FLUAD® vs. Fluzone® High-Dose Study

Study Overview
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Brief Summary
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The overall aim of the study is to compare safety and immunogenicity of inactivated influenza vaccine (IIV), adjuvanted (FLUAD®) versus High-Dose inactivated influenza (Fluzone® High-Dose) vaccine in persons ≥65 years (20% aged ≥80 years). A prospective, randomized, blinded clinical trial that will be conducted during the 2017/2018 and 2018/2019 influenza seasons. During each season, approximately 220 older adults will be enrolled at Duke University Medical Center and 140 older adults at Boston University Medical Center. Eligible subjects will be randomized to receive either adjuvanted influenza vaccine or High-Dose influenza vaccine. All subjects will receive vaccine and provide a blood draw at Visit 1, and then return for a second blood draw without vaccination about 4 weeks later to assess for influenza antibody titers. A subset of 100 subjects at Duke will provide a third blood draw 6 months post-vaccination to assess for waning of influenza antibody titers. Subjects will record the occurrence of local and systemic reactions (including fever, pain, tenderness, swelling, redness, general systemic systems), unsolicited adverse events, medical care utilization, and changes in medications over 8 days following vaccination. In addition, serious adverse events and events of clinical interest will be assessed through 42 days post-vaccination. Health-related quality of life will be assessed pre-vaccination (Day 1) and on Days 3 and 9 post-vaccination.

Detailed Description
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Full Analysis Population 1: Defined as all subjects who are randomized, vaccinated, and provide at least one day of complete data on the symptom diary. Full Analysis Population 2: Defined as all subjects who are randomized and vaccinated. Immunogenicity Population: Defined as subjects who received vaccine, provided baseline and Visit 4 blood draws of acceptable volume and quality within the protocol-defined time frame with no protocol violations affecting immunogenicity.

Official Title
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Safety and Immunogenicity of Adjuvanted Versus High-Dose Inactivated Influenza Vaccines in Older Adults

Conditions
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Pain, Quality of Life, Injection Site Reaction, Side Effect of Drug, Adverse Drug Event

Intervention / Treatment
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* Biological: FLUAD®
* Biological: Fluzone® High-Dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Persons aged ≥65 years, living in the community Intention of receiving IIV vaccine based on ACIP-CDC guidelines Willing to provide written informed consent prior to initiation of any study procedures Able to speak English Able and willing to complete baseline assessments and questionnaires, and to allow information to be collected from their electronic medical record Able and willing to complete post-vaccine assessments and questionnaires independently or with assistance Able and willing to have blood drawn for the study Able and willing to return in about one month for a follow-up visit including completing questionnaires and having another blood test Access to and ability to use a phone, independently or with assistance Adequate vision and motor skills to complete the diary form independently or with assistance. Not living in a skilled nursing facility/nursing home/long term acute care facility Exclusion Criteria: IIV receipt during the current influenza season prior to study enrollment Enrolled in this study during the 2017-18 (Year 1) influenza season Note: Year 1 study participants will only be enrolled in Year 2 if they are participating in the sub-study on repeat vaccination 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. 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 (not less than 12 months) Thrombocytopenia, bleeding disorder, or anticoagulant use contraindicating intramuscular injection History of febrile illness (> 100.0°F or 37.8°C) within the past 24 hours prior to IIV administration (temporary deferral) 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) Any history of Guillain-Barré syndrome Mild to severe dementia as determined by the Mini-Cog tool and the Rowland Universal Dementia Assessment Scale (RUDAS) Substance use that could interfere with study compliance 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) 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. Hearing loss determined by the investigators to prevent successful communication over the phone 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. Anyone who is a relative or subordinate of any research study personnel.

