are 
available for use in older adults, including FLUAD®, an adjuvanted trivalent inactivated influenza 
vaccine (aIIV3) and Fluzone® High-Dose IIV3 (IIV3-HD).  The ACIP has not indicated a 
preferential recommendation for any of the influenza vaccine preparations approved for older 
adults2.  
Older adults are at high risk for influenza-related morbidity and mortality due to 
immunosenescence (decreased immune responses with age), multimorbidity, specific age-
related diseases (e.g, congestive heart failure, chronic lung disease) and age-related changes 
in compensatory physiologic responses to inflammatory states3-6.  Although the incidence of 
influenza is usually higher in younger adults and children than older adults, 90% of influenza- 
related deaths occur in older adults7.  From 1976-2007, the estimated average number of 
annual influenza-associated deaths with underlying respiratory and circulatory causes in 
persons aged ≥65 years was 21,098 with a maximum number of 43,7278.  The risk of 
hospitalization associated with influenza is highest in persons aged ≥65 years9.  Influenza is 
also associated with functional decline, reduced quality of life, and disability in older adults10.    
 
Influenza vaccination is an important intervention to prevent influenza and its complications in 
older adults, but the immunogenicity and effectiveness of influenza vaccines are suboptimal in 
older adults due to immunosenescence11.  Vaccine scientists have pursued different strategies 
to improve the immunogenicity and clinical effectiveness of influenza vaccine in older adults.  
One strategy is to increase the dose of hemagglutinin antigen in the vaccine12.  The IIV3-HD 
has four times the dose of hemagglutinin antigen compared to standard-dose IIV3 (IIV3-SD).  
Compared with IIV3-SD,  IIV3-HD is significantly more immunogenic for the influenza A strains 
and non-inferior for the B strain13. Studies have also demonstrated that the IIV3-HD is more 
effective in preventing influenza than IIV3-SD in older adults14,15.  A large randomized controlled 
trial showed relative vaccine effectiveness of 24% for IIV3-HD compared with IIV3-SD, which 
equated to 4 fewer cases of laboratory-confirmed influenza per 1000 persons vaccinated after 
IIV3-HD compared with IIV3-SD14.  Another strategy is to add an adjuvant to the influenza 
vaccine.  The aIIV3 contains the MF59 adjuvant which is a squalene-based, oil-in-water 
emulsion16.  Non-inferiority of aIIV3 compared with IIV3-SD was demonstrated for all three 
vaccine strains based on pre-defined thresholds for seroconversion rate differences and 
geometric mean titer ratios13.  Observational studies conducted in Europe have found that aIIV3 
is more effective in preventing influenza than IIV3-SD16.  A confirmatory, randomized controlled 
clinical trial in the United States to verify and describe the clinical benefit of aIIV3 is required by 
the FDA under the accelerated approval regulations17. 
 
Clinicians and older adult patients now face an important choice between IIV3-SD, IIV-HD3 and 
aIIV3.  The superior immunogenicity (for IIV-HD) and clinical effectiveness of IIV3-HD and aIIV3 
may sway the choice towards these products compared with IIV3-SD, but the safety of these 
vaccines is a key factor in the decision.  Although aIIV3, IIV-HD and IIV3-SD appear to have 
similar proportions of serious adverse events, aIIV3 and IIV3-HD have higher proportions of 
local and systemic reactions compared with IIV3-SD15,18.  However, IIV3-HD and aIIV3 have not 
been compared directly with regards to safety in the same trial.  In separate clinical trials, the 

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most common moderate/severe injection-site reaction was pain (4.2% aIIV3 and 4% IIV3-HD) 
and the most common moderate/severe systemic reaction was malaise/fatigue (3.5% aIIV3 and 
6.3% IIV3-HD)13,18. These rates of moderate/severe reactions are higher than those reported for 
IIV3-SD.  Moderate/severe reactions are generally those which limit or prevent usual daily 
activities.   For older persons, the ability to independently perform basic activities of daily living 
(e.g., bathing, dressing, grooming, toileting, eating, mobility) and instrumental activities of daily 
living (e.g., cooking, housework, traveling, managing money, managing medications) are critical 
to quality of life.  Any reaction that limits or prevent these activities will have a significant impact 
on health-related quality of life and is likely to be more clinically important than in younger, 
healthier populations19-21. 
 
1.2 Summary and Rationale 
The safety profile or immunogenicity of aIIV3 and IIV3-HD have not been compared head-to-
head.  The decision of which vaccine to use in older adults will be enhanced by a better 
understanding of the safety and immunogenicity of these vaccines, as well as the relative 
impact on health-related quality of life, functioning and participant perspectives of the 
vaccination experience.   Furthermore, the best method for collecting information on health-
related quality of life, functional status and other non-medically attended adverse events after 
moderate to severe injection site or systemic reactions is not known.  This study will address 
this gap in knowledge in older adults after vaccination. This study will also add value to 
pandemic influenza preparedness by providing data on risks and benefits of influenza 
vaccination in older adults that are not currently available. 
 
2 STUDY OBJECTIVES AND OUTCOME MEASURES 
2.1 Study Objectives 
2.1.1 Primary Objectives: 
1. To compare the proportions of moderate/severe injection-site pain after aIIV3 and IIV3-
HD in the full study population   
a. Hypothesis:  the proportion of subjects who have moderate/severe injection site 
pain within the first week post-vaccination will be non-inferior for allV3 compared 
to IIV3-HD in the full study population  
2. To compare serious adverse events and events of clinical interest after aIIV3 and IIV3-
HD in the full study population and by age-group 
3. To compare the seroconversion rate for the H3N2 influenza A strain after aIIV3 and IIV3-
HD in the full study population  
a. Hypothesis: the seroconversion rate for the H3N2 influenza A strain in the full 
study population after aIIV3 will be non-inferior to IIV-  

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2.1.2 Secondary Objectives 
 
1. To compare the proportions of local and systemic reactions (other than moderate/severe 
injection site pain) after aIIV3 and IIV3-HD in the full study population and by age-group 
(65-79 years and ≥80 years) 
2. To describe and compare changes in health-related quality of life after aIIV3 and IIV3-
HD in the full study population and by age-group 
3. To compare serum hemagglutination inhibition (HAI) antibody titers after aIIV3 and IIV3-
HD for each of the three influenza vaccine strains contained in the respective vaccine for 
that season in the full study population and by age (except for seroconversion for the 
H3N2 strain in the full study population) 
 
2.1.3 Exploratory Objectives: 
1. To describe how the reactogenicity events affect health-related quality of life after IIV3 
and IIV3-HD in the full study population and by age-group 
2. To describe and compare participant perceptions about the vaccination experience  
3. To describe participant perceptions of methods of adverse event monitoring in older 
adults receiving influenza vaccines. 
4. To describe injection site pain immediately after vaccination after aIIV3 and IIV3-HD 
5. To describe and compare the proportions of immediate adverse events and unsolicited 
adverse events after aIIV3 and IIV3-HD in the full study population and by age-group 
(65-79 years and ≥80 years)  
6. To describe factors (e.g., statin use) associated with reactogenicity to aIIV3 and IIV3-HD 
7. To describe the safety of aIIV3 and IIV3-HD after repeat administration of the same 
product over 2 consecutive influenza seasons in a subset of subjects   
8. To describe the relationship between reactogenicity and immunogenicity for aIIV3 and 
IIV3-HD 
9. To explore factors (e.g., statin use) associated with immunogenicity for aIIV3 and IIV3-
HD 
10. To describe the immunogenicity of aIIV3 and IIV3-HD after repeat administration of the 
same product over 2 consecutive influenza seasons in a subset of subjects  
11. To assess changes in serum hemagglutination inhibition at 1 month after aIIV3 and IIV3-
HD vaccination, and at 6 months after vaccination in a subset of subjects  
2.2 Study Outcome Measures 
 
Where possible, all outcome measures will be evaluated and compared between the two 
treatment groups for the full population and in both age subsets (65-79 years and ≥80 years) 
2.2.1 Primary Outcome Measures:  
 
1. Comparison of the proportion of subjects reporting moderate/severe injection site pain 
within the first week post-vaccination in both treatment groups. 
 
2. The frequency and descriptions of serious adverse events and adverse events of clinical 
interest observed in the two treatment groups. 
 

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3. H3N2 HAI seroconversion:  The proportion of subjects achieving H3N2 seroconversion at 
day 29 (an HAI titer > 1:40 at day 29 if the baseline titer is < 1:10 or a minimum four-fold rise 
in HAI titer if the baseline titer is > 1:10) in the respective season’s vaccine.  
 
2.2.2 Secondary Outcome Measures 
 
1. Comparison of local and systemic reactions within the first week post-vaccination in both 
treatment groups. 
2. Change in scores on the Late Life Function & Disability Instrument (Year 1 only), 
EuroQOL 5 dimensions-5 level (EQ-5D-5L) and EuroQOL visual analogue scale (EQ VAS) 
pre-vaccination and post-vaccination will be compared between the vaccination groups and 
age groups. 
3. HAI titers by vaccination group and age group (except for seroconversion to H3N2 strain 
for the full study population): 
a. The proportion of subjects achieving seroconversion at day 29 (an HAI titer > 1:40 
at day 29 if the baseline titer is < 1:10 or a minimum four-fold rise in HAI titer if the 
baseline titer is > 1:10) for H1N1 and influenza B and H3N2 (by age group only) in 
the respective season’s vaccine  
b. Proportion of subjects with a seroprotective HAI titer (≥ 1:40) pre- and post-
immunization at day 29 for each IIV antigen in the respective season’s vaccine  
c. The geometric mean HAI titer (GMT) for each IIV antigen in the respective 
season’s vaccine 
 
2.2.3 Exploratory Outcome Measures 
 
1.  Associations between moderate/severe local and systemic reactogenicity events and 
quality of life outcomes in the full study population and by age group  
2.  Comparison between vaccination groups of proportion of participants with negative and 
positive perceptions of the vaccination experience based on responses to the Perceptions of 
Vaccination Experience questionnaire. 
3.  Proportion of participants with difficulty performing adverse event monitoring based on 
responses to a questions to the Perceptions of Vaccination Experience questionnaire 
4.  Mean injection site pain scores immediately after vaccination in both vaccination groups 
using the Faces Pain Scale 
5.  Compare the frequency and descriptions of immediate reactogenicity and immediate 
serious adverse events and adverse events of clinical interest between vaccination groups. 
6.  Associations between reactogenicity and demographic, co-morbidity and medication 
factors from subjects’ medical histories, including statin use 
7.  Compare changes in local and systemic reactions in subjects who receive vaccine in 
both study years 
8.  Associations between HAI titers and moderate/severe local and systemic reactogenicity 
events. 
9.  Associations between HAI titers and demographic, co-morbidity and medication factors in 
subjects’ medical histories including statin use 
10.  Comparison of seroprotection and seroconversion as defined by HAI titers and 
geometric mean HAI titers in subjects who receive vaccine in both study years 

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11.  Comparison of seroprotection and seroconversion as defined by HAI titers and 
geometric mean HAI titers between 1 month and 6 months in the same subjects (Year 1 
only) 
 
3 STUDY DESIGN 
3.1 Main study design 
This study is a prospective, randomized, blinded clinical trial to assess the safety of aIIV3 
versus IIV3-HD in ≥440 adults age ≥65 years enrolled at Duke University Medical Center (Lead 
Contractor), ≥340 adults age ≥65 years enrolled at Boston Medical Center (BMC) (Contributing 
Contractor), and 100 adults age ≥65 years enrolled at Cincinnati (Contributing Subcontractor). 
Participants will be enrolled in 2017-18 (Duke and Boston) and 2018-19 (Duke, Boston, and 
Cincinnati) influenza seasons.  Unblinded, licensed staff will perform vaccinations, and all other 
study personnel and subjects will be blinded throughout the study, with the exception of the 
Duke Project Manager, Boston Pharmacy, and Cincinnati Pharmacy staff (who have no 
involvement with study subjects).  In addition, the study statistician will be blinded during data 
analysis.  Older adults who have not received IIV during the respective influenza seasons during 
which they are recruited will be enrolled.  Detailed health, demographic and health-related 
quality of life data will be collected from study participants at baseline prior to influenza vaccine 
receipt. With Day 1 serving as the day of vaccination, participants will be followed through Day 8 
(total 8 days) for symptoms of reactogenicity as described in Section 5.4.  Health-related quality 
of life and vaccination experience data will be collected during this time period. Participants will 
be followed through Day 43 for serious adverse events and adverse events of clinical interest, 
including health care utilization, as described in Sections 5.4 and 5.6.   
3.2 Laboratory Studies 
 
3.2.1 Influenza Hemagglutination Inhibition Assay 
Participants will have blood draws on Day 1 (before vaccination) and Day 29 to be 
stored for serum hemagglutination inhibition (HAI) antibody titers.  During 2017-18 
influenza season (Year 1), a subset of approximately 100 patients at Duke will have 
a blood draw at Day 181 for an additional HAI titer. If funding is available, HAI 
antibody titers will be compared between groups receiving aIIV3 or IIV3-HD for each 
of the three influenza vaccine strains contained in the respective vaccines for that 
season.  Additionally, if funding available, 60 year 1 participants will receive repeat 
immunization with the same vaccine in year 2 at Duke, and HAI titers will be 
performed on serum from Day 1 and Day 29.  Participants will not receive individual 
HAI antibody titer results; these are not routinely used in clinical practice.  
 
