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Trial registered on ANZCTR


Registration number
ACTRN12621001063808p
Ethics application status
Submitted, not yet approved
Date submitted
29/07/2021
Date registered
12/08/2021
Date last updated
12/08/2021
Date data sharing statement initially provided
12/08/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised control trial to evaluate the reactions of co-administration of influenza and COVID-19 vaccines
Scientific title
The FLU-VID study: A single blinded, phase IV, adaptive randomised control trial to evaluate the safety of co-administration of seasonal influenza and COVID-19 vaccines in adults
Secondary ID [1] 304996 0
None
Universal Trial Number (UTN)
Trial acronym
The FLU-VID study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Influenza 322631 0
COVID-19 322632 0
Condition category
Condition code
Infection 320251 320251 0 0
Other infectious diseases
Respiratory 320733 320733 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will receive a single 0.5 mL intramuscular dose of a licensed seasonal influenza vaccine (inactivated, surface antigen, adjuvanted quadrivalent (containing 60 micrograms (µg) haemagglutinin (HA) per 0.5 mL dose) or inactivated, surface antigen, tetravalent (containing 60 µg HA per 0.5 mL dose)) within 6 hours of vaccination with a COVID-19 vaccine (ChAdOx1-S (recombinant) or 0.3 mL of BNT162b2 mRNA vaccine (nucleoside-modified)) (visit 1) and a single dose of a placebo vaccine (0.5 mL of 0.9% saline for injection administered intramuscularly) 7-14 days later (visit 2).
Intervention code [1] 321035 0
Treatment: Drugs
Intervention code [2] 321388 0
Prevention
Comparator / control treatment
Participants will each receive a single dose of a placebo vaccine (0.5 mL of 0.9% saline for injection administered intramuscularly) within 6 hours of vaccination with a COVID-19 vaccine (ChAdOx1-S (recombinant) or 0.3 mL of BNT162b2 mRNA vaccine (nucleoside-modified)) (visit 1) and a single 0.5 mL intramuscular dose of a licensed seasonal influenza vaccine (inactivated, surface antigen, adjuvanted quadrivalent (containing 60 micrograms (µg) haemagglutinin (HA) per 0.5 mL dose) or inactivated, surface antigen, tetravalent (containing 60 µg HA per 0.5 mL dose)) 7-14 days later (visit 2)
Control group
Placebo

Outcomes
Primary outcome [1] 328112 0
Any solicited adverse reaction of moderate or severe grade (grade 2 or above) occurring up to 7 days following administration of influenza vaccine or placebo with a COVID-19 vaccine. Local injection site reactions (pain, swelling/induration & erythema) and systemic reactions (temperature, headache, fatigue, chills, myalgia, joint pain, nausea/vomiting & diarrhoea) will be ascertained via electronic surveys sent to participants by SMS.
Timepoint [1] 328112 0
days 0-7 after visit 1 and 0-7 days after visit 2
Secondary outcome [1] 397687 0
Solicited local reactions (pain, swelling/induration & erythema) ascertained via electronic surveys sent to participants by SMS.
Timepoint [1] 397687 0
days 0-7 after visit 1 and 0-7 days after visit 2
Secondary outcome [2] 397688 0
Solicited systemic reactions (temperature, headache, fatigue, chills, myalgia, joint pain, nausea/vomiting & diarrhoea) ascertained via electronic surveys sent to participants by SMS.
Timepoint [2] 397688 0
days 0-7 after visit 1 and 0-7 days after visit 2
Secondary outcome [3] 397689 0
Any serious adverse event defined as any adverse event that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect, ascertained via electronic surveys (sent to participants by SMS daily for 7 days following visit 1, for 7 days following visit 2 and at 21 days following visit 1), reports from the participants regular doctor and interrogation of local hospital records.
Timepoint [3] 397689 0
Assessed at 0 - 7 days following visit 1, 0 - 7 days following visit 2 and at 21 days following visit 1 and followed-up to a maximum of 90 days following visit 1.
Secondary outcome [4] 397690 0
Any adverse events of special interest including Guillain-Barre Syndrome, thrombocytopaenia (G3 or above), acute liver injury and chilblain-like lesions, ascertained via a survey sent to participants by SMS, reports from the participants regular doctor and interrogation of local hospital records.
Timepoint [4] 397690 0
up to 21 days following visit 1
Secondary outcome [5] 397692 0
Any medical attendance ascertained via electronic surveys sent to participants by SMS, reports from the participants regular doctor and interrogation of local hospital records.
Timepoint [5] 397692 0
Assessed at 0 - 7 days following visit 1, 0 - 7 days following visit 2 and at 21 days following visit 1
Secondary outcome [6] 397693 0
Any self-reported days off work for participants in employment ascertained via electronic surveys sent to participants by SMS.
Timepoint [6] 397693 0
Assessed at 0 - 7 days following visit 1, 0 - 7 days following visit 2 and at 21 days following visit 1
Secondary outcome [7] 397694 0
Self-reported, laboratory-confirmed COVID-19 infection ascertained via electronic surveys sent monthly to participants by SMS, and verified by medical record review.
Timepoint [7] 397694 0
up to 180 days after visit 1
Secondary outcome [8] 397695 0
Influenza-like illness or laboratory confirmed influenza infection ascertained by self-report via surveys sent monthly to participants by SMS, and confirmed by medical record review
Timepoint [8] 397695 0
up to 180 days after visit 1