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Adjuvanted influenza vaccine (FLUAD®)<br>In the study arm, subjects will receive a single dose of FLUAD® adjuvanted influenza vaccine during Visit 1. | Biological: FLUAD®<br>* Advisory Committee on Immunization Practices (ACIP) Recommended Vaccine<br>* Other names: Adjuvanted influenza vaccine;|
| Active Comparator: High-dose influenza vaccine (Fluzone® HD)<br>In the study arm, subjects will receive a single dose of Fluzone® High-Dose influenza vaccine during Visit 1. | Biological: Fluzone® High-Dose<br>* Advisory Committee on Immunization Practices (ACIP) Recommended Vaccine<br>* Other names: High-dose influenza vaccine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Injection-Site Pain in Arm That Was Vaccinated, Population 1 | Comparison of the proportion of subjects reporting moderate/severe injection site pain within the first week post-vaccination in both treatment groups. | Days 1 through 8 post-vaccination | 
| Number of Participants With Adverse Events of Clinical Interest, Population 2 | The frequency and descriptions of adverse events of clinical interest observed in the two treatment groups. | 42 days post-vaccination and compared between the two groups. | 
| Observed Serious Adverse Events in Both Treatment Groups, Population 2 | The frequency and descriptions of serious adverse events observed in the two treatment groups. No analytical analysis was completed. | 42 days post-vaccination and compared between the two groups. | 
| Number of Participants With H3N2 HAI Seroconversion | H3N2 hemagglutination inhibition assay (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 four-fold rise in HAI titer if the baseline titer is > 1:10) in the respective season's vaccine | 29 days post-vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Local Reactions in Arm That Was Vaccinated - Full Study, Population 1 | Comparison of local reactions within the first week post-vaccination in both treatment groups. | Days 1 through 8 post-vaccination | 
| Number of Participants With Local Reactions in Arm That Was Vaccinated - Ages 65 - 79, Population 1 | Comparison of local reactions within the first week post-vaccination in both treatment groups by age group. | Days 1 through 8 post-vaccination | 
| Number of Participants With Local Reactions in Arm That Was Vaccinated - Ages 80 +, Population 1 | Comparison of local reactions within the first week post-vaccination in both treatment groups by age group. | Days 1 through 8 post-vaccination | 
| Number of Participants With Systemic Reactions - Full Study Population, Population 1 | Comparison of systemic reactions within the first week post-vaccination in both treatment groups. | Days 1 through 8 post-vaccination | 
| Number of Participants With System Reactions - Ages 65 - 79, Population 1 | Comparison of systemic reactions within the first week post-vaccination in both treatment groups by age group. | Days 1 through 8 post-vaccination | 
| Number of Participants With System Reactions - Ages 80 +, Population 1 | Comparison of systemic reactions within the first week post-vaccination in both treatment groups by age group. | Days 1 through 8 post-vaccination | 
| Quality of Life - Late Life Function & Disability Instrument - Full Population | Change in scores on the Late Life Function & Disability Instrument pre-vaccination to post-vaccination (Day 1 - Day 3) compared between the vaccination groups (Year 1 only). Response choices are ranked 1-5, High Scores indicate better outcomes. The Function/Activity Scale measured the amount of difficulty in completing a range of activities, or the amount of help required in doing an activity due to physical or mental heath. : None (5); A little (4) ; Some (3), Quite a lot (2), and Cannot Do (1). The Disability/Participation Scale measured participation levels in social, family, and community activities due to physical or mental health. Each question has two parts. For the first part of the question, response choices include: Very often (5), Often (4), Once in a while (3), Almost never (2), Never (1). For the second part of the question, response choices include: Not at all (5), A little (4), Somewhat (3), A lot (2), and Completely (1). | Pre-vaccination (Day 1), 2 days post-vaccination (Day 3) | 
| Quality of Life - Late Life Function & Disability Instrument - Ages 65 - 79 | Change in scores on the Late Life Function & Disability Instrument pre-vaccination to post-vaccination (Day 1 - Day 3) compared between the vaccination groups (Year 1 only). Response choices are ranked 1-5, High Scores indicate better outcomes. The Function/Activity Scale measured the amount of difficulty in completing a range of activities, or the amount of help required in doing an activity due to physical or mental heath. : None (5); A little (4) ; Some (3), Quite a lot (2), and Cannot Do (1). The Disability/Participation Scale measured participation levels in social, family, and community activities due to physical or mental health. Each question has two parts. For the first part of the question, response choices include: Very often (5), Often (4), Once in a while (3), Almost never (2), Never (1). For the second part of the question, response choices include: Not at all (5), A little (4), Somewhat (3), A lot (2), and Completely (1). | Pre-vaccination (Day 1), 2 days post-vaccination (Day 3) | 