3.2.2 Future studies 
Additional blood will be stored for further immune analyses depending on funding 
availability. Biologic specimens collected as part of this study and used in other 
studies examining the immune response to influenza vaccine will be linked to 
information (including identifying information) that participants provided in the current 
study. Participants are not expected to receive results of any future testing of their 
specimens.   
 

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4 STUDY ENROLLMENT AND WITHDRAWAL  
4.1 Subject Inclusion Criteria 
Subjects who meet all of the following criteria will be eligible to participate in this 
interventional study.   
1. Persons aged ≥65 years, living in the community 
2. Intention of receiving IIV vaccine based on ACIP-CDC guidelines   
3. Willing to provide written informed consent prior to initiation of any study procedures 
4. Able to speak English 
5. Able and willing to complete baseline assessments and questionnaires, and to allow 
information to be collected from their electronic medical record 
6. Able and willing to complete post-vaccine assessments and questionnaires 
independently or with assistance  
7. Able and willing to have blood drawn for the study 
8. Able and willing to return in about one month for a follow-up visit including completing 
questionnaires and having another blood test 
9. Access to and ability to use a phone, independently or with assistance  
10. Adequate vision and motor skills to complete the symptom diary form independently or 
with assistance. 
11. Not living in a skilled nursing facility/nursing home/long term acute care facility 
4.2 Subject Exclusion Criteria 
Subjects who meet any of the following criteria will not be eligible to participate in this 
study: 
1. Influenza vaccine receipt during the current influenza season prior to study enrollment 
2. Enrolled in this study during the 2017-18 (Year 1) influenza season 
Note: Year 1 study participant will only be enrolled in Year 2 if they are 
participating in the sub-study on repeat vaccination 
3. Has immunosuppression as a result of an underlying illness or treatment, or use of anti-
cancer chemotherapy or radiation therapy within the preceding 12 months. 
4. Has an active neoplastic disease (excluding non-melanoma skin cancer or prostate 
cancer that is stable in the absence of therapy) or a history of any hematologic 
malignancy* 
*Participants with a history of malignancy may be included if, after previous treatment by 
surgical excision, chemotherapy or radiation therapy, the participant has been observed 
for a period that in the investigator’s estimation provides a reasonable assurance of 
sustained cure 
5. Thrombocytopenia, bleeding disorder, or anticoagulant use contraindicating 
intramuscular injection  
6. Receipt of blood or blood-derived products in the past three months 
7. History of febrile illness (> 100.0°F or 37.8°C) within the past 24 hours prior to IIV 
administration (temporary deferral) 
8. Contraindication to IIV receipt including history of severe allergic reaction after a 
previous dose of any influenza vaccine; or to a vaccine component*, including egg 
protein; or a latex allergy 
*Formaldehyde, Octylphenol ethoxylate, neomycin, kanamycin, barium, 
cetyltrimethlyammonium bromide (CTAB) 
9. Any history of Guillain-Barré syndrome  

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10. Mild to severe dementia as determined by the Mini-Cog tool and the Rowland Universal 
Dementia Assessment Scale (RUDAS) 
11. Substance use that could interfere with study compliance 
12. Receipt of any inactivated licensed vaccine within 2 weeks, or live attenuated licensed 
vaccine within 4 weeks prior to enrollment in this study, or planning receipt of any 
vaccines during the 42 days post-vaccination period (including pneumococcal vaccines) 
13. Receipt of Shingrix (Zoster Vaccine Recombinant, Adjuvanted) or HEPLISAV-B 
(Hepatitis B Vaccine (Recombinant), Adjuvanted) vaccine within 6 weeks prior to 
enrollment in this study, or planning receipt of Shingrix or HEPLISAV-B during the 42 
days post-vaccination period.  
14. Anyone who is already enrolled or plans to enroll in another clinical trial with an 
investigational product within 28 days of vaccine receipt. Co-enrollment in observational 
or behavioral intervention studies are allowed at any time while enrollment in a clinical 
trial involving an investigational product (other than vaccine) may occur after 30 days 
following vaccine receipt. 
15. Hearing loss determined by the investigators to prevent successful communication over 
the phone 
16. Any condition which, in the opinion of the investigators, may pose a health risk to the 
subject or interfere with the evaluation of the study objectives.   
17. Anyone who is a relative or subordinate of any research study personnel.   
4.3 Recruitment 
Participants ≥65 years of age will be recruited from several sources at Duke University Medical 
Center (DUMC), Boston Medical Center (BMC), and Cincinnati using varying techniques.  Study 
investigators will enroll at least 440 persons including at least 20% adults ≥ 80 years of age at 
Duke over two seasons (~220 participants per season), ~340 persons including at least 20% 
adults ≥ 80 years of age at Boston over two seasons (~170 per season), and ~ 100 persons 
including at least 20% adults ≥ 80 years of age at Cincinnati in 2018-2019 only.    During 2017-
2018 at Duke only, a subset of approximately 100 subjects will be assigned to receive an 
additional blood draw at day 181 (Section 5.2.1). 
 
The general techniques for how subjects will be recruited include the following:  Study staff, 
including PIs and study nurses, will approach their patients in clinic directly about the study 
during clinic visits; notify other health care professionals in their health system about the study 
via letters and flyers for potential referrals; notify potential subjects about the study via study 
registries and recruitment service programs;  letters and talks to senior groups in various 
venues including Senior Centers and Continuing Care Retirement Communities;  advertising in 
newspapers; flyers posted at senior locations; letters and talks to potential referral sources; and 
letter campaigns to older adults in the surrounding catchment area.  More specific mechanisms 
to DUMC, BMC, and Cincinnati are described below.   
 
At DUMC potential subjects will be approached via the following mechanisms:  1) Older 
participants of previous vaccine studies who have agreed to enroll in future studies; 2) Duke 
Center for Aging Human Subjects Registry, a unique long-standing registry of over 3000 
individuals who volunteer for human studies; 3) Croasdaile and The Forest at Duke continuing 
care retirement communities. Medical care for these communities is provided by the Duke 
Division of Geriatrics, overseen by Dr. Schmader; 4) Duke’s “Aging” network of senior centers; 
senior activities; and referrals from professionals who work with seniors cultivated via the work 

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of the Center for Aging; 5) Duke Geriatric Evaluation and Treatment Clinic (GET Clinic) and 
Duke University Health System primary care clinics.  These sources are likely to be sufficient, 
but if not, we will utilize other past successful strategies such as a letter campaign to 
households of older adults and advertising in senior citizen newspapers and general local 
newspapers.  
 
At BMC, recruitment will take place in the Boston Medical Center Geriatric Ambulatory Practice, 
during routine primary care visits and during dedicated influenza vaccine clinics.  Information 
about the study will also be posted on the BMC Recruitment Services Program of the Clinical 
Translational Science Institute (ReSPECT) Registry, a source of research study information 
available to the BMC community.  The BMC Clinical Research Resources Office may also help 
identify approaches to recruit subjects.  We may also recruit older adults from outside the BMC 
system using databases available to the BMC investigators, or advertisements in local 
newspapers known to carry information about research studies recruiting participants. 
 
At Cincinnati (CCHMC), recruitment will take place at Maple Knoll Village, a retirement community 
with over 800 older adults living independently and the greater Cincinnati community through the 
CCHMC Office of Clinical Trials (OCTR). Participants will be recruited via Lunch and Learn 
Seminars, the resident newsletter, the community e-newsletter, information sessions at their 
happy hours, direct approach pieces in their mailboxes, employee email, CCHMC flyer boards 
and OCTR approved social media postings. Subjects will conduct study visits either at the clinic 
within Maple Knoll Village or at the Schubert Research Clinic at CCHMC. 
 
At all sites, existing patients may be approached by phone call.  The study will be reviewed with 
the patient, and if the patient is interested, then initial eligibility screening will take place on the 
phone following an IRB-approved script.  A waiver of documentation of consent will be approved 
from the reviewing IRB in order to carry out these screening activities. 
 
A subset of approximately 60 subjects enrolled and vaccinated in the first year of the study at 
Duke will be included in a repeat vaccination sub-study in the second year of the study.  The 
sub-study will explore the safety and immunogenicity of repeat vaccination with the same 
vaccine product in the subsequent influenza season.  The study enrollment procedures will be 
the same, with the following modifications: At the time of enrollment in the first year, the subjects 
will be asked in sequential order if they would like to participate in a repeat vaccination sub-
study during the next season. The first subjects enrolled at Duke (up to n=60), who express 
interest in this repeat vaccination sub-study will be included. Subjects need not consent to this 
part of the study to participate in the main study.  In the first year, this convenience sample of 
sub-study subjects will undergo the same randomization procedures as other subjects in section 
5.2.1.  The subjects will complete procedures for the first study influenza season as in section 
5.1.  Contact information will be maintained, and subjects will be contacted and reminded to 
return to the study center in September/October the next influenza season. Upon return for the 
second year of the study, subjects will be consented for the sub-study and screened to see if 
they continue to meet the study eligibility criteria.  In year 2, these subjects will receive the same 
vaccine product as in year 1, using the formulation licensed by FDA for the year 2 season; 
influenza strains included in the vaccines may be different in the consecutive years. These 
subjects will remain blinded to the vaccine product in Year 2.  Year 1 study participants will only 
be enrolled in Year 2 of the study if they consent to and are still eligible for participating in the 
sub-study on repeat vaccination. 

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4.4 Reasons for and Handling of Withdrawals 
The following may be reason for study withdrawal: 
• 
As deemed necessary by the principal investigator (PI).  
• 
Subject withdrawal of consent. 
• 
Loss to follow-up. 
• 
Subject unable to return for study appointments 
• 
Termination of the study by the sponsor. 
• 
Subjects not meeting eligibility criteria in the repeat vaccination study will be withdrawn 
at the time this is determined 
 
Subjects may withdraw their consent for study participation at any time and for any reason, 
without penalty. Subjects who withdraw from the study prior to randomization will be replaced. 
Subjects who withdraw from the study after randomization will not be replaced. Data collected 
before withdrawal will still be used for analysis. 
 
4.5 Termination of Study 
This study may be terminated for safety concerns of the principal investigators from the Lead or 
Contributing sites, CDC, or participating Institutional Review Boards (IRBs).   
 
5 STUDY SCHEDULE, PROCEDURES, & EVLAUTIONS  
5.1 Schedule of events and data collection 
Persons meeting the proposed eligibility criteria (Section 4) will be recruited. Written informed 
consent (Appendix A) will be obtained from study participants prior to conducting any study 
procedures. Prescreening may take place over the phone prior to Visit 1. Table 1 describes the 
schedule of study visits with further details below.   
Table 1.  Visit Schedule 
Procedure 
Visit 1 
Day 1 
Visit 2 
Day 3 + 2 
 Unscheduled 
Visit 
Visit 3 
Day 9 + 3 
Visit 4 
Day 29 + 7 
 
Visit 5 
Day 43 + 7 
Visit 6 
Day 181 + 
14a 
Type of contact 
Clinic 
Phone or 
Clinic 
Clinic 
Phone or 
Clinic 
Clinic 
Phone or 
Clinic 
Clinic 
Informed consent & 
Medical Release of 
Information 
X 
 
 
 
 
 
 
Review Eligibility 
Criteria 
X 
 
 
 
 
 
 
Cognitive 
Assessment 
X 
 
 
 
 
 
 
Sociodemographics 
X 
 
 
 
 
 
 
Medical history 
X 
X 
X 
X 
X 
X 
X 
Medications, 
including statins 
X 
X 
X 
X 
X 
X 
X 
Influenza Vaccination 
History 
X 
 
 
 
 
 
 
Vital 
signs/temperature 
X 
 
X 
 
X 
 
X 
Body mass index 
X 
 
 
 
 
 
X 
Obtain health-related 
quality of life 
assessment 
X 
 
 
Xe 
 
 
 

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Procedure 
Visit 1 
Day 1 
Visit 2 
Day 3 + 2 
 Unscheduled 
Visit 
Visit 3 
Day 9 + 3 
Visit 4 
Day 29 + 7 
 
Visit 5 
Day 43 + 7 
Visit 6 
Day 181 + 
14a 
Participant 
perception of 
vaccination  
Xd 
 
 
Xd 
Xd 
 
 
Baseline 
reactogenicity 
Xc 
 
 
 
 
 
 
Venipuncture 
X 
 
 
 
X 
 
X 
Randomization 
Xd 
 
 
 
 
 
 
Vaccination 
X 
 
 
 
 
 
 
Diary & supplies 
X 
 
 
 
 
 
 
Assess for injection 
site pain at least 15 
min. after 
immunization 
X 
 
 
 
 
 
 
At ≥ 15 min. assess 
for any immediate 
reactogenicity 
symptoms 
X 
 
 
 
 
 
 
Obtain solicited 
adverse events 
 
X 
Xb 
X 
 
 
 
Obtain unsolicited 
adverse events 
 
X 
X 
X 
X 
X 
 
Obtain SAE 
information, AEs of 
clinical interest, and 
new onset medical 
conditions 
 
X 
X 
X 
X 
X 
 
Obtain health care 
utilization data 
 
X 
X 
X 
X 
X 
 
aFor subset of approximately 100 subjects receiving third blood draw 6 months post-vaccination in 2017-18 
bFor unscheduled visits, solicited AEs will be collected only for days ≤9 
cBaseline reactogenicity will be performed before venipuncture and vaccination 
dDoes not apply to subjects participating in the Year 2 repeat vaccination during study Year 2 
eWill collect Day 3 and Day 9 health related quality of life instruments (EQ-5D-5L and Vaccine Reaction 
Questionnaire) on V3 phone call 
 
Visit 1, Study Day 1 - Screening, Enrollment, and Vaccination (Clinic Visit) 
• Obtain written informed consent and release of medical record information 
• 
Note: In Year 2, subjects participating in the sub-study on repeat vaccination will 
sign a new consent form  
• Determine if subject will participate in long term immunogenicity sub-study or repeat 
vaccination sub-study (Year 1 only) 
• Review and confirm study eligibility 
• Perform cognitive assessment with the Mini-Cog tool22 (and RUDAS if needed)(Appendix 
B,C) 
• 
Scores 3-5 on MiniCog will be eligible  
• 
Scores 0-1 on MiniCog will be ineligible 
• 
Scores of 2 on MiniCog:  person will undergo further screening with RUDAS. If 
person scores 23 or higher (range = 0-30), they will be eligible. 
• 
Potential participants may have low scores on the cognitive screening tests and be 
ineligible for the study.  In this case, the study doctor or designee will review the 
results with the individual and recommend follow-up with the individual’s health care 
provider. 