Eligibility
Key inclusion criteria
1. Be aged 18 years old or over

2. Have received within 6 hours, or must be eligible, willing and scheduled to receive, a COVID-19 vaccine on the day of enrolment

3. Be eligible and willing for seasonal influenza vaccine in accordance with the Australian Immunisation Handbook

4. Provide informed consent
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Unwilling or unable to adhere to follow-up (including electronic completion of 7-day diary card)

2. Contra-indicated to receive seasonal influenza vaccine

3. Previously received a COVID-19 vaccine not licenced in Australia

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
A computer generated randomisation list, generated by the study statistician will be uploaded to the study database by the study data manager, Randomisation will then occur within the study database upon enrolment of the participant and completion of the information required for stratification. The randomisation list will be concealed and password protected. Study nurses performing the randomisation will not have access to the randomisation list.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated permuted block randomisation list stratified by site, by COVID-19 vaccine type and dose number, and by seasonal influenza vaccine type, with balanced 1:1 allocation across treatment groups will be prepared by the trial statistician.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Parallel
Other design features
At each vaccination visit, an unblinded member of the research team will dispense and administer the study vaccine (seasonal influenza vaccine or saline placebo) to a blinded participant. Pre-filled syringes containing either the seasonal influenza vaccine or a saline placebo will be covered with opaque tape and concealed in an opaque box until ready for administration. Prior to opening the box the participant will be asked to look away. The member of the research team will record the assigned study number and administer the study vaccine intramuscularly per Australian guidelines.

Research staff involved in the follow-up of adverse reactions will be blinded to the group assignment of the participants.

Laboratory staff processing or analysing trial specimens will be blinded to the group assignment of participants.

Trial analysts preparing interim reports will be unblinded and unmasked.
Phase
Phase 4
Type of endpoint(s)
Safety
Statistical methods / analysis
Inference for the trial will be derived from the accruing data at recurrent interim analyses. Generalised linear models will incorporate relevant aspects of the design, accounting for variation by site and time. The model for the primary analysis will use logistic regression (or equivalent) to compute posterior distributions that characterise the change in frequency of solicited adverse events of at least moderate severity, following COVID-19 vaccine co-administered with seasonal influenza vaccine relative to COVID-19 vaccine co-administered with placebo, for each COVID-19 vaccine brand, and for each COVID-19 vaccine dose if differential effects are apparent.

We will adopt general-purpose weakly informative priors on the parameters for all models. For the primary analysis, the intercept term uses a normal prior centred on zero with a scale set to 1.5 on the log-odds scale. On the probability scale, this is centred at 0.5 and is approximately uniform over the domain. Each additional parameter in the linear predictor uses a weakly informative normal prior centred on zero with scale set to 3 having approximately 90% of the probability mass between -4 and 4 on the log-odds scale. For sample sizes in excess of 50 per arm, these priors produce results that are practically identical to frequentist maximum likelihood estimates.

