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Trial registered on ANZCTR


Registration number
ACTRN12614001193662
Ethics application status
Approved
Date submitted
30/10/2014
Date registered
13/11/2014
Date last updated
16/11/2015
Type of registration
Retrospectively registered

Titles & IDs
Public title
Investigating the association between timing of routine childhood vaccinations and food allergy
Scientific title
In 1 year old children, is there an association between early versus delayed routine childhood immunisations and subsequent challenge proven food allergy at 1 year of age?
Secondary ID [1] 285569 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Food allergy 293400 0
Atopic sensitisation 293401 0
Condition category
Condition code
Inflammatory and Immune System 293679 293679 0 0
Allergies
Public Health 293743 293743 0 0
Epidemiology

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Timing of immunisations delivered at routine immunisation contacts. Data is being collected from the Australian Childhood Immunisation Register which record all childhood vaccination contacts. Date of all childhood immunisations received in the first 18 months of life will be obtained from this register.
Intervention code [1] 290520 0
Not applicable
Comparator / control treatment
N/A
Control group
Uncontrolled

Outcomes
Primary outcome [1] 293493 0
Challenge proven food allergy. Children in the HealthNuts cohort were enrolled at immunisation contacts at 1 year of age and invited to undergo skin prick testing. Those with a positive skin prick test were invited to undergo oral food challenge. Hence children who were sensitised to a particular allergen were tested with the gold standard oral food challenge soon after turning one year of age. A description of the formal food challenges and assessment of outcomes has been described (Osbourne et al. 2010 Clinical & Experimental Allergy, 40, 1516–1522)
Timepoint [1] 293493 0
At 1 year of age
Primary outcome [2] 293494 0
Atopic sensitisation defined as a positive skin prick test to any food allergen at the time of enrolment into the HealthNuts cohort (skin prick testing protocol described in Osbourne et al. 2010 Clinical & Experimental Allergy, 40, 1516–1522)
Timepoint [2] 293494 0
At 1 year of age
Secondary outcome [1] 311154 0
Eczema, defined as parental report of eczema diagnosis requiring treatment in the first year of life or eczematous rash observed by nurse at the time of recruitment into the HealthNuts cohort
Timepoint [1] 311154 0
At 1 year of age
Secondary outcome [2] 311155 0
Use of eczema medication, assessed by parental report at the time of recruitment into the HealthNuts cohort
Timepoint [2] 311155 0
At 1 year of age
Secondary outcome [3] 311156 0
Bronchiolitis admissions: parent reported admissions to hospital with bronchiolitis in the first year of life
Timepoint [3] 311156 0
before 1 year of age
Secondary outcome [4] 311157 0
Wheeze: parent reported wheeze in the first year of life
Timepoint [4] 311157 0
At 1 year of age

Eligibility
Key inclusion criteria
Previously enrolled in the HealthNuts cohort, a large population based study of childhood food allergy in Melbourne, Australia. Briefly, healthy one-year old children were recruited at immunisation contacts and invited to participate.
Minimum age
1 Years
Maximum age
1 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Refused consent to access Australian Childhood Immunisation Register data

Study design
Purpose
Natural history
Duration
Cross-sectional
Selection
Defined population
Timing
Retrospective
Statistical methods / analysis
1. Timing of pertussis-containing vaccinations
The primary analysis will be based on timing of the first aP-containing vaccination. First, the association between administration of the first aP and challenge proven food allergy will compared using a multiple logistic regression model. Delay in the first dose of aP will be modeled as a continuous variable, and any association will be assessed for linearity. Further analyses will be performed comparing children vaccinated early versus late according if a threshold can be determined. It is expected that children vaccinated >2 weeks late (ie >10 weeks of age) will be compared to those vaccinated <2 weeks late, as this is the threshold previously used by us to explore association between vaccination timing at atopic sensitisation (Kiraly et al. 2013 Allergy; 68: 1168–1176.) Adjustment for potential confounders will be performed by including background variables in the model if they alter the association between aP and food allergy by >=10%. A minimum number of potential confounders will be included in the model based on prior data; these are parental income (stratified into 5 groups), number of courses of antibiotics (0, 1-3, >=4), day-care attendance (yes/no), number of older siblings (0, 1, >=2), country of birth of the child’s parents (Australia/overseas), presence of smokers at the home (yes/no). Receipt and timing of other vaccines will also be included if they confound the result. A similar analysis will be performed for subsequent doses of aP controlling for timing of the first dose. All analyses will be stratified by sex, as sex may be an effect modifier.
Vaccination coverage is very high in the population covered by this study (approximately 94% fully vaccinated at 12 months of age), and is expected to be higher in this particular cohort as they were recruited at vaccination clinics. Thus it is expected that there will be too few children missing aP vaccination to be able to association between aP-vaccination doses and food allergy. Analyses of vaccination doses and food allergy will be performed if possible.
2. Receipt of Hep B vaccine: doses and timing
A dose of Hep B is scheduled to be given between 0 and 7 days of life. Receipt of the birth dose of Hep B will be compared with food allergy using multiple regression as described above, including adjustment for timing of aP.
3. Other vaccinations
Association between doses and timing of other vaccinations and food allergy or atopic sensitisation will be investigated in explorative analyses.