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• Obtain information on preferred method of contact for follow-up (telephone or email 
reminder), and obtain contact info for caregiver/significant other 
• Obtain demographic data 
• 
Age, gender, race/ethnicity, language spoken, contact information, education, 
insurance payer, employment status, living alone or not 
• Obtain medical history including chronic conditions, hearing and sensory impairment, chronic 
pain 
• Obtain concomitant medications, including use of statin medications. 
• Obtain influenza immunization history for the previous two seasons (identify whether vaccine 
used was FLUAD, Fluzone-High Dose, some other inactivated influenza vaccine, or unknown, and 
indicate if this information came from the patient or their chart) 
• Obtain vital signs including oral temperature, blood pressure, and pulse; and height and 
weight in order to calculate body mass index (BMI) 
• Obtain baseline health-related quality of life assessments prior to vaccination (Section 5.5) 
• Obtain answers to first two questions of perceptions of the vaccination experience questionnaire 
• Perform pre-vaccination baseline immediate reactogenicity assessment  (Appendix D) 
• Obtain one tube of blood (~10 mL) prior to vaccination for serologic analysis (Section 5.7.1) 
• 
If unable to draw blood, subject will remain in study 
• 
If less than 1 mL of processed serum is collected, it is a protocol deviation 
• Randomize study participant to aIIV3 or IIV3-HD administration (Section 5.2.1) 
• 
Subjects in the second year of the repeat vaccination sub-study will be assigned 
to receive the same vaccination product that they received the first year (using the 
FDA-formulation for the year 2 season)  
• 
Administer assigned study products – Unblinded trained, licensed staff will administer either 
aIIV3 or IIV3-HD as described in Section 5.3.1. Ensure participants receive inactivated 
influenza Vaccine Information Sheets (VIS) during visit. 
(https://www.cdc.gov/vaccines/hcp/vis/vis-statements/flu-largetype.pdf) Participants and 
study staff doing follow-up evaluations are to remain blinded. 
• Dispense symptom diary (Appendix E), paper version of EQ-5D-5L quality of life tool, oral 
digital thermometer with large display, and injection site measurement tool with 
predetermined local reaction measurement scales. Review instructions for use of 
thermometer, injection site reaction measurement tool, diary completion, and EQ-
5D-5L.  Encourage participants to complete diary at the same time every evening. 
Should a subject misplace the study-provided thermometer, any oral thermometer 
can be used for symptom diary reporting. 
• Assess for immediate injection site pain using the Faces Pain Scale (Appendix F), at ≥ 15 
minutes after vaccination 
•  At ≥ 15 minutes after vaccination assess for any immediate reactogenicity symptoms and 
other adverse events using the assessment form used for baseline reactogenicity 
(Appendix D) 
• Confirm preferred method of contact for follow-up (telephone or email reminder) 
• Confirm date of next appointment 
 
Study Days 1 – 8 
Participants complete symptom diary form and FACES pain scale (injection site pain) on days 
1-8 and complete the paper version of EQ-5D-5L on Day 3. 

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Visit 2, Study Day 3 (window Days 3 – 5) Phone Call or Clinic Follow-Up 
Study staff will contact study participants to review and record the following: 
• 
Diary data and any solicited and unsolicited AEs, SAEs, adverse events of clinical 
interest, any new medical conditions, and any change in medications as described in 
Section 5.4. 
• 
Health care utilization data (Sections 5.6).   
• 
Participants will be reminded to complete diary card, and the health related quality of life 
questionnaires, EQ-5D-5L and Vaccine Reaction Questionnaire at home and that they 
will be contacted again after Day 8. Study team members have the option to complete the 
EQ-5D-DL and/or Vaccine Reaction Questionnaire over the phone or in person with the 
subject 
• 
Should this visit not occur or occur out of window, it will not be a protocol deviation 
 
 
Visit 3, Study Day 9 (window Days 9 – 12) Phone Call or Clinic Follow-Up 
Study staff will contact study participants to review and record the following: 
• 
Diary data and any solicited and unsolicited AEs, SAEs, adverse events of clinical 
interest, any new medical conditions, and any change in medications as described in 
Section 5.4. 
• 
Health-related quality of life assessment administered by study personnel (Section 5.5) 
• 
Participant perception of vaccination experience (Section 5.5.3) 
• 
Participant experience will not be recorded for subjects in the second year of the 
repeat vaccination sub-study.  
• 
Collect responses from the Day 3 EQ-5D-5L and Vaccine Reaction Questionnaire 
• 
Health care utilization data (Sections 5.6).   
• 
Participants who are lost to follow-up by phone contact will be called weekly until contact 
made or until approximately Day 47, whichever comes first, following vaccination for 
safety assessment.  
 
Visit 4, Study Day 29 (window Days 22 – 36) Clinic Visit 
• Obtain vital signs including oral temperature, blood pressure, and pulse 
• Record any unsolicited AEs, SAEs, adverse events of clinical interest, any new medical 
conditions, and any change in medications (Section 5.4) 
• Participant perception of vaccination experience (Section 5.5.3) 
• 
Participant experience will not be recorded for subjects in the second year of the 
repeat vaccination sub-study.  
• Record health care utilization data (Section 5.6.) 
• Obtain one tube of blood (~10 ml) for serologic analysis (Section 5.7.1) 
• 
If less than 1 mL of processed serum is collected, it is a protocol deviation 
• Confirm preferred method of contact for follow-up (telephone or email reminder) 
 
Visit 5, Study Day 43 (window Days 43 – 50) Phone Call or Clinic Follow-up  
• Record any unsolicited AEs, SAEs, adverse events of clinical interest, any new medical 
conditions, and any change in medications (Section 5.4) 
• The study team will follow-up on any SAEs to the extent possible that occurred during the 43-day 
study period, even if follow-up occurs after the Day 43-50 window. 

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• Record health care utilization data (Section 5.6.) 
 
Visit 6, Day 181 (window Days 181-195) Clinic Visit for immunogenicity subset at Duke 
during 2017-2018 season only, (n ≥ 100) 
• Review changes in medical history and medications and AEs/SAEs 
• Obtain vital signs and BMI 
• Obtain one tube of blood (~10 ml) from subset of approximately 100 subjects for serologic 
analysis (Section 5.7.1) 
• 
If less than 1 mL of processed serum is collected, it is a protocol deviation 
 
Unscheduled Visits associated with study/vaccine (≤43 days) 
• Obtain vital signs including oral temperature, blood pressure, and pulse 
• Record any solicited (≤ day 9) AEs, unsolicited (≤ day 43) AEs, SAEs, adverse events of 
clinical interest, new onset chronic medical conditions, and concomitant medications (≤ day 
43) as described in Section 5.4 
• Obtain health care utilization data (Section 5.6) (≤ day 43) 
• Confirm preferred method of contact for follow-up (telephone or email reminder) 
 
End of Study 
After unblinding, study staff will contact subjects to inform them which vaccine they received. 
Study staff will also inform primary care providers which vaccine their patient received. 
Subjects will be provided with a letter thanking them for their participation and a plain language 
summary of the main results of the study when available.  The main results will not be provided 
to participants earlier than public release of the findings.  
 
5.2 Treatment Assignment Procedures 
This study is a prospective, randomized, blinded clinical trial involving subjects aged ≥65 years 
of age who are to receive IIV vaccines.   
5.2.1 Randomization 
Participants aged 65 to 79 will be randomized (1:1) to receive either aIIV3 or IIV3-HD using a 
permuted block randomization scheme stratified by Lead and Contributing Site(s) for a total of 
≥704 subjects.  In Year 1 there will be 2 sites (Duke and Boston) and in Year 2 there will be 3 
sites (Duke, Boston, and Cincinnati).  A separate permuted block will be allocated for ≥176 
subjects who are age 80 or older, thus getting an overall N≥880.  Additionally, the first ≈100 
patients at Duke who opt-in will be assigned to return on day 181 for an additional blood draw.  
The repeat vaccination sub-study in year 2 will use a convenience sample and will not require a 
1:1 distribution of subjects into the two study arms, and may include Duke subjects in the 
waning immunity sub-study (i.e., those that consented to blood draw at Study Day ≥181).  The 
project statistician will generate permuted block randomization schemes that will be uploaded to 
the Research Electronic Data Capture (REDCap) study database (Section 7.2). The 
randomization schedule will not be available to the study staff, so the next randomization 
allocation will not be known before randomization occurs. Following confirmation of study 
eligibility criteria during Visit 1, participant randomization will be through REDCap with treatment 
allocation recorded on the case report form (CRF) by unblinded research staff who administer 
the vaccine.   Participants and study staff doing follow-up evaluations will not have access to the 
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randomization will occur through the use of envelopes. The project statistician will prepare 20 
envelopes per age group per site (total of 40 per site) that will use the same randomization 
strategy as the primary scheme embedded in REDCap. When an unblinded team member is 
informed of the age group, he/she will pull the next envelope in order. In order to capture the 
allocation per subject, a separate form in REDCap will be used by the unblinded personnel to 
add the assignment. A log will need to be kept at the site capturing these instances. 
 
 
5.3 Data Collection 
5.3.1 Vaccine Supply, Storage, Administration, and Blinding 
In order to ensure adherence to study randomization assignment, licensed aIIV3 FLUAD® 
(Seqirus) and IIV3-HD Fluzone® High-Dose (Sanofi) vaccines will be administered as study 
procedures. FLUAD® and Fluzone® High-Dose vaccines (prefilled syringes) will be purchased 
for study administration and maintained at the respective study locations and stored at 2° to 8°C 
in a research-specific medication refrigerator according to package insert specifications and 
site-specific standard operating procedures (SOPs). While research staff maintain daily 
temperature logs for the medication refrigeration, it is also monitored 24/7 with alarm activation 
if out of range. Research staff are notified of any alarm activations and have an on-call system 
in place to report to the research center for further investigation. Any potentially compromised 
vaccine will be quarantined for further disposition based on site-specific standard operating 
procedures (SOPs) and investigator assessment.   
A single administration of both aIIV3 and IIV3-HD comprises intramuscular delivery of 0.5mL 
total volume of each vaccine for adults. Vaccine type, lot number, dosage, and site of vaccine 
administration will be recorded by research staff.  There is a visual difference between aIIV3 
and IIV3-HD, therefore the study will involve personnel who are blinded to the treatment 
allocation and data analysis and different personnel who are unblinded to treatment allocation.   
• 
Emergency management supplies will be available for initial treatment of an allergic 
reaction, if needed.  
 
The following groups will be blinded to treatment allocation: 
• Investigational site staff performing data collection and analysis including the Investigator  
• Participants 
The following study personnel will be unblinded to treatment allocation: 
• Investigational site staff involved in preparation and administration of the study vaccines. 
Unblinded personnel may also assist in pre-vaccination assessments of study subjects. 
aIIV3 and IIV3-HD will be administered in blinded participants in the deltoid, preferably in the 
non-dominant arm by unblinded licensed staff.  In order to keep the participant blinded, the 
vaccine administrator will keep the prefilled syringes out of view of the participant at all times 
and will instruct the participant to turn their head in the opposite direction of the arm in which the 
vaccine is being administered. Similar instructions will be given to any persons accompanying 
the patient in the room.  After administration, used study syringes will be disposed of according 
to site-specific SOPs.  A licensed provider (MD, NP, PA, DO, RN), who will be trained on 
treating adverse reactions, will be present and immediately available at the time of vaccine 
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allergic reaction if needed.  Additionally, clinical members of the blinded data collection team will 
be present to assist study subjects. 
 
