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Trial registered on ANZCTR


Registration number
ACTRN12623000650695
Ethics application status
Approved
Date submitted
26/05/2023
Date registered
15/06/2023
Date last updated
14/06/2024
Date data sharing statement initially provided
15/06/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluation of the psychoneuroimmunological state of healthy humans following intramuscular injection of the influenza (FluQuadriTM) vaccine, a two-way crossover double-blinded placebo-controlled trial
Scientific title
Evaluation of the psychoneuroimmunological state of healthy humans following intramuscular injection of the influenza (FluQuadriTM) vaccine, a two-way crossover double-blinded placebo-controlled trial
Secondary ID [1] 309756 0
36936-H-2023
Universal Trial Number (UTN)
U1111-1293-1315
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cognitive impairment 330154 0
Psychomotor impairment 330155 0
Immune responses 330158 0
Condition category
Condition code
Inflammatory and Immune System 327036 327036 0 0
Normal development and function of the immune system
Neurological 327097 327097 0 0
Studies of the normal brain and nervous system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1: Influenza (FluQuadriTM) vaccine; single dose (0.5ml) once only via intramuscular route. Each 0.5 ml contains 15 micrograms from each of the following types of influenza
virus:
A/Victoria/2570/2019 (H1N1)pdm09-like strain
A/Darwin/9/2021 (H3N2)-like strain
B/Austria/1359417/2021-like strain
B/Phuket/3073/2013-like strain.

We have employed several registered pharmacists who are experienced in clinical trials (lead pharmacist is Dr Peter McCarthy, and co-lead is Louise Jarman) who will give the injections and remain on standby for a minimum of 15 mins to administer adrenaline or use an EpiPen, should the need arise. All pharmacists' will be giving participants their own consent form which they will take Medicare details to update the Australian Immunisation Registry at the end of the trial.

We are not accessing electronic medical records but have captured medical history of participant in our pre-screening questionnaire, which will be maintained following university guidelines.

The wash out period is 4-8 weeks, being that the second study day for each participant will be at a minimum 4 weeks and up to 8 weeks following the first visit.
Intervention code [1] 326202 0
Early detection / Screening
Intervention code [2] 326241 0
Treatment: Other
Comparator / control treatment
Arm 2: Placebo is a single dose administered once only and is a buffered sterile sodium chloride pH 7.4 (neutral) injection (0.5ml) via intramuscular route on a different study day
Control group
Placebo

Outcomes
Primary outcome [1] 335048 0
Assess the cognitive and physical status of healthy participants after receiving the seasonal influenza vaccine or placebo. This will be determined using the following functional measures: Psychomotor Vigilant Test (PVT), Attentional Network Test (ANT), the 6-minute walk test, the Timed Up and Go, and sit-to-stand tasks.

Adverse events: In the unlikely event of an adverse reaction to the influenza vaccination, the following steps will be taken. As stipulated in the Australian Immunisation Handbook (AIH), most acute adverse events relate to symptoms that mimic influenza. As stated by the AIH, the risk of anaphylactic shock (allergy to either components of the vaccine or egg) from a single vaccine dose is about 1 case per million (https://immunisationhandbook.health.gov.au/contents/vaccination-for-special-risk-groups/vaccination-for-people-who-have-had-an-adverse-event-following-immunisation). The response occurs within the first 15 mins following the influenza vaccination. We have employed study pharmacists and a study nurse who are qualified to handle this response, as well as 2 other members of the research team are First Aid responders. Should the signs or symptoms of anaphylaxis occur, the following protocol will occur:
1) Early signs/symptoms of a response will be identified by study pharmacist/nurse and/or the research team members and one of the team will call 000 services.
2) The participant will be safely laid flat on the floor.
3) Study pharmacist will immediately administer the EPI pen to the outer-mid thigh of the participant. This is the first line of treatment for anaphylactic shock. Additional vials of adrenaline are available, should they be required.
4) The participant will be closely monitored by the research team. The anaphylactic shock signs/symptoms should resolve.
5) Following administration of the EPI pen (and/or adrenaline vials), if the participant’s symptoms do not improve and they show signs of difficulty breathing, the study nurse will initiate appropriate steps to safely open an airway until the SA Ambulance services arrive to take over.
6) The response of the participant and the adverse event will be reported to SA Heath (immunization section) on 1300 232 272.
Timepoint [1] 335048 0
All timepoints (+15mins, 30mins, 1h, 2h, 4h, 8h) will be compared against the baseline (-1h) with 0h being the injection administration time.
Primary outcome [2] 335050 0
Assess the ability of healthy participants to process emotional cues and perform speech metrics following administration of the seasonal influenza vaccine or placebo. This will be determined using the Emotional Processing Test (EPT), and through reading reading and speech tasks, such as performing sustained vowels, reading text, delivering an unprepared monologue, and repeating syllables.