| Quality of Life - Late Life Function & Disability Instrument - Ages 80 + | Change in scores on the Late Life Function & Disability Instrument pre-vaccination to post-vaccination (Day 1 - Day 3) compared between the vaccination groups (Year 1 only). Response choices are ranked 1-5, High Scores indicate better outcomes. The Function/Activity Scale measured the amount of difficulty in completing a range of activities, or the amount of help required in doing an activity due to physical or mental heath. : None (5); A little (4) ; Some (3), Quite a lot (2), and Cannot Do (1). The Disability/Participation Scale measured participation levels in social, family, and community activities due to physical or mental health. Each question has two parts. For the first part of the question, response choices include: Very often (5), Often (4), Once in a while (3), Almost never (2), Never (1). For the second part of the question, response choices include: Not at all (5), A little (4), Somewhat (3), A lot (2), and Completely (1). | Pre-vaccination (Day 1), 2 days post-vaccination (Day 3) | 
| Quality of Life - EQ-5D-5L -Full Population | Change in scores on the EuroQOL 5 dimensions-5 level (EQ-5D-5L) pre-vaccination and post-vaccination compared between the vaccination groups (Year 1 only). Responses on the EQ-5D-5L measure is converted to a Utility Index that ranges from -0.109 (worst health) to 1.000 (best health). | Pre-vaccination (Day 1), 2 days post-vaccination (Day 3) | 
| Quality of Life - EQ-5D-5L - Ages 65 - 79 | Change in scores on the EuroQOL 5 dimensions-5 level (EQ-5D-5L) pre-vaccination and post-vaccination compared between the vaccination groups and age group (Year 1 only). Responses on the EQ-5D-5L measure is converted to a Utility Index that ranges from -0.109 (worst health) to 1.000 (best health). | Pre-vaccination (Day 1), 2 days post-vaccination (Day 3) | 
| Quality of Life - EQ-5D-5L - Ages 80 + | Change in scores on the EuroQOL 5 dimensions-5 level (EQ-5D-5L) pre-vaccination and post-vaccination compared between the vaccination groups and age group (Year 1 only) Responses on the EQ-5D-5L measure is converted to a Utility Index that ranges from -0.109 (worst health) to 1.000 (best health). | Pre-vaccination (Day 1), 2 days post-vaccination (Day 3) | 
| Quality of Life - EQ VAS -Full Population | Change in scores on the EuroQOL visual analogue scale (EQ VAS) pre-vaccination and post-vaccination compared between the vaccination groups (Year 1 only). 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). | Pre-vaccination (Day 1), 2 days post-vaccination (Day 3) | 
| Quality of Life - EQ VAS - Ages 65 - 79 | Change in scores on the EuroQOL visual analogue scale (EQ VAS) pre-vaccination and post-vaccination compared between the vaccination groups and age group (Year 1 only). 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). | Pre-vaccination (Day 1), 2 days post-vaccination (Day 3) | 
| Quality of Life - EQ VAS - Ages 80 + | Change in scores on the EuroQOL visual analogue scale (EQ VAS) pre-vaccination and post-vaccination compared between the vaccination groups and age group (Year 1 only). 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). | Pre-vaccination (Day 1), 2 days post-vaccination (Day 3) | 
| Seroconversion - 65 and Older | 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 four-fold rise in HAI titer if the baseline titer | Day 29 (28 days post-vaccination) | 
| Seroprotection - 65 and Older | 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 | Day 29 (28 days post-vaccination) | 
| Geometric Mean HAI Titer - 65 and Older | The geometric mean HAI titer (GMT) for each IIV antigen in the respective season's vaccine | Day 29 (28 days post-vaccination) | 
| Seroconversion - Ages 65-79 | The proportion of subjects aged 65-79 achieving seroconversion at day 29 (an HAI titer > 1:40 at day 29 if the baseline titer is < 1:10 or a four-fold rise in HAI titer if the baseline titer | Day 29 (28 days post-vaccination) | 
| Seroconversion - Ages 80 and Older | The proportion of subjects ages 80 and older achieving seroconversion at day 29 (an HAI titer > 1:40 at day 29 if the baseline titer is < 1:10 or a four-fold rise in HAI titer if the baseline titer | Day 29 (28 days post-vaccination) | 
| Seroprotection - Ages 65-79 | Proportion of subjects ages 65-79 with a seroprotective HAI titer (≥ 1:40) pre- and post-immunization at day 29 for each IIV antigen in the respective season's vaccine | Day 29 (28 days post-vaccination) | 
| Seroprotection - Ages 80 and Older | Proportion of subjects ages 80 and older with a seroprotective HAI titer (≥ 1:40) pre- and post-immunization at day 29 for each IIV antigen in the respective season's vaccine | Day 29 (28 days post-vaccination) | 
| Geometric Mean HAI Titer - Ages 65-79 | The geometric mean HAI titer (GMT) for each IIV antigen in the respective season's vaccine for ages 65-79 | Day 29 (28 days post-vaccination) | 
| Geometric Mean HAI Titer - Ages 80 and Older | The geometric mean HAI titer (GMT) for each IIV antigen in the respective season's vaccine for ages 80 and older | Day 29 (28 days post-vaccination) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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influenza vaccine, fever following vaccination, pain following vaccination, quality of life