The participant and primary care provider will receive documentation of receipt of influenza 
vaccine without specification of whether it was high dose or adjuvanted vaccine to preserve 
blinding.   In the event of individual participant clinical safety issues or overall study safety 
concerns, then blinding may be broken 
 
5.4 Reactogenicity and Safety Assessment 
Participants will have an assessment of well-being and reactogenicity symptoms at baseline 
(pre-vaccination) and will be assessed for any immediate reactogenicity or other unsolicited 
adverse events at least 15 minutes after vaccine administration while at the study site.  They will 
be assessed for medical symptoms (e.g., fatigue, malaise, myalgia, arthralgia, headache, 
nausea) at baseline and at ≥15 minutes after vaccination using the assessment form in 
Appendix D.  They will be assessed for any potential injection site reactions including 
tenderness, pruritus, ecchymosis, erythema or induration at baseline and at ≥15 minutes 
following vaccination.  They will also be assessed for potential systemic reactions such as 
anaphylaxis related symptoms (e.g., dyspnea, chest tightness, wheezing, cough, stridor, 
urticaria, flushing, nasal congestion, dizziness, syncope, diaphoresis, emesis) immediately 
following vaccination until discharge.  The severity of any reaction will be graded according to 
the severity ratings in Tables 3 and 4.  Injection site pain severity will be assessed at ≥15 
minutes after vaccination using the FACES pain scale23 with 0-10 numeric rating, with 4-6 being 
moderate pain and 7-10 being severe pain (Appendix F).    
 
In addition to immediate post-vaccination assessments, the occurrence of adverse events 
[including  SAEs (Section 5.4.2), solicited reactogenicity events, and unsolicited adverse events  
(including events of clinical interest (Section 5.4.1.1)], new onset of medical conditions, 
concomitant medication use, and unscheduled medical care will be assessed daily through 
post-vaccination Day 8 using a standard symptom diary. Participants will also be instructed to 
self-report worst pain at the injection site in the past 24 hours using the Faces Pain Scale 
through post-vaccination Day 8.  At the time of immunization, participants will be given a 
thermometer and injection site reaction measurement aid and instructed on using the symptom 
diary to document oral temperatures and post-injection symptoms. Beginning on the evening of 
Study Visit 1 (Day 1) following vaccination, participants will record their oral temperature using 
the study-supplied thermometer, the occurrence of AEs, and concomitant medication use for 
Days 1 – 8. Temperature will be recorded at roughly the same time each day. If a temperature ≥ 
99.5°F (37.5°C) is recorded, a second measurement will be taken. If more than one temperature 
is taken on the same day, the highest temperature should be recorded. Participants will be 
queried during Visits 2 and 3 to review solicited injection site AEs that occurred each day, with 
the help of the information they have recorded in the symptom diary.  These AEs will be 
classified as mild, moderate, or severe based on the criteria used for licensure of Fluzone® 
High-Dose and FLUADTM and as described in Table 2.   

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Table 2. Solicited Injection-site Reactogenicity 
Symptom 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Pain  
Noticeable with no 
limitation in normal daily 
activity 
Some limitation in 
normal daily activity  
Completely unable to 
perform normal daily 
activity 
Tenderness  
Noticeable with no 
limitation in normal daily 
activity 
Some limitation in 
normal daily activity  
Completely unable to 
perform normal daily 
activity 
Shoulder Pain on Side 
of Vaccination 
Noticeable with no 
limitation in normal daily 
activity 
Some limitation in 
normal daily activity  
Completely unable to 
perform normal daily 
activity 
Induration/  
Swelling 
Any to <25 mm 
≥25 to <50  mm 
≥50 mm 
Erythema/ 
Redness  
Any to <25 mm 
≥25 to <50  mm 
≥50 mm 
 
Participants will also be queried during Visit 3 on common post-injection systemic symptoms as 
described in Table 3. Participants will also be encouraged to report any significant unsolicited 
adverse events in an open-ended question format, e.g. “How are you doing? Are you having any 
new issues since we saw you last? If so, please tell me about them.” Unsolicited adverse events 
will be graded as described in Table 4.  Participants who report severe solicited adverse events 
or express any concern about symptoms/unsolicited events will be encouraged to follow up with 
their primary care provider. Study staff will assist with coordination of referral appointments as 
necessary. Medical records will be obtained and reviewed for any unscheduled medical 
appointment through post-vaccination Day 43.  
 
Table 3. Solicited Systemic Reactogenicity 
Systemic 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Fever (° C)         
           (° F) 
 ≥37.5 -  ≤38.0 
≥99.5 -  ≤100.4 
>38.0 -  ≤39.0 
>100.4 - ≤102.2 
>39.0 
>102.2 
Chills 
Noticeable with no 
limitation in normal daily 
activity 
Some limitation in 
normal daily activity  
Completely unable to 
perform normal daily 
activity 
Fatigue 
Noticeable with no 
limitation in normal daily 
activity 
Some limitation in 
normal daily activity  
Completely unable to 
perform normal daily 
activity 
Malaise 
Noticeable with no 
limitation in normal daily 
activity 
Some limitation in 
normal daily activity  
Completely unable to 
perform normal daily 
activity 
Myalgia  
Noticeable with no 
limitation in normal daily 
activity 
Some limitation in 
normal daily activity  
Completely unable to 
perform normal daily 
activity 
Arthralgia 
Noticeable with no 
limitation in normal daily 
activity 
Some limitation in 
normal daily activity  
Completely unable to 
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Systemic 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Nausea 
Noticeable with no 
limitation in normal daily 
activity 
Some limitation in 
normal daily activity  
Completely unable to 
perform normal daily 
activity 
Vomiting 
Noticeable with no 
limitation in normal daily 
activity 
Some limitation in 
normal daily activity  
Completely unable to 
perform normal daily 
activity 
Diarrhea 
Noticeable with no 
limitation in normal daily 
activity 
Some limitation in 
normal daily activity  
Completely unable to 
perform normal daily 
activity 
Headache 
Noticeable with no 
limitation in normal daily 
activity 
Some limitation in 
normal daily activity  
Completely unable to 
perform normal daily 
activity 
 
Table 4  Unsolicited Adverse Events 
Systemic Illness 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Illness or clinical 
adverse event 
Noticeable with no 
limitation in normal daily 
activity 
Some limitation in 
normal daily activity  
Completely unable to 
perform normal daily 
activity 
 
 
We will monitor study participants for the development of new onset acute or chronic medical 
conditions during the protocol-defined surveillance period of 42 days post-vaccination.  These 
AEs will be reviewed periodically by a safety monitoring panel (Section 5.4.3). We will monitor 
study participants for SAEs during the protocol-defined surveillance period of 42 days post-
vaccination and up to 181 days for the longer-term immunogenicity subset (Section 5.4.2). 
5.4.1.1 
Adverse events of clinical interest 
We will also collect information regarding the occurrence of any adverse events of clinical 
interest.  Events of clinical interest include syncope during post-vaccination monitoring in clinic, 
anaphylaxis in the first 24 hours after immunization, and new onset immune-mediated disease 
as defined in Appendix G. 
 
5.4.1.2 
Causality (relatedness) Assessment  
Study site investigators will assess relatedness to vaccine or study procedures (related, possibly 
related, unlikely related, or not related) for SAEs, AEs, and AEs of clinical interest. Relatedness 
determinations of these events will inform IRB reporting and safety monitoring (Section 5.4.3).    
Solicited symptoms in Table 3 will all be considered to be related to vaccine and causality 
assessment will not be done for these events. The study investigators will use their clinical 
judgement to make causality assessments and may consult the Expert Safety Panel or CISA 
Project for assistance with causality determinations. The final causality assessment decision is 
the responsibility of the site PI where the subject was enrolled. 
 
 
 
 
 

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5.4.2 Reporting of Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
If indicated, AEs occurring during the study will be reported to the Vaccine Adverse Event 
Reporting System (VAERS). The National Childhood Vaccine Injury Act requires healthcare 
providers to report the following AEs to VAERS: 
• 
Any adverse event listed by the vaccine manufacturer as a contraindication to further 
doses of the vaccine; or 
• 
Any adverse event listed in the VAERS Table of Reportable Events Following 
Vaccination [PDF - 75KB] that occurs within the specified time period after vaccination. 
In addition, CDC encourages reporting of any clinically significant adverse event that occurs in a 
patient following a vaccination, even if there is uncertainty regarding if a vaccine caused the 
event. 
 
 
A serious adverse event (SAE) is defined as an AE that meets one of the following conditions24: 
• Results in death 
• Is life-threatening (defined as immediate risk of death at the time of the event) 
• Requires inpatient hospitalization (initial or prolonged) 
• Results in a persistent or significant disability/incapacity 
• Any other important medical event that may not result in death, be life threatening, or require 
hospitalization, may be considered an SAE when, based upon appropriate medical judgment, 
the event may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above.   
 
 
SAE and AE reporting will occur consistent with institutional policy. The original verbatim terms 
used by investigators to identify SAEs and adverse events of clinical interest in the case report 
form will be mapped to preferred terms using the Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary (http://www.meddra.org/).  
 
 Vaccine-related SAEs will be medically attended per routine care  
 
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 reported promptly to the reviewing IRBs and CDC, in accordance with institutional 
procedures. 
 
The duration of subject’s participation in the study varies based on their involvement in the 
immunogenicity sub-study. Therefore, the period for monitoring and reporting SAEs varies 
among subjects as shown below: 
 

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• 
Subjects NOT participating in long-term immunogenicity subset: duration of study 
participation is 42-days post vaccination 
• 
Subjects participating in long-term immunogenicity subset: duration of study participation is 
181 days post-vaccination 
 
The study will report only SAEs occurring during each subject’s participation in the study. 
 
More information on potential risks and benefits is located under Human Subjects, section 8.3. 
5.4.3 Safety Monitoring Plan 
Although FLUAD® and Fluzone® High-Dose are licensed vaccines, there is less US safety 
experience with these vaccines than with standard influenza vaccines, particularly for FLUAD®, 
which was recently licensed in the United States (November 24, 2015). Fluzone® High Dose 
was licensed on December 23, 2009 in the United States.  Also, less data are available in 
persons ≥80 years or for those with mild cognitive impairment than in younger, healthier adults.  
This is the first study conducted in the CISA Project where at least one death is somewhat likely 
to occur during the study period in a study participant (due to the older age-group of the 
participants).  Therefore, the goal of the safety monitoring plan is to protect the health of the 
study population and ensure adequate communication of potential risks, and to provide 
situational awareness of potential safety signals from this study to CDC Immunization Safety 
Office (ISO) leadership.  This plan is designed to monitor safety while minimizing introduction of 
bias into the study and minimizing burden to study investigators.  The safety monitoring plan is 
described in Appendix H.   
5.5 Health-Related Quality of Life (HRQOL) 
5.5.1 Generic Measures of HRQOL 
 
Late-Life Function & Disability Instrument (LLFDI) and Late-Life Function & Disability 
Instrument – Computer Adaptive Test (LLFDI-CAT) (Year 1 Only) 
The Late-Life FDI is an HRQOL instrument for assessing function (ability to perform discrete 
actions or activities as part of daily routines) and disability (socially-defined tasks) in community-
dwelling older adults25-27.  The function component is a 32-item questionnaire that assesses how 
much difficulty a person has doing a range of upper extremity, basic lower extremity, and 
advanced lower extremity functions.  The response categories for the function instrument are 
none, a little, some, quite a lot, cannot do in relation to the question, ‘How much difficulty do you 
have?’.  The disability component is a 16-item questionnaire that assesses how frequently a 
community dwelling older adult performs a particular task and the extent to which they feel 
limited in doing the task.  The response categories for the disability instrument are very often, 
often, once in a while, almost never, never in response to ‘how often do you . . ?’ and not at all, 
a little, somewhat, a lot, completely in response to ‘to what extent do you feel limited in?’ 
 
Each instrument generates a raw score, scaled score, and standard error for each dimension. 
The function component displays a total function score as well as separate scores for upper 
extremity, basic lower extremity, and advanced lower extremity subscales. The disability 
component displays a frequency total score, with social role and personal role subscale scores, 
and a limitation total score, with instrumental role and management role subscale scores. The 
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For the function section, the minimum clinically important difference ranges from 2.7 – 4.3.   The 
disability section is split into two dimensions: limitations and frequency in doing a task.  For 
limitations, the minimum clinically important difference is 16.7.  For frequency, the minimum 
clinically important difference is 7.8. 
 
The Late-Life Function & Disability Instrument – Computer Adaptive Test (LLFDI-CAT) is a 
modification of the LLFDI that expands the number of items and incorporates the World Health 
Organization’s International Classification of Functioning, Disability Health domains of activity 
limitations (function) and participation restriction (disability)28 (Appendix I). The Computer 
Adaptive Test method significantly reduces administration time and respondent burden.  The 
LLFDI-CAT uses the same response categories as the LLFDI and generates similar summary 
and subscale scores 
 
These instruments have several advantages for use in this study.   They provide measures of 
extremity function and multiple activities for community dwelling older adults.  They are 
validated, reliable, and responsive in older populations and various diseases.  They are 
designed for self-completion. They employ a standardized scoring system, and are free of 
charge. 
 