Adverse events: In the unlikely event of an adverse reaction to the influenza vaccination, the following steps will be taken. As stipulated in the Australian Immunisation Handbook (AIH), most acute adverse events relate to symptoms that mimic influenza. As stated by the AIH, the risk of anaphylactic shock (allergy to either components of the vaccine or egg) from a single vaccine dose is about 1 case per million (https://immunisationhandbook.health.gov.au/contents/vaccination-for-special-risk-groups/vaccination-for-people-who-have-had-an-adverse-event-following-immunisation). The response occurs within the first 15 mins following the influenza vaccination. We have employed study pharmacists and a study nurse who are qualified to handle this response, as well as 2 other members of the research team are First Aid responders. Should the signs or symptoms of anaphylaxis occur, the following protocol will occur:
1) Early signs/symptoms of a response will be identified by study pharmacist/nurse and/or the research team members and one of the team will call 000 services.
2) The participant will be safely laid flat on the floor.
3) Study pharmacist will immediately administer the EPI pen to the outer-mid thigh of the participant. This is the first line of treatment for anaphylactic shock. Additional vials of adrenaline are available, should they be required.
4) The participant will be closely monitored by the research team. The anaphylactic shock signs/symptoms should resolve.
5) Following administration of the EPI pen (and/or adrenaline vials), if the participant’s symptoms do not improve and they show signs of difficulty breathing, the study nurse will initiate appropriate steps to safely open an airway until the SA Ambulance services arrive to take over.
6) The response of the participant and the adverse event will be reported to SA Heath (immunization section) on 1300 232 272.
Timepoint [2] 335050 0
Due to time constraints, we will only assess timepoints 1h, 2h, 4h, 8h which will be compared against the baseline (-1h) with 0h being the injection administration time.
Primary outcome [3] 335051 0
Assess the cellular and molecular changes in the peripheral blood of healthy participants following seasonal influenza vaccine or placebo. This will be determined via high dimensional blood cell immunophenotyping using flow cytometry approaches.
Timepoint [3] 335051 0
All timepoints (+15mins, 30mins, 1h, 2h, 4h, 8h) will be compared against the baseline (-1h) with 0h being the injection administration time.
Secondary outcome [1] 422547 0
Neuroelectrophysiological activity of healthy participants following seasonal influenza vaccine or placebo will be recorded with 36 channels using an ActiveTwo BioSemi electroencepholograph (EEG) system.
Timepoint [1] 422547 0
All timepoints (+15mins, 30mins, 1h, 2h, 4h, 8h) will be compared against the baseline (-1h) with 0h being the injection administration time.
Secondary outcome [2] 422548 0
Examine the facial expressions and pupils of healthy participants whilst performing the battery of tasks and tests outlined in the primary outcomes following seasonal influenza vaccine or placebo. This will be determined using high frame video cameras.
Timepoint [2] 422548 0
All timepoints (+15mins, 30mins, 1h, 2h, 4h, 8h) will be compared against the baseline (-1h) with 0h being the injection administration time.
Secondary outcome [3] 422756 0
Heart rate variability of healthy participants following seasonal influenza vaccine or placebo will be assessed using a Photoplethysmography system.
Timepoint [3] 422756 0
All timepoints (+15mins, 30mins, 1h, 2h, 4h, 8h) will be compared against the baseline (-1h) with 0h being the injection administration time.
Secondary outcome [4] 422864 0
Quantify innate immune signalling cytokine and chemokine protein levels in the peripheral blood of healthy participants following seasonal influenza vaccine or placebo. This will be determined via standard Luminex multiplex array approaches.
Timepoint [4] 422864 0
All timepoints (+15mins, 30mins, 1h, 2h, 4h, 8h) will be compared against the baseline (-1h) with 0h being the injection administration time.
Secondary outcome [5] 422865 0
Quantify the innate immune signaling pathway activation potential of circulating factors in the peripheral blood of healthy participants following seasonal influenza vaccine or placebo. This will be determined using the plasma portion of the blood and applying it to engineered cell lines using Bioluminescence Resonance Energy Transfer (BRET) and A Real Time Innate Immune Screening Technology (ARTIIST) approaches.
Timepoint [5] 422865 0
All timepoints (+15mins, 30mins, 1h, 2h, 4h, 8h) will be compared against the baseline (-1h) with 0h being the injection administration time.

