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Trial registered on ANZCTR


Registration number
ACTRN12620000644965
Ethics application status
Approved
Date submitted
15/05/2020
Date registered
3/06/2020
Date last updated
3/06/2020
Date data sharing statement initially provided
3/06/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
FluBub Study: Early influenza vaccination in infants
Scientific title
Safety and Immunogenicity of Early Quadrivalent Influenza Vaccine: A phase 2 prospective randomised open-label feasibility study
Secondary ID [1] 301237 0
Nil known
Universal Trial Number (UTN)
Trial acronym
EQIV
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Influenza 317405 0
Condition category
Condition code
Infection 315503 315503 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Young children, particularly those younger than six (6) months are at increased risk of severe influenza infection. There are no data on the safety and immune response in infants under 6 months of age to quadrivalent influenza vaccines (QIV; conferring protection against four strains; routinely used in Australia since 2016), nor is anything known about the impact of the now recommended maternal influenza vaccination on vaccine responses in infants under 6 months of age. Lastly, it has never been assessed if maternal influenza infection during pregnancy impacts standard infant influenza vaccine responses.

This clinical trial is a phase 2, prospective randomised open-label feasibility study to assess both the safety of early (under 6 months) influenza vaccination in healthy young infants and its ability to generate a protective immune response via antibody production (immunogenicity). This will be compared with infants vaccinated according to the currently recommended schedule. We will utilise a QIV currently recommended on the Australian National Immunisation Program for all children from 6 months of age; this vaccine targets one influenza A/H1N1 strain, one A/H3N2 strain and two influenza B lineages (15µg haemagglutinin for each strain). 150 infants will be randomised to a vaccination strategy which will either have an early start to the schedule or commence according to the currently recommended schedule (Arms 1 to 3). We also include one additional (non-randomised) study arm that is to assess the impact of maternal influenza infection during pregnancy on standard infant influenza vaccination (Arm 4, n=50).

Arm 1: Early vaccination and booster (receipt of QIV at 2-3 months followed by a booster one month later);

Arm 2: Early vaccination and delayed booster (receipt of QIV at 2-3 months and a booster at 7-8 months);

Arm 3: [Control] Standard vaccination (receipt of QIV at 6-7 months followed by a booster one month later);

Arm 4: Standard vaccination following confirmed maternal influenza infection in pregnancy.

QIV will be administered to participating infants by experienced study nurses, in a hospital clinic. A single maternal blood sample will be collected during the first study visit for infant vaccination. Infant blood samples will be collected immediately prior their first ever and second (booster) influenza vaccinations and one month following the infant's second influenza vaccination i.e. up to three blood samples will be collected before age 12 months. Optional maternal breast milk samples will be requested at study visits so long as breastfeeding continues.

All infants will be invited to continue participation into their second year of life (participation is optional and declined participation will not compromise core trial aims). Participating infants will receive QIV at 15-18 months, immediately preceded by blood collection, with a second blood sample collected one month later.
Intervention code [1] 317537 0
Prevention
Comparator / control treatment
Arm 3 of the study will serve as the control Arm. Infants in Arm 3 of the study will receive standard QIV vaccination following the timing currently recommended on the Australian National Immunisation Program.
Control group
Active

Outcomes
Primary outcome [1] 323747 0
Frequency of solicited local reactions (pain, redness, or swelling at the vaccination site)
or systemic reactions (fever, nausea and/or vomiting, diarrhoea; loss of appetite, irritability, sleepiness, unusual crying).
Timepoint [1] 323747 0
The first week following vaccination, using parental assessment data entered daily into electronic diaries for 7 consecutive days beginning on the day of vaccination.
Primary outcome [2] 323748 0
Severity of solicited local reactions (pain, redness, or swelling at the vaccination site)
or systemic reactions (fever, nausea and/or vomiting, diarrhoea; loss of appetite, irritability, sleepiness, unusual crying).
Timepoint [2] 323748 0
The first week following vaccination, using parental assessment data entered daily into electronic diaries for 7 consecutive days beginning on the day of vaccination.
Primary outcome [3] 323991 0
Proportion of infants in each study arm with potential seroprotection against the four strains included in the vaccine, assessed using haemagglutination inhibition (HI) and micro-neutralization (MN) assays. HI titre above 1:40 and/or MN titre above 1:160 will be considered positive.
Timepoint [3] 323991 0
Assessed from blood collected 4 weeks after the second QIV dose.
Secondary outcome [1] 382781 0
Frequency of unsolicited adverse events, using parental assessment data entered into electronic diaries.
Timepoint [1] 382781 0
Within 28 days of QIV receipt.
Secondary outcome [2] 382782 0
Frequency of unsolicited severe adverse events, using parental assessment data entered into electronic diaries.
Timepoint [2] 382782 0
Within 28 days of QIV receipt.
Secondary outcome [3] 383514 0
Frequency of medically-attended adverse events, using parental assessment data entered into electronic diaries.
Timepoint [3] 383514 0
Within 28 days of QIV receipt.
Secondary outcome [4] 383515 0
Proportion of infants in each study arm with seroconversion, assessed using haemagglutination inhibition (HI) and micro-neutralization (MN) assays. Seroconversion will be defined as a switch from below to above detection threshold for those with no detectable antibodies pre-vaccination, or a 4-fold increase in HI or MN titres in those with detectable antibody prior to vaccination.
Timepoint [4] 383515 0
Four weeks following the second dose of QIV.
Secondary outcome [5] 383516 0
Post-vaccination geometric mean titre increase, measured using haemagglutination inhibition and micro-neutralization assays.
Timepoint [5] 383516 0
Baseline compared with results 4 weeks after the first and the second QIV doses.