EQ-5D  
The EQ-5D is a standardized, generic measure of health status that provides information on 
health-related quality of life and activities of daily living relevant to older adults:  mobility, self-
care, usual activities, pain/discomfort and anxiety/depression (http://www.euroqol.org/)29.  In 
addition, the instrument contains the EQ Visual Analogue Scale (EQ-VAS) which measures the 
respondent’s self-rated health. 
 
The EQ-5D-5L is the new version of the EQ-5D that increases the levels of severity from three 
to five to significantly increase reliability and sensitivity while maintaining feasibility and reducing 
ceiling effects (Appendix J)30,31.  The descriptive system comprises 5 dimensions of mobility, 
self-care, usual activities, pain/discomfort, anxiety/depression.  For each of these dimensions, 
there are 5 response levels:  no problems, slight problems, moderate problems, severe 
problems, and extreme problems.  The respondent is asked to indicate his/her health state by 
ticking in the box against the most appropriate statement in each of the 5 dimensions. This 
decision results in a 1-digit number expressing the level selected for that dimension. The digits 
for 5 dimensions can be combined in a 5-digit number describing the respondent’s health state 
from 11111 as best health and 55555 as worst health These numbers are converted to a Utility 
Index that ranges from -0.109 (worst health) to 1.000 (best health) for US specific values. The 
minimum clinically important difference ranges from 0.05 to 0.1 depending on health conditions 
being studied. The EQ VAS records the respondent’s self-rated health on a 20 cm vertical, 
visual analogue scale with endpoints labelled ‘the best health you can imagine’ (100) and ‘the 
worst health you can imagine’ (0).  The respondent marks an ‘X’ on the scale number to indicate 
how their health is ‘today.’  The minimum clinically important difference on the VAS is 8. 
 
The EQ-5D-5L, EQ-VAS have several advantages for use in this study.  The measure is 
applicable to a wide range of health conditions and treatments and provide a simple descriptive 
profile and a single index value for health status. It has been validated in US and international 
populations and in older adults29,32,33. The measure is useful for monitoring the health status of 
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different moments in time. The measure is designed for self-completion by respondents.  It is 
simple, straightforward, take only a few minutes to complete and can easily be completed by 
older adults.  The instrument was designed to reduce respondent burden while achieving 
standards of precision for purposes of group comparisons involving multiple health dimensions.  
It has been widely used throughout the world in many different studies, including randomized 
controlled clinical trials, vaccine studies, and health-related quality of life studies in older adults. 
5.5.2 Vaccination Specific Measure of HRQOL  
An important issue with the proposed health status instruments is that they are generic 
measures of HRQOL.  Therefore, the instruments are sensitive to anything that occurs in a 
participant’s life and are not specific to vaccine reactogenicity  We will employ a measure 
that relies on the concept of vaccine reactogenicity specific interference with activities and 
impact on HRQOL 34,35.   
The vaccination reaction specific measure will consist of specific instructions and interference 
with daily living items using a five-category word response as “not at all”; “a little”; “somewhat”; 
“a lot”; or “completely” (Appendix K). The participant would be asked to “circle the response that 
best describes how these problems from your flu shot  have made things harder to” followed by 
key functional activities for older adults 34,36.    
5.5.3 Perceptions of the Vaccination Experience and Methods of Adverse Event 
Monitoring (Not Applicable for Repeat Vaccination Sub-Study) 
The participant’s perception of the vaccination experience and methods of adverse event 
monitoring will be collected with a questionnaire that includes their preferences, values and 
knowledge about vaccination.  The participant’s perceptions about their participation in the 
vaccine clinical trial will be assessed with a questionnaire as well (Appendix L). 
           
5.6 Health Care Utilization 
Participants will be asked to report health care utilization including: telephone calls to the 
medical provider for medical advice, e-mail portal, electronic health record, clinic visits, urgent 
care visits, emergency department visits and hospital admissions occurring through day 43 
according to the schedule in Table 1 above.  The reason for health care use will also be 
obtained. Electronic or paper health records will be obtained and reviewed to confirm reports of 
clinic visits, urgent care visits, emergency department visits and hospital admissions. Health 
care utilization and the reason for health care utilization will be recorded on the symptom diary. 
5.7 Biospecimens Collection & Handling 
5.7.1 Serum 
Blood specimens will be collected during study visits as described in Table 1. 
All blood samples (≈10 mL) will be collected into serum separator tubes and processed as 
follows: 
• Allow blood to clot at room temperature for at least 30 minutes while standing upright in a 
rack. 
• Centrifuge tube within 8 hours of collection at 1100 to 1300 RCF(g) for 10 minutes. 
• 
Gently remove the vacutainer stopper avoiding serum contamination with red blood 
cells. Using a single-use pipette, transfer 1.0 mL aliquots of serum (top layer) into 
1.0mL or 1.8 mL cryovials, up to 5 cryovials are expected.  If less than 1 mL of 
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• All cryovial aliquots will be barcode labelled and contain a unique identifier via REDCap.  
Numbers should be placed lengthwise on the tube.  
• Freeze the cryovials at -80°C in the temperature-monitored research center freezer for 
future shipment.   
• Serum aliquots will be stored in the Duke Human Vaccine Institute Accessioning Lab, the 
Boston at the Maxwell Finland Laboratory for Infectious Diseases, and at Cincinnati 
Children’s Hospital until planned HAI analyses at which point the samples stored at BMC 
and Cincinnati will be shipped to Duke where all HAI analyses will be done 
 
6 LABORATORY ANALYSES 
6.1 Influenza Hemagglutination Inhibition (HAI) Assay 
Influenza Hemagglutination Inhibition (HAI) Assays will be performed on sera collected, 
contingent on additional funding.  Briefly, reference wild-type, reassortant, or vaccine virus 
strains representative of the specific viral antigens included in the 2017-2018 and 2018-2019 
influenza vaccine will be used to evaluate the relative levels of all three influenza strain-specific 
antibodies in participant serum samples collected pre- and 28 days post-vaccination from all 
study participants and at 181 days post-vaccination in a subset of 100 participants at Duke. To 
accomplish these activities all participant samples will be interrogated for influenza antibodies 
against the strains of interest using the influenza hemagglutination inhibition assay (HI).  This 
assay is considered the “gold-standard” measure by which to evaluate 
seroconversion/seroprotection in response to seasonal influenza vaccination. This assay will be 
performed in accordance with the Duke Regional Biocontainment Laboratory Virology Unit’s 
fully optimized and approved SOP (RVUSOP004 Influenza HI of Serum Samples).  Briefly, test 
samples will be assayed by HAI as duplicate 2-fold dilution series starting at 1:10.  Serum 
dilutions are then incubated with a concentration of virus verified to possess a known potential 
for red blood cell (RBC) agglutination.  The presence of virus-specific antibodies is visualized 
via incubation of the virus-serum mixture with a RBC solution; the endpoint titer for a given 
dilution series is then expressed as the reciprocal of the final dilution in which complete HAI is 
observed.  By convention, seronegative samples are defined as having an endpoint HAI titer < 
40 and seropositive samples as having an endpoint titer of ≥1:40; and seroconversion as a 4-
fold change in endpoint titer relative to pre-immunization baseline or a change from <10 to 
≥1:40 37. 
 
7 STATISTICAL CONSIDERATIONS 
In collaboration with the Boston Medical Center and Cincinnati sites, the research team at Duke 
will oversee the statistical analysis. Data will reside on a secure Duke server maintained by 
Duke Health Technology Solutions (DHTS).  For the study, a database will be developed and a 
data set for the study without personal identifiers will be made available to the CDC upon 
request.  Duke statisticians will develop a comprehensive Statistical Analysis Plan.  The 
summary points of the analysis plan are presented below. 
 
 

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7.1 Analysis Plan 
 
Should an interim safety analysis be required, the alpha level will be adjusted to assure the 
overall type I error is maintained at the one-sided alpha 0.025 level for the primary outcome of 
non-inferiority.   
7.1.1 Sample Size 
 
Safety:  Based on data from prelicensure studies 4,5,7, we assume that 5% of older adults have 
moderate/severe injection-site reactions after aIIV3 or IIV-HD.  We have selected a clinically 
meaningful non-inferiority margin of 5%.  Statistical calculations, without consideration of drop-
out, show that with an alpha of 0.025 (one-sided), we would need 668 total subjects (334 
subjects in each group across all study sites) to have at least 80% power be able to 
demonstrate that the proportion of moderate/severe pain was non-inferior after aIIV3 vs. IIV3-
HD.  Enrollment in this study shall occur during two influenza seasons (2017-18 and 2018-19). 
 
Immunogenicity:  Based on data from prelicensure studies 4,5,7, we conservatively estimate that 
50% of older adults demonstrate seroconversion after vaccination with aIIV3 or IIV3-HD for the 
H3N2 strain.  We have selected a clinically meaningful non-inferiority margin of 10%.  Statistical 
calculations, without consider of drop-out, show that with an alpha of 0.025 (one-sided), we 
would need 780 total subjects (390 subjects in each group across all study sites) to have 
approximately 80% power to able to demonstrate that the seroconversion rate after aIIV3 was 
non-inferior to IIV3-HD. 
The total number of subjects needed for this study was derived based on 4 factors:  1) Sample 
size needed for adequate statistical power to test the safety hypothesis; 2) sample size needed 
for adequate statistical power to test the immunogenicity hypothesis; 3) potential for subject 
drop-out; and 4) feasibility of dividing subjects across 2 sites.  Based on these considerations, 
the study aims to enroll at least 880 subjects to assess both the safety and immunogenicity 
endpoints.  The study aims to enroll at least 720 to test only the safety hypothesis.   
 
7.1.2 Analysis Populations 
 
Full Analysis Population: 
• 
For Primary Objective 1 and Secondary Objective 1, the primary analysis population will 
be the Full Analysis Population; defined as all subjects who are randomized, vaccinated, 
and provide at least one day of complete data on the symptom diary. 
• 
For Primary Objective 2 and Secondary Objective 2, the primary analysis population will 
be the Full Analysis Population; defined as all subjects who are randomized and 
vaccinated. 
 
Immunogenicity Population: 
For Primary Objective 3 and Secondary Objective 3 the primary analysis will be for the 
Immunogenicity Population; defined as subjects who received vaccine, provide baseline and 
Visit 4 blood draws of acceptable volume and quality within the protocol-defined time frame with 

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no protocol violations affecting immunogenicity. Protocol violations affecting the immunogenicity 
analyses will be defined in the Statistical Analysis Plan (SAP). 
The Full Analysis Population is the primary population for analysis unless otherwise stated. 
 
7.1.3 Primary Objective 1  
• 
To compare the proportions of moderate/severe injection site pain after aIIV3 and IIV3-
HD in the full study population   
o Hypothesis:  the proportion of subjects who have moderate/severe injection site 
pain within the first week post-vaccination will be non-inferior for allV3 compared 
to IIV3-HD in the full study population 
This objective will be assessed using a one-sided non-inferiority test with the alpha level set at 
0.025 and non-inferiority margin of 5%.   
The null hypothesis is allV3 is inferior to IIV3-HD in regards to the proportion of subjects having 
moderate or severe injection site pain in the first week post vaccination. 
 
 
 
 
Ho: allV3 - IIV3-HD ≥ 0.05 (5%) 
 
The alternative hypothesis is allV3 is non-inferior to IIV3-HD in regards to the proportion of 
subjects having moderate or severe injection site pain in the first week post vaccination. 
 
 
 
Ha: allV3 - IIV3-HD < 0.05 (5%) 
 
The upper bound of the one-sided binomial confidence interval of the difference will be used to 
make this assessment. 
 
7.1.4 Primary Objective 2  
• 
To compare serious adverse events and events of clinical interest after aIIV3 and IIV3-
HD in the full study population and by age-group 
 
The proportion and 95% exact binomial confidence interval of serious adverse events and 
events of clinical interest, as well as the total number of events, will be presented by site, 
vaccine group, severity, and relatedness.  Listings of the serious adverse events will also be 
presented.  This information will also be prepared for the subset (N≥176) of subjects 80 or older. 
 
7.1.5 Primary Objective 3 
• 
To compare the seroconversion rate for the H3N2 influenza A strain after aIIV3 and IIV3-
HD in the full study population  
o Hypothesis: the seroconversion rate for the H3N2 influenza A strain in the full 
study population after aIIV3 will be non-inferior to IIV-HD 
 
 
This objective will be assessed using a one-sided non-inferiority test with the alpha level set at 
0.025 and non-inferiority margin of 10%.   

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The null hypothesis is the allV3 H3N2 seroconversion rate is inferior to IIV3-HD seroconversion 
rate. 
 
 
 
 
Ho: allV3 H3N2 rate - IIV3-HD H3N2 rate ≥ 0.1 (10%) 
 
The alternative hypothesis is the allV3 H3N2 seroconversion rate is non-inferior to IIV3-HD 
H3N2 seroconversion rate. 
 
 
 
Ha: allV3 H3N2 rate - IIV3-HD H3N2 rate < 0.1 (10%) 
 
The upper bound of the one-sided binomial confidence interval of the difference will be used to 
make this assessment. 
 