Eligibility
Key inclusion criteria
- Healthy participants aged between 18 and 40 years.
- No history of seizures, head injury or head physiognomy (head shape) that would preclude EEG cap placement.
- Able to provide written and informed consent in English.
- Are willing to receive the influenza vaccination during the trial.
- Body weight greater than 50 kg (minimum blood donation weight set by the Red Cross Blood Bank); BMI index between 18.5-29.9.
- Must be non-smokers or have ceased smoking for more than 3 months.
Minimum age
18 Years
Maximum age
40 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- Have been diagnosed with neurological conditions or neurodegenerative diseases, such as depressive, anxiety or post-traumatic stress disorder, sleep conditions, or Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder.
- 2 week exclusion for vaccination of any type, if infected with Covid or influenza during the testing period, adjustments will be made to the testing protocol to allow for recovery from infection.
- Have received an immunisation for the influenza strains contained within the current year’s influenza vaccine formulation.
- Participants have had a positive test response for active influenza infection during the same season.
- Have medical conditions which preclude them from having an influenza vaccination.
- Have a history of anaphylaxis to eggs or past vaccinations.
- Have had a ever had a severe allergic reaction to any of the ingredients listed in the FluQuadriTM vaccine as indicated on the Consumer Medicine Information summary (Sodium chloride, dibasic sodium phosphate, monobasic sodium phosphate, water for injection, and traces of ovalbumin (egg protein), octoxinol-9 and formaldehyde).
- Be pregnant or actively trying to conceive.
- Have an ongoing chronic inflammatory condition.
- Have a phobia with needles.
- Have used any prescription, or over-the-counter medication (other than paracetamol and oral contraceptives) in the 24 hours leading up to the study days, including the use of illicit drugs and/or alcohol.
- Are a regular user of marijuana. Must be able to withstand using for duration of trial.
- Have had any caffeine in the 12 hours leading up to the study days.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation involved contacting the holder of the allocation schedule who was "off-site" or at central administration site
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computerised sequence generation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Participants are made fully aware of the double-blinded placebo controlled nature of the study and consent to their vaccination details being updated on the Australian Immunisation Registry after their second attendance at the clinic (unless they withdraw earlier). This will ensure they remain blinded throughout the course of the trial. Participants will also have consented to supplying the study pharmacist with a separate consent form on each study day that contains information for their vaccination status to be update to the AIR and this remains completely separate to information we collect at pre-screening. The study pharmacist has control of the blinding and randomisation schedule - this has been arranged in confidence between the pharmacist and our pharmacy employed to prepare the blinding kits (the Royal Adelaide Hospital).
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The statistical methods adopted for this study are complex nature of the trial. The 3 main types of data we will generate; 1) Behavioural response data from psychometric tests 2) Physiological response data from video, EEG and PPG 3) Biological data from blood samples, we have on our team, We have employed a mathematical statistician who will undertake computational modelling and machine learning approaches that will extract individual level temporal dynamics of the individual psychoneuroimmunological state using the processed data of all 3 data types.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
27/06/2023
Actual
22/08/2023
Date of last participant enrolment
Anticipated
31/10/2024
Actual
Date of last data collection
Anticipated
31/01/2025
Actual
Sample size
Target
40
Accrual to date
8
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment postcode(s) [1] 40462 0
5005 - Adelaide University

Funding & Sponsors
Funding source category [1] 313949 0
Government body
Name [1] 313949 0
Australian Government, Department of Defence (Defence Science and Technology Group, DMTC)
Country [1] 313949 0
Australia
Primary sponsor type
Government body
Name
Australian Government, Department of Defence (Defence Science and Technology Group, DMTC)
Address
Level 2, 24 Wakefield Street, Hawthorn, Victoria, Australia 3122
Country
Australia
Secondary sponsor category [1] 315814 0
University
Name [1] 315814 0
The University of Adelaide
Address [1] 315814 0
Level 7, 10 Pulteney Street, The University of Adelaide, South Australia, Australia, 5005
Country [1] 315814 0
Australia
Other collaborator category [1] 282690 0
University
Name [1] 282690 0
The University of Melbourne
Address [1] 282690 0
Grattan Street, Parkville, Victoria, Australia 3010
Country [1] 282690 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313086 0
Bellberry Human Research Ethics Committee Limited
Ethics committee address [1] 313086 0
Ethics committee country [1] 313086 0
Australia
Date submitted for ethics approval [1] 313086 0
05/04/2023
Approval date [1] 313086 0
25/05/2023
Ethics approval number [1] 313086 0
2023-03-238
Ethics committee name [2] 313189 0
The University of Adelaide
Ethics committee address [2] 313189 0
Ethics committee country [2] 313189 0
Australia
Date submitted for ethics approval [2] 313189 0
02/06/2023
Approval date [2] 313189 0
08/06/2023
Ethics approval number [2] 313189 0
23023-H-038

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 126950 0
Prof Mark Hutchinson
Address 126950 0
Level 7, 10 Pulteney Street, The University of Adelaide, South Australia, Australia 5005
Country 126950 0
Australia
Phone 126950 0
+61 08 8313 0322
Fax 126950 0
Email 126950 0
[email protected]
Contact person for public queries
Name 126951 0
Juliana Bajic
Address 126951 0
L5, Helen Mayo South Building, The University of Adelaide
30 Frome Road, Adelaide, South Australia, 5005
Country 126951 0
Australia
Phone 126951 0
+61 424 724 916
Fax 126951 0
Email 126951 0
[email protected]
Contact person for scientific queries
Name 126952 0
Mark Hutchinson
Address 126952 0
Level 7, 10 Pulteney Street, The University of Adelaide, South Australia, Australia 5005
Country 126952 0
Australia
Phone 126952 0
+61 08 8313 0322
Fax 126952 0
Email 126952 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
19270Ethical approval    385973-(Uploaded-26-05-2023-16-13-22)-Study-related document.pdf
19271Informed consent form    385973-(Uploaded-26-05-2023-16-16-19)-Study-related document.docx



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.