Eligibility
Key inclusion criteria
Term infants younger than 2 months of age will be eligible for inclusion (Arm 1 to 3).

To limit the breadth of past maternal early life influenza exposures, we will primarily target the babies of women born between 1985 and 1995.

Infants will be enrolled in the study only if, in the opinion of the investigator, they and their mothers are considered able and likely to comply with the requirements of the research protocol.

An additional group of infants will be recruited but not randomised. This includes those born to mothers with confirmed influenza infection who will be vaccinated as per the standard schedule.
Minimum age
2 Months
Maximum age
7 Months
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1) Infants born <37 weeks or >42 weeks gestation;
2) Infants with congenital malformations, immunodeficiency or receiving immunosuppressive therapy
3) Infants born to mothers with immunodeficiency or receiving immunosuppressive therapy;
4) Infants previously receiving any monoclonal or polyclonal antibody (e.g, IV immunoglobulin);
5) Infants currently enrolled in a clinical trial for a drug or vaccine.
6) Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results;
7) infants whose parents/guardians are unwilling to comply with study requirements and follow-up until at least 8 months of age;
8) Children of employees of the clinical study site, or any other individuals involved with the conduct of the study, or immediate family members of such individuals.

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)
Central randomisation by computers.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Infants will be randomised in a 1:1:1 fashion to study arms 1 to 3 using computer-generated randomisation codes. This randomisation will be stratified by maternal vaccination receipt during pregnancy to give even distribution of vaccinated mothers. Allocation to Arm 4 will not be randomised; it will be require a reported and confirmed maternal influenza infection during pregnancy.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Laboratory assays will be performed in a blinded fashion; blinding will be subsequently removed to enable statistical analysis and comparison between outcomes.
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The study is descriptive and not intended to test statistical hypotheses nor designed to detect significant differences between vaccine schedules.

Demographics :
Demographic characteristics will be summarised by group using descriptive statistics. Frequency tables will be generated for categorical variables. Mean, median, standard deviation and range will be provided for continuous data.

A number of key safety endpoints will be assessed:
1) Solicited adverse events: The number and percentage with exact 95% confidence intervals (CI) of infants with reported solicited local and systemic adverse event (AE) during the 7 day follow up period after vaccination will be tabulated for each study arm.
2) Unsolicited adverse events: The number and percentage with exact 95%CI of infants with unsolicited AE during the 28 day follow up period after vaccination will be tabulated for each study arm.
3) For fever during the 7 day follow up period after vaccination, the number and percentage of infants with reported fever with exact 95%CI, fever by predetermined increments and any grade 3 fevers will be reported with exact 95%CI

The proportions of infants with reported AE will be presented for varying time points and considered relative to the standard schedule arm using confidence intervals and application of the Chi-squared test.

Immunogenicity endpoints
Arms 3 and 4 will initially be combined to quantify impact of varying vaccination schedules. Logistic regression will be utilized to further explore differences in seroprotection and seroconversion rates across schedules and assess the impact of maternal vaccination/HAI status. Linear regression of log-transformed GMT ratios will be utilised to explore differences across schedules and assess the impact of maternal vaccination/HAI status on this measure of immunogenicity.

1) Seroprotection: The primary immunogenicity endpoint will be the proportion of vaccine recipients with potential seroprotection to the four viral strains measured at least 4 weeks after a second dose of QIV. The proportions of infants who achieve seroprotection will be presented across schedules as percentages with 95% CIs.
2) Seroconversion: a further immunogenicity endpoint will be the proportion of vaccine recipients with seroconversion, measured at least 4 weeks after a second dose of QIV. For each strain the proportions of infants who achieved seroconversion will be presented across schedules as percentages with 95% CIs.
3) Geometric mean titre (GMT) ratios, calculated as ratios of post-vaccination titres to pre-vaccination titres using a geometric mean scale, will be tabulated with 95% CIs (derived using a natural logarithmic transformation).

Immunogenicity endpoints:
Immunogenicity endpoints will be primarily assessed 4 weeks after the second dose of QIV (approximately 4 months of age in Arm 1; approximately 8 months of age in arms 2,3 and 4). Given the difference in age and potential impact on immunogenicity, further assessments will occur using the samples collected at approximately 8 months of age (4th bleed in Arm 1; 3rd bleed in Arm 2,3 and 4; Figure 1).