7.1.6 Secondary Objective 1 
• 
To compare the proportions of local and systemic reactions after aIIV3 and IIV3-HD in 
the full study population and by age-group (65-79 years and ≥80 years) (other than 
moderate/severe injection site pain in the full study population)  
 
The proportions in the full study population will be conducted as for Primary Objective 1 using a 
non-inferiority test to determine if allV3 is non-inferior to IIV3-HD with a 5% non-inferiority 
margin.  These secondary objectives will be conducted with a one-sided alpha at the 0.01 level 
to adjust for multiple comparisons.  It is recognized that with 12 different assessments at the 
alpha 0.01 level (given the events are truly independent) we are allowing an 11.4% chance of 
making a type I error. 
 
The age-group assessments will be assessed using standard two-sided 95% confidence 
boundaries of the difference in proportions between the groups.  No formal statistical testing will 
be implemented for the age-group comparisons. 
   
7.1.7 Secondary Objective 2 
• 
To describe and compare changes in health-related quality of life after aIIV3 and IIV3-
HD in the full study population and by age-group 
 
Each HRQOL instrument produces a summary score to measure health-related quality of life.   
The change in score from pre-vaccination (baseline, Visit 1) to post-vaccination (Day 3, Visit 2) 
time points will be compared within and between the two groups. 
 
The Late-Life Disability and Function Instrument and Late-Life Disability and Function 
Instrument-Computer Adapted Test (Year 1 Only) 
The function and disability sections scale raw scores are transformed to a 0 (worst health) to 
100 (best health) scale.   The changes from baseline will be assessed within vaccine group 
using a paired t-test for the function and disability outcomes.  If normality assumptions are not 
met, the testing will be performed with a Wilcoxon signed-rank test. The Mann-Whitney U test 
(Wilcoxon rank-sum test) will be used to compare the difference scores from baseline between 
the two vaccine groups for the function and disability outcomes.      

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EQ-5D-5L and Visual Analogue Scale (VAS) 
The EQ-5D-5L responses are converted to a Utility Index that ranges from -0.109 (worst health) 
to 1.0 (best health) using the US specific value sets 
(http://www.euroqol.org/fileadmin/user_upload/Documenten/Excel/Crosswalk_5L/EQ-5D-
5L_Crosswalk_Value_Sets.xls).  The EQ VAS has a range of 0 (worst health) to 100 (best 
health). The changes from baseline will be assessed within vaccine group using a paired t-test 
for the index values and VAS.  If normality assumptions are not met, the testing will be 
performed with a Wilcoxon signed-rank test. The Mann-Whitney U test (Wilcoxon rank-sum test) 
will be used to compare the difference scores from baseline between the two vaccine groups for 
the index values and VAS. 
 
These health-related quality objectives will be conducted with a two-sided alpha at the 0.01 level 
to adjust for multiple comparisons.  It is recognized that with 12 different assessments at the 
alpha 0.01 level (given the events are truly independent) we are allowing a 11.4% chance of 
making a type I error. 
 
The statistical tests described above will also be performed for the subset (N=176) of subjects 
80 or older.  This testing will be considered exploratory with an alpha level of 0.05 with no alpha 
adjustment. 
 
7.1.8 Secondary Objective 3 
To compare serum hemagglutination inhibition (HAI) antibody titers after aIIV3 and IIV3-
HD for each of the three influenza vaccine strains contained in the respective vaccine for 
that season in the full study population and by age-group (except for seroconversion for 
the H3N2 strain in the full study population) 
 
Responses to each influenza antigen will be analyzed, with the exception of seroconversion for 
H3N2, which is analyzed in Primary Objective 1.  The proportion of subjects with seroprotection 
(pre- and post-immunization) seroconversion (4-fold rise from baseline) in the two treatment 
groups will be presented along with 95% exact binomial confidence intervals. A 95% confidence 
interval of the difference in proportions between the treatment groups will also be presented.  
 
The GMTs for each influenza antigen, including H3N2, and 95% confidence boundaries will be 
presented for both treatment groups. A 95% confidence interval of the difference in GMTs 
between the treatment groups will also be presented. This information will also be prepared for 
the subset (N≥176) of subjects 80 or older. 
 
7.1.9 Sensitivity Analyses 
For Primary Objective 1 a sensitivity analysis will be performed on the following sub-group of the 
Full Analysis Population: subjects who provided complete/informative symptom diary 
information for injection-site pain (i.e., eight days of completed pain field data on diary or graded 
pain if present) and have no specified protocol violations as described in the Manual of 
Operations.  This a supporting safety analysis. 
 

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7.1.10 Exploratory Objectives 
The analysis for the exploratory objectives will be detailed in the comprehensive 
Statistical Analysis Plan. 
7.2 Data Management 
The novel Vanderbilt-designed resource developed specifically for online collection of research 
information, the Research Electronic Data Capture (REDCap) platform 
(https://projectredcap.org/), will be used to design study forms, including the reaction forms, and 
short customized questionnaires to collect information from study subjects. REDCap provides: 
1) a streamlined process for rapidly building a database; 2) an intuitive interface for collecting 
data, with data validation and audit trail; 3) automated export procedures for seamless data 
downloads to common statistical packages; 4) branching logic, file uploading, and calculated 
fields; and 5) a quick and easy protocol set-up.  This system will be used by Duke for data 
management.  All electronic linkages will fulfill regulations for protection of human subjects and 
requirements to minimize the risk of breach of confidentiality.  
 
All study-related documents containing protected health information, e.g. enrollment logs, case 
report forms, diaries (Appendix E) completed by study participants, will be maintained in secure 
research offices at Duke, Boston University, and Cincinnati Children’s Hospital, which are 
accessible to research staff only.  
 
The study team will utilize a secure, encrypted, file transfer method for sharing study documents 
and data with the CDC.  No personal identifiers will be included in any shared documents or 
datasets.   
 
7.2.1 Research Electronic Data Capture (REDCap)  
REDCap (http://project-redcap.org/), assists with the collection and management of data for 
diverse clinical and translational research studies. REDCap was designed around the concept 
of giving research teams an easy method to specify project needs and rapidly develop secure, 
web-based applications for collection, management and sharing of research data. REDCap 
accomplishes these key functions through use of a single study metadata table referenced by 
presentation-level operational modules. Based on this abstracted programming model, 
databases are developed in an efficient manner with little resource investment beyond the 
creation of a single data dictionary. The concept of metadata-driven application development is 
well established, and the critical factor for successful data collection lies in creating a simple 
workflow methodology allowing research teams to autonomously develop study-related 
metadata in an efficient manner. Both products include secure institutional data hosting and 
include full audit-trails in compliance with Health Insurance Portability and Accountability Act 
(HIPAA) security requirements. The REDCap Consortium is comprised of 647 active institutions. 
The REDCap currently supports 68,000 projects with over 89,000 users spanning numerous 
research focus areas across the consortium.  The current project will use this software 
application for the design of electronic forms to collect information from study participants, to link 
the baseline data, sample collection date, and laboratory results in an automated database 
family, to perform data cleaning and data quality assurance efficiently, and to design an 
analytical dataset for the analysis of the project data.  
 

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Data will be entered into the REDCap database by members of the study team from Duke, 
Boston Medical Center, and Cincinnati Children’s Hospital using the paper case report forms 
utilized to record data collected as part of study procedures.  Study investigators will be 
responsible for assuring that all paper records are securely stored according to the 
requirements of their IRBs.  The study investigators will be responsible for assuring the 
accuracy of the data entered from the paper forms into REDCap.  Only the assigned identifiers 
will be used in REDCap. Therefore, personal health identifiers will not appear in the REDCap 
database. 
 
In order to perform data cleaning and data quality assurance efficiently, numerous built-in filters 
and checks for consistency of the data including range and limit checks, branching logic and pull 
down menus to limit choices for categorical variables to a pre-specified list will be implemented 
and performed automatically to minimize data entry error. The data will be randomly sampled 
and checked against source records on a regular basis. The data and related analytical 
datasets will also be stored at the lead and contributing sites with secured password-protected 
computers. 
7.3 Role of the CDC Investigators in the Project 
This study is funded by a CDC contract with Duke University and Boston University as Task 
Orders in the CISA Project Contract.  The Duke University PI (Ken Schmader) will oversee the 
study in partnership with the Boston University PI (Elizabeth Barnett).  Boston University has a 
subcontract with Cincinnati Children’s Hospital (PI Elizabeth Schlaudecker). CDC staff will 
collaborate with both sites to develop the protocol, conduct the study, ensure the study is 
aligned with US Department of Health and Human Services (CDC) public health priorities, and 
analyze the data and disseminate the results. CDC may receive access to coded data not 
containing any directly identifying information.  
 
8    HUMAN SUBJECTS  
8.1 Human Subjects Involvement, Characteristics, and Design 
 
Duke, Boston University, and Cincinnati Children’s Hospital investigators will be responsible for 
submitting the protocol, informed consent (Appendix A), diaries (Appendix E), recruitment letters 
(Appendix M), flyers (Appendix N), and any written or verbally conveyed materials (Appendix O) 
specific to this project to their institutional review boards.  CDC staff will be responsible for 
submitting materials to the CDC for Human Subjects review and approval.   
  
To facilitate subject recruitment at the practices, we will request a waiver of consent and HIPAA 
authorization for ascertainment (identification, selection) and/or recruitment of potential subjects 
while recording identifiable private health information (PHI) prior to obtaining the subject’s 
consent.  This information will be obtained from review of the electronic scheduling and medical 
record systems in the clinics in order to determine eligibility for study enrollment. We will review 
only the minimum amount of information necessary to determine eligibility, i.e. date of birth, 
medical and surgical history, and recent laboratory test results. The PHI collected prior to 
consent will be used to recruit and screen only. Use of PHI in this manner involves no more than 
minimal risk to subjects and no information will leave the study sites. 
 

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Requests for continuing review, when required, will be submitted at each engaged institution in 
accordance with institutional procedures.  Protocol deviations or concerns about study integrity 
will be reported promptly to the overseeing IRB or CDC in accordance with institutional 
requirements. 
 
8.2 Sources of Material 
Medical history and immunization history will be obtained from the medical record and from 
patient report.  Demographic information will be obtained from the medical record and patient 
report.  Subjects will record solicited adverse reactogenicity events and any medical intervention 
sought on study days 1-8 on the symptom diary (Appendix E).  Diary information will be reported 
to the study team during a telephone call. The research staff will assess one or more of the 
following:  weight, height, temperature, blood pressure, and pulse.   
8.3 Potential Risks and Benefits 
aIIV3 or IIV-HD3 are FDA-licensed vaccines approved for use in adults ≥65 years old. Both 
vaccines are standard clinical practice and recommended by the CDC.  Participants will be 
provided with the CDC Vaccine Information Statement (VIS) for IIV 
(https://www.cdc.gov/vaccines/hcp/vis/vis-statements/flu.pdf).  
 
IIV risks include minor problems such as soreness, redness, swelling, or pain where the shot 
was given, hoarseness, sore, red or itchy eyes, cough, fever, aches, headache, itching, fatigue, 
all of which usually occur within 1-2 days of vaccination and are self-limiting. Some people get 
severe pain in the shoulder and have difficulty moving the arm where a shot was given. This 
happens very rarely. Syncope (fainting) can occur in association with administration of injectable 
vaccines. Sitting or lying down for about 15 minutes can help prevent fainting, and injuries 
caused by a fall, as recommended in the ACIP General Recommendations on Immunization1. 
Subjects should inform their doctor should they feel dizzy, or have vision changes or ringing in 
the ears. More serious problems including a small increased risk of Guillain-Barré Syndrome 
estimated at 1 or 2 additional cases per million people vaccinated. This is much lower than the 
risk of severe complications from influenza infection, which can be prevented by IIV38.  In 
addition, any medication can cause a severe allergic reaction, or anaphylaxis, which is 
estimated at ~ 1 in one million doses of IIV administered39. 
 
Risks of blood drawing include pain, swelling, bleeding, or bruising at the site where the blood 
sample is collected. Subjects may also experience dizziness or fainting. There is a small risk of 
infection around the vein where the blood was collected.  Each study subject will be asked to 
have up to 3 blood samplings with the total volume not to exceed 30mL over approximately 6 
month period of time.  Participants who return for repeat vaccination in the second year will be 
asked to have 2 additional blood sampling with the volume in the second year not to exceed 20 
mL. 
 
As with any licensed vaccine, protection may not occur in 100% of vaccinated persons.  
 
An additional risk of study participation is the potential for loss of confidentiality. 
 
8.4 Adequacy of Protection Against Risks 
 

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8.4.1 Protections against Risk 
To decrease the possibility of infection at the site of blood drawing, the area on the arm above 
the vein where blood will be taken will be prepped with 70% isopropyl alcohol antiseptic prior to 
venipuncture. 
Subjects will be counseled on possible side effects following vaccination and followed closely 
during the 8 days post-vaccination for assessment of moderate to severe local or systemic 
reactogenicity. Subjects will be evaluated and cared for as described in the Unscheduled Visit 
section above. All subjects will be monitored in a sitting or lying position for 15 minutes following 
vaccinations to help prevent fainting, and injuries caused by a fall. Subjects with a prior history 
of severe allergic reaction after a previous dose of any influenza vaccine, or to a vaccine 
component, including egg protein, will be excluded from study enrollment.  Data Safety 
monitoring, as described above (Section 5.4.3 and Appendix H), shall also be done.  
The study team will provide documentation to the participant and primary care provider 
regarding receipt of influenza vaccine without specification of whether it was high dose or 
adjuvanted vaccine to preserve blinding.    
If a participant’s care requires the identity of the vaccine received, blinding will be broken for that 
patient.  At the end of the study, the participants and providers will receive documentation about 
which vaccine the participant received. 
Every effort possible will be made to keep information about participants confidential. 
Computerized participant information will be kept in password-protected files on secured 
servers.  Paper case report forms will be kept in locked files belonging to the study personnel.   
Any publications resulting from this work will not contain any identifiable participant information. 
8.4.2 ClinicalTrials.gov Requirements 
The project is registered on ClinicalTrials.gov (NCT # NCT03183908). 
 