The posterior distributions will be used to evaluate decision points for declaring inferiority and non-inferiority. There is no broadly accepted minimum clinically important difference for the frequency of adverse reaction following vaccination. An absolute 15% non-inferiority margin is used for the trial, and corresponds to the expected rate of moderate or severe reaction when seasonal influenza vaccine is administered alone, and about one additional moderate or severe reaction for every 7 vaccinated people. However it will be for policy-makers to determine whether any observed increase is acceptable. The reference thresholds used to control when decisions are made will be refined based on further trial simulations under a range of scenarios.
A comprehensive statistical analysis plan (SAP) will be prepared prior to the first interim analysis. Development of the SAP will only be done by personnel who are blinded to the participant data.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 19876 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 34577 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 309038 0
Government body
Name [1] 309038 0
Sydney Local Health District
Address [1] 309038 0
Level 11, KGV Building
Missenden Road
CAMPERDOWN NSW 2050
Country [1] 309038 0
Australia
Funding source category [2] 309048 0
Charities/Societies/Foundations
Name [2] 309048 0
Snow Medical Research Foundation
Address [2] 309048 0
Level 3/223 Liverpool St, Darlinghurst NSW 2010
Country [2] 309048 0
Australia
Primary sponsor type
Government body
Name
Sydney Local Health District
Address
Level 11, KGV Building
Missenden Road
CAMPERDOWN NSW 2050
Country
Australia
Secondary sponsor category [1] 309990 0
None
Name [1] 309990 0
Address [1] 309990 0
Country [1] 309990 0
Other collaborator category [1] 281899 0
University
Name [1] 281899 0
The University of Sydney
Address [1] 281899 0
The University of Sydney, Camperdown NSW 2006
Country [1] 281899 0
Australia

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 308916 0
Sydney Local Health District (RPAH Zone)
Ethics committee address [1] 308916 0
Level 11, KGV Building Missenden Road, Camperdown NSW 2050

Ethics committee country [1] 308916 0
Australia
Date submitted for ethics approval [1] 308916 0
17/06/2021
Approval date [1] 308916 0
Ethics approval number [1] 308916 0

Summary
Brief summary
This study will aim to evaluate, pragmatically and efficiently, the safety (reactogenicity) of seasonal influenza vaccines co-administered with licenced COVID-19 vaccines in Australia. Simultaneous administration of vaccines is common practice within vaccine programs for children and adults worldwide. Co-administration of COVID-19 vaccines with seasonal influenza vaccines could offer significant advantages for health systems planning (including cost, administrative practicalities and effective use of resources) and for increasing the uptake of both vaccines. These benefits may be substantial given the likely need for booster doses of COVID-19 vaccines. It is envisioned that this study will be extended to assess the safety and immunogenicity of other potentially co-administered vaccines.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 112334 0
Prof Ian Caterson
Address 112334 0
Boden Collaboration, Charles Perkins Centre D17, University of Sydney, Johns Hopkins Dr, Camperdown, NSW 2006
Country 112334 0
Australia
Phone 112334 0
+61 02 8627 1944
Fax 112334 0
Email 112334 0
ian.caterson@sydney.edu.au
Contact person for public queries
Name 112335 0
Prof Ian Caterson
Address 112335 0
Boden Collaboration, Charles Perkins Centre D17, University of Sydney, Johns Hopkins Dr, Camperdown, NSW 2006
Country 112335 0
Australia
Phone 112335 0
+61 02 8627 1944
Fax 112335 0
Email 112335 0
ian.caterson@sydney.edu.au
Contact person for scientific queries
Name 112336 0
Prof Ian Caterson
Address 112336 0
Boden Collaboration, Charles Perkins Centre D17, University of Sydney, Johns Hopkins Dr, Camperdown, NSW 2006
Country 112336 0
Australia
Phone 112336 0
+61 02 8627 1944
Fax 112336 0
Email 112336 0
ian.caterson@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All non-identifiable individual patient data will be made available subject to approval by the Coordinating Principal Investigator.
When will data be available (start and end dates)?
From 1 months after publication of clinical trial results. No end date determined.
Available to whom?
On a case-by-case basis at the discretion of the Coordinating Principle Investigator to researchers who provide a methodologically sound proposal.
Available for what types of analyses?
Analyses to achieve the aims in the approved proposal only.
How or where can data be obtained?
Access via secure file transfer subject to approvals by Coordinating Principal Investigator (Ian Caterson, Ian.Caterson@sydney.edu.au)
What supporting documents are/will be available?
No other documents available
Summary results
No Results