Arm 3 and 4 will initially be combined to assessment of impact of varying vaccination schedules. To further assess the impact of clinically relevant predictors on vaccine response (e.g. maternal vaccination status; maternal antibody levels), linear regression models with change in log antibody level as the dependent variable will be constructed. These will be constructed incorporating data from all arms and separately by individual vaccine schedules.

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)
WA
Recruitment hospital [1] 16636 0
Perth Children's Hospital - Nedlands
Recruitment postcode(s) [1] 30231 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 305686 0
Charities/Societies/Foundations
Name [1] 305686 0
Telethon Kids Institute
Address [1] 305686 0
Telethon Kids Institute
North Entrance, Perth Children's Hospital
15 Hospital Avenue
Nedlands W.A. 6000
Country [1] 305686 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Telethon Kids Institute
Address
Telethon Kids Institute
North Entrance, Perth Children's Hospital
15 Hospital Avenue
Nedlands W.A. 6000
Country
Australia
Secondary sponsor category [1] 306097 0
None
Name [1] 306097 0
Address [1] 306097 0
Country [1] 306097 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305966 0
Child and Adolescent Health Service Human Research Ethics Committee (EC00268)
Ethics committee address [1] 305966 0
CAHS
Perth Children's Hospital
15 Hospital Avenue
Nedlands W.A. 6000
Ethics committee country [1] 305966 0
Australia
Date submitted for ethics approval [1] 305966 0
20/01/2020
Approval date [1] 305966 0
19/03/2020
Ethics approval number [1] 305966 0
RGS0000003848

Summary
Brief summary
Influenza (flu) is the most common disease that can be prevented by vaccines. Babies under 6 months have an especially high risk of severe influenza infection – this is partly because the influenza vaccine which is used safely from 6 months of age in Australia is not currently approved for use in younger babies.

We are running a clinical trial to carefully test the safety of giving this same influenza vaccine 3 to 4 months earlier than is currently recommended. The trial will also tell us whether early influenza vaccination offers the same level of protection as when it is given after age 6 months.

This study will give us valuable information about how influenza vaccines work, to help researchers to develop new vaccines that offer better protection for everyone. We will look at how the timing of vaccination changes protective responses both after the first vaccination and during the following influenza season, as well as how a mother’s influenza infection and/or vaccination history might influence how well influenza vaccines work in their babies.

We are looking for mothers and their babies to take part in this study. Babies younger than 8 weeks born between 37 and 42 weeks of pregnancy without major health concerns will be eligible to participate. Babies will be given an influenza vaccine in this study that is already approved for use in Australia by the Therapeutic Goods Administration (TGA).

This is a pilot study that will tell us whether a larger, more informative study will be worthwhile. We aim to have 150 babies allocated to one of three influenza vaccination schedules:
Arm 1: Early vaccination & booster (vaccine at 2-3 months of age; a booster one month later);
Arm 2: Early vaccination & delayed booster (vaccine at 2-3 months; a booster at 7-8 months of age);
Arm 3: Standard vaccination (vaccine at 6-7 months; a booster one month later).

We also aim to recruit up to 50 babies of mothers who caught influenza during pregnancy to Arm 4 of the study. These babies will follow the standard vaccination schedule as for Arm 3, which will let us look at how influenza during pregnancy may change a baby's protective responses to flu vaccination.

This study will run for 3 years. Vaccinations and sample collection will take place as long as influenza vaccine is available in Australia. Mothers will give a blood sample (10ml, which is 2 teaspoons) at their first baby's first study visit, and we will ask them to give samples of breast milk at each visit while they are still breastfeeding (optional). Babies in the study will have a 5ml blood sample (1 teaspoon) collected immediately before their first and second flu vaccinations plus 1 month after their second flu vaccination.

All babies will be invited to stay in the study for their second year of life. Babies joining in this part of the study will give a 5ml blood sample just before getting a flu vaccination when they are 15 to 18 months old and will give a final 5ml blood sample 1 month later.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 102242 0
A/Prof Christopher Blyth
Address 102242 0
Telethon Kids Institute
North Entrance, Perth Children's Hospital
15 Hospital Ave
Nedlands W.A. 6009
Country 102242 0
Australia
Phone 102242 0
+61 8 6456 5614
Fax 102242 0
Email 102242 0
christopher.blyth@uwa.edu.au
Contact person for public queries
Name 102243 0
A/Prof Christopher Blyth
Address 102243 0
Telethon Kids Institute
North Entrance, Perth Children's Hospital
15 Hospital Ave
Nedlands W.A. 6009
Country 102243 0
Australia
Phone 102243 0
+61 8 6456 5614
Fax 102243 0
Email 102243 0
christopher.blyth@uwa.edu.au
Contact person for scientific queries
Name 102244 0
A/Prof Christopher Blyth
Address 102244 0
Telethon Kids Institute
North Entrance, Perth Children's Hospital
15 Hospital Ave
Nedlands W.A. 6009
Country 102244 0
Australia
Phone 102244 0
+61 8 6456 5614
Fax 102244 0
Email 102244 0
christopher.blyth@uwa.edu.au

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?
No other documents available
Summary results
No Results