8.5 Human Subjects 
In obtaining and documenting informed consent, the Investigator and study team will comply 
with the applicable regulatory requirements, Good Clinical Practices, and ethical principles. The 
written informed consent form must be signed and dated by the study participant prior to 
initiation of any study activities.   
 
8.5.1 Vulnerable Subjects Research 
This study proposes to include subjects with mild cognitive impairment.  All potential subjects 
will undergo cognitive assessment to ensure they are capable of providing consent.  Mild 
cognitive impairment is a common age-related condition that is defined by the presence of 
short-term memory impairment that does not interfere the individual’s ability to perform activities 
of daily living or affect other areas of cognition, including judgment and independent decision-
making.  Therefore, persons with mild cognitive impairment have the capacity to make decisions 
about their health care choices, including influenza vaccination, and participation in research 
studies.  Influenza vaccination is recommended for these individuals.  The benefits and burdens 
of the proposed study apply equally to these individuals as to persons without mild cognitive 
impairment.   
 

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Potential participants may have low scores on the cognitive screening tests and be ineligible for 
the study.  In this case the study doctor or designee will review the results with the individual 
and recommend follow-up with the individual’s health care provider. 
 

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SF-36 health survey questionnaire. Qual Life Res 1993;2:169-80. 
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Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new 
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van Hout B, Janssen MF, Feng YS, et al. Interim scoring for the EQ-5D-5L: mapping the 
EQ-5D-5L to EQ-5D-3L value sets. Value Health 2012;15:708-15. 
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Gandek B, Ware JE, Aaronson NK, et al. Cross-validation of item selection and scoring 
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Coplan PM, Schmader K, Nikas A, et al. Development of a measure of the burden of 
pain due to herpes zoster and postherpetic neuralgia for prevention trials: adaptation of the brief 
pain inventory. J Pain 2004;5:344-56. 
35. 
Schmader KE, Sloane R, Pieper C, et al. The impact of acute herpes zoster pain and 
discomfort on functional status and quality of life in older adults. Clin J Pain 2007;23:490-6. 
36. 
Schmader KE, Johnson GR, Saddier P, et al. Effect of a zoster vaccine on herpes 
zoster-related interference with functional status and health-related quality-of-life measures in 
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37. 
Katz JM, Hancock K, Xu X. Serologic assays for influenza surveillance, diagnosis and 
vaccine evaluation. Expert Rev Anti Infect Ther 2011;9:669-83. 
38. 
Kwong JC, Vasa PP, Campitelli MA, et al. Risk of Guillain-Barre syndrome after 
seasonal influenza vaccination and influenza health-care encounters: a self-controlled study. 
Lancet Infect Dis 2013;13:769-76. 
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APPENDIX 
Appendix A:  Written Informed Consent 
Appendix B:  Mini-Cog 
Appendix C:  Rowland Universal Dementia Assessment Scale (RUDAS) 
Appendix D:  Treatment Administration Record/Immediate Reactogenicity Assessment Form 
Appendix E:  Patient Symptom Diary 
Appendix F:  FACES Pain Scale 
Appendix G:  Immune-Mediated Conditions 
Appendix H:  Safety Monitoring Plan 
Appendix I:  LLFDI-CAT 
Appendix J:  EQ-5D-5L 
Appendix K:  Vaccine Reaction Questionnaire  
Appendix L:  Perceptions of the Vaccination Experience  
Appendix M:  Recruitment Letter  
Appendix N:  Flyer 
Appendix O:  Phone Script 
 

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Appendix A:  Written Informed Consent
 
 

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Appendix B:  Mini-Cog
 
 

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Appendix C:  Rowland Universal Dementia Assessment Scale (RUDAS) 
 
 

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Appendix D:  Treatment Administration Record/Immediate Reactogenicity Assessment 
Form 
 
 

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Appendix E:  Patient Symptom Diary 
 
 
 

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Appendix F:  FACES Pain Scale  
 
 

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Appendix G:  Immune-Mediated Conditions 
 
Gastrointestinal disorders 
Liver disorders 
• Celiac disease 
• Crohn’s disease 
• Ulcerative colitis 
• Ulcerative proctitis 
• Autoimmune cholangitis 
• Autoimmune hepatitis 
• Primary biliary cirrhosis 
• Primary sclerosing cholangitis 
Musculoskeletal disorders 
Neuroinflammatory disorders 
• Antisynthetase syndrome 
• Dermatomyositis 
• Mixed connective tissue disorder 
• Polymyalgia rheumatic 
• Polymyositis 
• Psoriatic arthropathy 
• Relapsing polychondritis 
• Rheumatoid arthritis 
• Scleroderma, including diffuse systemic 
form and CREST syndrome 
• Spondyloarthritis, including ankylosing 
spondylitis, reactive arthritis (Reiter's 
Syndrome) and 
undifferentiated spondyloarthritis 
• Systemic lupus erythematosus 
• Systemic sclerosis 
• Acute disseminated encephalomyelitis, 
including site specific variants (e.g., non-
infectious 
encephalitis, encephalomyelitis, myelitis, 
myeloradiculomyelitis) 
• Cranial nerve disorders, including 
paralyses/paresis (e.g., Bell’s palsy) 
• Guillain-Barré syndrome, including Miller 
Fisher syndrome and other variants 
• Immune-mediated peripheral neuropathies 
and plexopathies, including chronic 
inflammatory demyelinating polyneuropathy, 
multifocal motor neuropathy and 
polyneuropathies associated with monoclonal 
gammopathy 
• Multiple sclerosis 
• Narcolepsy 
• Optic neuritis 
• Transverse myelitis 
• Myasthenia gravis, including Eaton-Lambert 
syndrome 
Metabolic diseases 
Skin disorders 
• Addison’s disease 
• Autoimmune thyroiditis (including 
Hashimoto thyroiditis) 
• Diabetes mellitus type I 
• Grave's or Basedow’s disease 
• Alopecia areata 
• Autoimmune bullous skin diseases, 
including pemphigus, pemphigoid and 
dermatitis 
herpetiformis 
• Cutaneous lupus erythematosus 
• Erythema nodosum 
• Erythema multiforme 
• Morphoea 
• Lichen planus 
• Psoriasis 
• Sweet’s syndrome 
• Vitiligo 
Vasculitides 
Others 
• Large vessels vasculitis including: giant cell 
arteritis such as Takayasu's arteritis and 
temporal 
arteritis 
• Antiphospholipid syndrome 
• Autoimmune hemolytic anemia 
• Autoimmune glomerulonephritis (including 
IgA nephropathy, glomerulonephritis rapidly 

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• Medium sized and/or small vessels 
vasculitis including: polyarteritis nodosa, 
Kawasaki's disease, microscopic polyangiitis, 
Wegener's granulomatosis, Churg–Strauss 
syndrome (allergic granulomatous angiitis), 
Buerger’s disease thromboangiitis obliterans, 
necrotizing vasculitis and anti-neutrophil 
cytoplasmic antibody (ANCA) positive 
vasculitis (type unspecified), Henoch- 
Schonlein purpura, Behcet's syndrome, 
leukocytoclastic vasculitis 
progressive, membranous 
glomerulonephritis, membranoproliferative 
glomerulonephritis, and mesangioproliferative 
glomerulonephritis) 
• Autoimmune myocarditis/cardiomyopathy 
• Autoimmune thrombocytopenia 
• Goodpasture syndrome 
• Idiopathic pulmonary fibrosis 
• Pernicious anemia 
• Raynaud’s phenomenon 
• Sarcoidosis 
• Sjögren’s syndrome 
• Stevens-Johnson syndrome 
• Uveitis 
 
 
 
 

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Appendix H:  Safety Monitoring Plan 
 
The safety monitoring plan includes 3 types of adverse events described in the Table below.  
The plan includes two components:  an ongoing adverse event case report review, and an 
interim safety data review with the expert safety panel. 
 
Type A adverse events 
Type B adverse events 
Type C adverse events 
o Syncope occurring post-
vaccination while patient is 
under clinic observation for 
Day 1 study activities.  
o Anaphylaxis within 24 hours 
of vaccination 
o Guillain-Barré syndrome 
(GBS) occurring within 42 
days of vaccination  
o Death within 42 days 
following vaccination 
o Serious adverse events 
(SAE) occurring within 42 
days of vaccination, unless 
unrelated to vaccine  
o New onset immune-
mediated diseases 
occurring within 42 days of 
vaccination other than GBS  
(Appendix G), unless 
unrelated to vaccine 
o Severe injection-site 
reactions occurring within 7 
days of vaccination (Table 
2)  
o Severe fever occurring 
within 7 days of vaccination 
(Table 3) 
 
Ongoing AE case report review will be performed as follows: 
• 
A site identifying a Type A AE in a study subject should notify study investigators at both 
sites and CDC within one business day of identifying the AE. Site investigators should 
make an assessment as to relatedness to study product (related, possibly related, 
unlikely related or unrelated) and provide this information when available, but should not 
delay reporting.  
 
• 
A site identifying a Type B AE should make an assessment as to relatedness to study 
product before reporting it.  An SAE that is considered to be related or possibly related to 
vaccine should be reported to study investigators at both sites and CDC within one 
business day of making this relatedness determination.  Type B AEs that are not related 
do not need to be urgently reported.   
 
• 
Type C AEs do not need to be reported as part of ongoing monitoring, unless they also 
result in an SAE.  
 
Information about AE case reports that is shared with the study teams will be blinded with 
respect to vaccine product used.  Reporting to the respective IRB will be per the respective 
institutional IRB requirements and will also initially be blinded.  Sites will provide narrative case 
reports for Type A AEs and Type B AEs (unless unrelated to vaccine) to CDC within 1 week.  
No personal identifiable information (PII), including date of vaccination, should be included.  
Discussions about AE case reports for Type A and B events will take place on routine or ad hoc 
calls with the study investigators and team.  If a site or CDC have clinical safety concerns that 
they feel need more urgent attention, then the study team will meet promptly to determine a plan 
of action, which might include consultation with the safety monitoring panel.  The following 
events should lead to a prompt study team meeting:   
• 
If there are 3 or more Type A syncope events  
• 
If there are 2 or more other Type A AEs 

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• 
If there are 2 or more other serious AEs or new onset autoimmune diseases (unless 
unrelated to the study vaccine) that are clinically similar (e.g. same organ class) 
• 
If a clinical investigator involved with the study has a safety concern not specified above 
that he/she feels needs prompt attention. 
 
The interim safety data review will provide an opportunity to make changes to the protocol or 
consent before the second year of influenza study enrollment.  This data review will include 
either the first 200 subjects vaccinated with the opportunity for 42 days of follow-up OR all 
subjects vaccinated with 42 days of follow at the time the report is prepared.  This review will 
include all randomized subjects who received vaccine, including those with protocol violations or 
who dropped out or died.  The review will maintain blinding and will describe the following in 
aggregate and will also be stratified into two age groups:  65-79 and ≥80 years.   
• 
Proportion of each Type A AE (all, related, possibly related, unlikely related or unrelated) 
• 
Proportion of serious AEs (including any Type A AEs also considered serious) (all, 
related, possibly related, unlikely related, or not related) 
• 
Proportion new immune-mediated diseases (except GBS) (all, related, possibly related, 
unlikely related, or not related) (Appendix G) 
• 
Proportion of each severe injection-site reaction (Table 2) and severe fever (assume all 
related)  
 
The interim review will include clinical summary line lists for the AEs described above, except 
for the reactogenicity events.  An appendix of clinical narratives for all Type A and Type B AEs 
will also be included.  The Duke statistical team in collaboration with the study team will prepare 
and present this summary.  Background information about reactogenicity frequencies from the 
package inserts will be provided.  This information will be shared and reviewed with the expert 
safety panel.  The safety panel will consider any concerning findings and determine if there is 
need to consider additional actions including statistical analyses and reassessment, changes to 
study eligibility or procedures to minimize or assess risk, or addition of information to the 
informed consent. The safety panelists will provide individual expert input but will not make final 
decisions.  There are no pre-specified statistical criteria to guide decisions; rather clinical 
judgement will be used.  For all of these steps study investigators and the safety panel will see 
the same data.  The safety panel may make any of the following suggestions at the end of the 
interim data review.   
• 
No substantial safety concerns and either:   
o No further analysis and continue routine safety monitoring  
o There are some small changes recommended in routine monitoring such as 
adding a new AE.   
• 
Specific safety concern:   
o If there is a specific safety concern, such as a higher than expected proportion of 
severe fever after vaccine, than the first step will be to clinically describe the AEs 
without breaking randomization or blinding.  For example, the duration of the 
fever could be assessed and the level of medical utilization.   
o If after in-depth clinical review, a concern remains, then the next step will be to 
break randomization into treatment groups (while maintaining blinding).  If there 
is an isolated concern, then it may be sufficient to do this only for the specific AE.  
For example, if there are 5 SAEs of kidney failure and after breaking into two 
groups, no imbalance is seen, that may be sufficient.  