Sample size
The sample size is predetermined by the size of the HealthNuts cohort. This population size of 5000 was originally calculated to provide power to detect risk factors present in at least 10% of the population with a food sensitisation or food allergy rate of 5 to 10%. At the time of this association study, the prevalence of sensitisation and challenge proven food allergy in the HealthNuts population are known at 21.0% and 10.4% respectively. The potential effect size of timing of vaccination on atopic sensitisation or food allergy are unknown. We have no data on the proportion of the population with a delay in pertussis containing vaccination >2 weeks; hence we are unable to perform a power calculation based on the possible association between delay in vaccination of 2 weeks and food allergy.
Interpolation from outdated ACIR data indicated that approx 4.9% of children have a delay >1 month in the first dose of DTP (Hull and McIntyre 2006 Vaccine; 24;4403–4408). Our population is likely to have improved vaccination timeliness than this cohort. However assuming 4.9% of the included population have a delay in 1st dose of pertussis-containing vaccination >30 days and with alpha set to 0.05, the study population of 5200 would provide a power of 76% to detect a 33% reduction in sensitisation, and 99% power to detect reduction of 50% in sensitisation. The same population will provide power of 34% to detect 33% reduction in food allergy, and power of 78% to detect a 50% reduction in food allergy associated with delay in pertussis-containing vaccination.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
31/10/2014
Actual
31/10/2014
Date of last participant enrolment
Anticipated
Actual
17/03/2015
Date of last data collection
Anticipated
Actual
Sample size
Target
4858
Accrual to date
Final
4487
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 290171 0
Self funded/Unfunded
Name [1] 290171 0
Country [1] 290171 0
Primary sponsor type
Other Collaborative groups
Name
Murdoch Childrens Research Institute
Address
Royal Children's Hospital
50 Flemington Rd Parkville, VIC 3052
Country
Australia
Secondary sponsor category [1] 288882 0
None
Name [1] 288882 0
Address [1] 288882 0
Country [1] 288882 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291880 0
Human Research Ethics Committee
Ethics committee address [1] 291880 0
Royal Children's Hospital
50 Flemington Rd Parkville Vic, 3052
Ethics committee country [1] 291880 0
Australia
Date submitted for ethics approval [1] 291880 0
Approval date [1] 291880 0
07/07/2014
Ethics approval number [1] 291880 0
27047 P

Summary
Brief summary
Epidemiological studies of routine vaccinations and allergic disease have had mixed results, with studies showing positive, negative or no association. Very few randomised studies have been performed. Observational studies have the potential to be confounded by reasons for not receiving vaccination which may be associated with allergic disease. To minimise confounding associated with receipt of vaccination, McDonald et al. (JACI 2008;121(3):626-31) investigated the effect of timing of vaccination on asthma, finding that risk of asthma was reduced when the first dose of DTP was delayed by greater than one month.

The HealthNuts cohort was initiated in 2007 to study environmental and genetic determinates of food allergy. This population provides an opportunity to test the association between vaccination timing and food allergy using the gold standard outcome of oral food challenges. We hypothesise that there may be an association between delay in the first dose of pertussis-containing vaccine and protection from food allergy at one year of age.

Methods:
Enrolment, examination and food-allergy testing have been performed as part of the HealthNuts study. Briefly, 5276 parents agreed to enroll their children in the cohort and 5120 had a skin prick test performed at 1 year of age. 1089 children had a positive skin prick test and were invited for an oral food challenge within the following months, of which 928 children completed, along with 197 skin-prick negative control children. Parents also completed an extensive survey of symptoms of allergic disease, family history of allergic disease, demography, environmental factors, and other risk factors for allergic disease.
Data on vaccination doses and timing up to 18 months of age will be obtained for children of the HealthNuts cohort from the Australian Childhood Immunisation Register. Statistical analyses will be performed as described.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 52402 0
Dr Nicholas Kiraly
Address 52402 0
Gastro and Food Allergy
Murdoch Childrens Research Institute
Royal Children's Hospital
50 Flemington Rd Parkville VIC 3052
Country 52402 0
Australia
Phone 52402 0
+61393455522
Fax 52402 0
Email 52402 0
[email protected]
Contact person for public queries
Name 52403 0
Dr Nicholas Kiraly
Address 52403 0
Gastro and Food Allergy
Murdoch Childrens Research Institute
Royal Children's Hospital
50 Flemington Rd Parkville VIC 3052
Country 52403 0
Australia
Phone 52403 0
+61393455522
Fax 52403 0
Email 52403 0
[email protected]
Contact person for scientific queries
Name 52404 0
Dr Nicholas Kiraly
Address 52404 0
Gastro and Food Allergy
Murdoch Childrens Research Institute
Royal Children's Hospital
50 Flemington Rd Parkville VIC 3052
Country 52404 0
Australia
Phone 52404 0
+61393455522
Fax 52404 0
Email 52404 0
[email protected]

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