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o If it is clinically needed, then blinding may be broken either for a selected AE or 
for the full interim data.  
• 
Substantial safety concerns: 
o The interim safety dataset will be analyzed by vaccination group and blinding will 
be discontinued for these data.  
 
The safety panel will consist of three to four expert physicians who are not investigators on this 
study.  The physicians will consist of staff from the CDC and from CISA site(s) other than Duke 
or BMC, including at least one internal medicine physician.  The panel will meet initially before 
study enrollment to review the study and the monitoring plan and to share background 
information about what is known about aIIV and IIV3-HD safety (package insert review).  A 
meeting will be scheduled in 2018 for an interim review of safety data.  Study investigators and 
statisticians will be invited to participate, and the meetings will consist of open discussions 
between the panel and study investigators (under CISA confidentially agreement).  Ad hoc 
meetings will be scheduled as needed. 
 
 

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Appendix I:  LLFDI-CAT 
 
 
 

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Appendix J:  EQ-5D-5L and VAS 
 
 
 

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Appendix K:  Vaccine Reaction Questionnaire 
 
 
 

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Appendix L:  Perceptions of the Vaccination Experience 
 
 
 

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Appendix M:  Recruitment Letter 
 
Dear Sir or Madam, 
The Duke Division of Geriatrics and the Duke Vaccine and Trials Unit are conducting an 
influenza vaccine research study. We are contacting you because as an older adult you 
or someone you know may be interested in this study. Every eligible study participant 
will be randomized (like flipping a coin), to receive an injection of either FLUAD™, an 
adjuvanted inactivated influenza vaccine, or Fluzone® High-Dose, inactivated influenza 
vaccine. An adjuvant is a substance added to a vaccine to increase the immune 
response. Both vaccines are currently licensed and approved in the United States for 
older people. 
 
Vaccines can help prevent infection and disease. Vaccines work by causing the body to 
make proteins called antibodies that fight infection. When you get flu vaccine 
(sometimes called a flu shot), your immune system makes antibodies against the flu 
virus.  
 
The purpose of this research study is to determine if there is a difference in older 
people for side effects following vaccination, and also to compare the immune response 
to the two flu vaccines. Previous studies have shown that both vaccines provide 
protection from the flu in older people. 
 
What is involved with this study?  
 Come in for 2 visits: baseline and day twenty-nine. You will receive the vaccine 
at the baseline visit 
 Have about 2 teaspoons of blood taken from your arm at each visit 
 Have your temperature, blood pressure and pulse measured at each visit 
 Complete post vaccination assessments and questionnaires 
 Receive 3 telephone calls following your vaccination to review questionnaires 
 Receive payment for your time and travel 
If you would like to participate, please call the study team at 919-660-7581 or 919-668-
8728. 
Sincerely, 
 
 
Kenneth Schmader, M.D.,  
Principal Investigator 
Chief, Division of Geriatrics 
Department of Medicine 
 
 
 
 
 
 
 
 
 
 
 
 
Pro00083845 
 
 

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Appendix N:  Flyer 
 
 
 

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Appendix O:  Phone Script 
 
   
Hi, this is _____________________________calling from the Division of Geriatrics/Duke Clinical 
Vaccine Unit. Thank you for your interest in this influenza vaccine research study.  
I would like to tell you about this study and then, if you are still interested, ask you a few 
questions about your medical history to see if you qualify for participation. 
 
Are you still interested in learning more about this study? 
 
□Yes                □No 
If no, thank them for their time. 
 
Principal Investigator and Purpose 
The principal investigator is Dr. Kenneth Schmader. The purpose of this study is to compare the 
safety of FLUAD™ and Fluzone® High-Dose in older people and to see if one vaccine or the other 
helps older adults make protective antibodies better against the flu. 
 
Procedures 
As part of this study, you will be asked to come in for 2 study visits and you will receive 3 
scheduled phone calls over a 6-week period.  
Visit 1 (clinic visit) Study Day #1:  Study staff will explain the study, review the consent form 
with you, and answer any questions you may have. You will then read and sign the consent 
form. Your medical history, medications that you are currently taking, as well as study criteria 
will be reviewed, to make sure that you qualify for the study.  Study staff will take your 
temperature, blood pressure, and heart rate. You will be asked about your history of flu 
vaccination, and will you be asked about any pain, swelling, or redness you are experiencing in 
your arm before vaccination.  You will also be asked questions about your quality of life.  A 
blood sample of 10 mL (2 teaspoons) will be taken to test for antibody levels. You will be 
randomly assigned (like flipping a coin) to receive either the FLUADTM or Fluzone® High-Dose flu 
vaccine.  You will need to stay in the clinic for at least 15 minutes after that to be watched for 
any reactions. You will be given a symptom diary form, measurement tool and thermometer, 
and shown how to use them for the study.  
Visit 2 (phone call follow-up) Study Day #3:  A member of the study staff will contact you to 
review the information about your symptoms and medications that you should have been 
recording daily in the symptom diary.  You will also be asked about your quality of life.   
Visit 3 (phone call follow-up) Study Day #9:  A member of the study staff will contact you again 
to review the information about your symptoms and medications that you should have been 
recording daily in the symptom diary.  You will also be asked about your quality of life, and 
about your experience with this study.   
Visit 4 (clinic visit) Study Day #29:   About 28 days after the first visit you will return to the clinic 
for another in-person visit. You will be asked about your health and any medicines you are 
taking. A blood sample of 10 mL (2 teaspoons) will be taken to test for antibody levels.   

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 Visit 5 (phone call follow-up) Study Day #43:  A member of the study staff will contact you to 
ask you about your symptoms and medications since your last visit.   
 
 
Risks 
Possible risks with receiving the Flu vaccine include: redness, swelling, or pain where the shot 
was given; fever, body aches, headache, or fatigue; nausea; cough or hoarseness; sore, red or 
itchy eyes; or itching. 
Guillain-Barré syndrome (GBS) is a rare but serious condition that can occur after certain 
infections or after receiving certain vaccines such as the flu vaccine.  There is a small increased 
risk of GBS (about 1 or 2 additional cases per million people vaccinated) after vaccination with 
flu vaccine.  GBS causes inflammation and damage to the nerves in your body. Minor symptoms 
such as muscle tiredness or more severe symptoms, such as paralysis (weakness, or inability to 
move certain parts of the body) may occur.  
 
Benefits/Compensation 
There may be direct medical benefit to you. Study participation will confirm that you receive 
the recommended flu vaccination. The two flu vaccines in this study have both been shown to 
prevent influenza in older people. You may develop protective antibodies against influenza.  
Information learned from this study may also help researchers understand if there are 
difference in how older people respond to FLUADTM and Fluzone® High-Dose vaccines. 
All study participants will be compensated $50 after completing each blood draw visit and $25 
after completing each phone contact. 
 
Consent for Prescreening/Confidentiality 
I will need to ask a few questions about your medical history to determine if you potentially 
qualify to take part in this study. Answering is voluntary, and refusing to answer will have no 
effect on your status as a patient, employee or volunteer at Duke, but we will not be able to 
schedule you if you choose not to answer the questions. 
 
The information we collect is kept confidential, and if, for any reason, you do not qualify for this 
study, none of your answers to any questions will be kept. 
 
May I ask these questions?   
 
 
 
 
 
□Yes    
□No 
If no, thank them for their time. 
 
 
 
 
STUDY CANDIDATE QUESTIONNAIRE 
 

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What is your age?    _____ (Must be ≥ 65) 
 
Have you already received your flu shot for the current flu season? 
 
□Yes □No   
(Answering “YES” is exclusionary) 
 
Have you been a participant in a research study involving an investigational product 
(drug/biologic/device) within the past 30 days? 
  
 
 
 
  
Co-enrollment in observational or behavioral intervention studies are allowed at any time, 
enrollment in a clinical trial involving and investigational product (other than vaccine) may occur 
after 30 days following vaccine receipt. 
 
 
 
 
 
□Yes □No   
(Answering “YES” is exclusionary) 
 
Do you have confirmed or suspected immunosuppressive condition resulting from disease 
(Malignancy, HIV), or currently undergoing treatment for cancer (chemotherapy or radiation 
therapy) within the preceding 12 months?   
 
 
 
 
□Yes □No   
(Answering “YES” is exclusionary) 
 
Do you have an active neoplastic disease (excluding non-melanoma skin cancer or prostate 
cancer that is stable in the absence of therapy) or a history of any hematologic malignancy? 
(Participants with a history of malignancy may be included if, after previous treatment by 
surgical excision, chemotherapy or radiation therapy, the participant has been observed for a 
period that in the investigator’s estimation provides a reasonable assurance of sustained cure.) 
(Answering “YES” is exclusionary) 
 
 
 
 
 
 
□Yes □No   
 
Do you have a history of thrombocytopenia (low platelet count), bleeding disorders or 
anticoagulant use that may interfere with intramuscular injection?  
 
□Yes □No 
(Answering “YES” is exclusionary) 
 
Have you received any blood transfusions in the past 3 months? 
(Answering “YES” is exclusionary) 
 
 
 
 
 
 
□Yes □No 
 
Have you received any vaccinations in the past 6 weeks or planned vaccinations during the 42 
day post vaccination period (including  pneumococcal vaccines)? 
(Receipt of Shingrix or HEPLISAV-B within 6 weeks prior to enrollment in this study, or planning 
receipt of Shingrix during the 42 days post vaccination is exclusionary) 
 
□Yes □No   
(Answering “YES” is exclusionary) 
 
Do you currently have an acute illness with a fever of 100.0°F? 
 
 
□Yes □No   
(Answering “YES” is exclusionary) 
 

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Have you had a severe allergic reaction after a previous dose of any influenza vaccine a vaccine 
component (Formaldehyde, Octylphenol ethoxylate, neomycin, kanamycin, barium, or 
cetyltrimethylammonium bromide (CTAB)), allergy to egg proteins, or latex, or history of 
Guillain-Barre̒ syndrome? 
 
 
 
 
 
 
 
□Yes □No   
(Answering “YES” is exclusionary) 
 
Do you have a history of substance abuse?  
 
 
 
 
□Yes □No 
 
(Answering “YES” is exclusionary) 
 
What medications (including medication dose) and supplements are currently taking? 
______________________________________________________________________________ 
______________________________________________________________________________ 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________ 
 
Do you have a history of any of the following medical conditions? 
Liver disease  
 
   ___Yes     
___ No 
Cognitive Impairment                 ___Yes     
___ No 
Endocrine disease                        ___Yes     
___ No  
Kidney disease 
                 ___Yes     
___ No 
Gastrointestinal disease  
   ___Yes     
___ No  
Cardiovascular disease  
   ___Yes     
___ No  
HIV or Hepatitis A, B or C 
   ___Yes     
___ No 
Coronary Artery disease             ___Yes     
___ No 
Cancer  
 
                 ___Yes     
___ No 
Pulmonary disease                       ___Yes     
___ No 
 
If yes to any of the above, describe:_________________________________________________ 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________ 
(Any condition that, in the investigator’s opinion, might pose a health risk to the candidate or 
adversely affect compliance is exclusionary) 
 
(If candidate is eligible, please provide the following information) 
 
Name  ___________________________________    
 
Address __________________________________ 

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  ___________________________________ 
 
  ___________________________________  
 
e-mail address:______________________________ 
 
 
 
 
 
Phone #:  
Primary _______________________ Type _____ 
 
 
Secondary____________________ Type _____ 
 
Gender: Male _____   Female ____ Date of birth:  _____/_____/_____ 
 
 
 
Screening date & time:  _____/_____/_____ @ _____:______  ( 24 hour ) 
 
 
 
      mm       dd        yy 
 
Duke patient? Yes ____ No ____   MRN, if applicable ___________________ 
 
Finish with this Maestro Scheduling statement 
I need to ask your permission to use your health information to schedule your initial study visit 
in Duke’s electronic scheduling system prior to your visit. If you agree to grant your permission 
to use your health information in this way, it means that your information will be linked to this 
study and may be seen by members of the study team and the Duke personnel who are 
associated with scheduling. The only risk to you in agreeing to this use of your information is 
the risk of loss of confidentially. However, all of the individuals who will see your information 
and its link to the study are trained professionals who work with healthcare information daily 
and are aware of the importance of maintaining confidentiality of health records. Your health 
information will be used solely to pre-schedule your initial visit prior to the formal written 
consent process.   
May I have your permission to use your health information to schedule this research visit, with 
the understanding that this in no way obligates you to participate in the study? 
 
Yes_____     No_____    Date_____/_____/_____   Time____:_____  ( 24 hour ) 
 
 
 
       
mm 
dd 
 yy 
 
 
 
___________________________ 
 
 
_____________________ 
Interviewer’s signature 
 
 
 
Date