History of Changes for Study: NCT02112734

Version	Submitted Date	Changes
1	April 10, 2014	None (earliest Version on record)
2	April 13, 2014	Arms and Interventions, Eligibility and Study Status
3	January 21, 2015	Recruitment Status, Study Status, Contacts/Locations, Arms and Interventions, References, Oversight and Study Identification
4	September 23, 2015	Study Status
5	May 18, 2016	Contacts/Locations, Sponsor/Collaborators, Study Status, References, Eligibility, Study Design and Study Description
6	August 12, 2016	Study Status and Study Design
7	November 26, 2017	Study Status
8	May 17, 2019	Outcome Measures, Contacts/Locations, Sponsor/Collaborators, Study Status, Eligibility, Arms and Interventions and Study Design
9	May 28, 2019	Study Status and Contacts/Locations
10	October 20, 2020	Study Status and Contacts/Locations
11	March 4, 2022	Study Status and Contacts/Locations
12	November 7, 2022	Recruitment Status, Study Status, Outcome Measures, Contacts/Locations, Study Design, Study Description, Study Identification and Eligibility
13	November 19, 2023	Study Status

Brief Summary:

We report that Australia has the highest prevalence of Immunoglobulin(Ig)E-mediated food allergy in the world, with 10% of infants having challenge-proven food allergy in Melbourne. There has been a 5-fold increase in hospital admissions for life-threatening anaphylaxis. These changes are most pronounced in children less than 5 years, suggesting a causal role for early life determinants. We have primary data to inform hypotheses for the rise in food allergy, which appears to result from potentially modifiable factors related to the modern lifestyle, particularly Vitamin D insufficiency (VDI). We propose an intervention study to assess if infant Vitamin D supplementation during the first year of life significantly decreases the risk of early-onset food allergy and other allergic disease at 12 months (part 1) and 6 years of age (part 2). Australia is ideally placed to answer this important question since, unlike the USA, Canada and Europe, there are no population recommendations for routine infant supplementation with Vitamin D and we are one of the few developed countries that do not supplement the food chain supply with Vitamin D.

Detailed Description:

There is an urgent need to prevent the onset and progression of food allergy in our population. Evidence demonstrates that food allergy and atopic eczema represent the earliest manifestations of the atopic march with 50% of infants with food allergy predicted to develop respiratory allergic diseases later in life. We report that Australia has the highest prevalence of Immunoglobulin(Ig)E-mediated food allergy in the world, with 10% of infants having challenge-proven food allergy in Melbourne. There has been a 5-fold increase in hospital admissions for life-threatening anaphylaxis. These changes are most pronounced in children less than 5 years, suggesting a causal role for early life determinants. We have primary data to inform hypotheses for the rise in food allergy, which appears to result from potentially modifiable factors related to the modern lifestyle, particularly Vitamin D insufficiency (VDI), and have demonstrated an association between VDI and increased risk of challenge-proven food allergy in 12-month old infants, which supports numerous ecological studies showing an increased risk of food allergy the further a child resides from the equator (associated with decreased UV exposure and Vitamin D levels). Despite Australia's sunny climate, population rates of VDI have steadily increased in infants and pregnant women in parallel to the apparent rise in food allergic disease. This association is biologically plausible, as there is evidence Vitamin D is critical to the healthy development of the immune system in early life. We propose an intervention study to assess if infant Vitamin D supplementation during the first year of life significantly decreases the risk of early-onset food allergy and other allergic disease at 12 months (part 1) and 6 years of age (part 2). Australia is ideally placed to answer this important question since, unlike the USA, Canada and Europe, there are no population recommendations for routine infant supplementation with Vitamin D and we are one of the few developed countries that do not supplement the food chain supply with Vitamin D.

Outcome Measures


Primary Outcome Measures:
1.	The prevalence of challenge-proven food allergy at 12 months of age [ Time Frame: At 12 months of age ] The prevalence of challenge-proven food allergy at 12 months of age determined by a positive SPT and a positive oral food challenge
2.	The occurrence of definite food allergy or tolerance at 6 years of age [ Time Frame: At 6 years of age ] The occurrence of definite food allergy or tolerance at 6 years of age can only be determined by combining data from an oral food challenge, a skin prick test (SPT) and/or serum specific IgE test, and/or parent/self-reported ingestion history and reactions to the index food.
Secondary Outcome Measures:
1.	The prevalence of food sensitisation at 12 months of age determined by SPT positive [ Time Frame: At 12 months of age ] The prevalence of food sensitisation at 12 months of age determined by SPT positive
2.	The prevalence of doctor diagnosed eczema during the first postnatal year [ Time Frame: During the first postnatal year ] The prevalence of doctor diagnosed eczema during the first postnatal year
3.	The prevalence of vitamin D insufficiency (serum concentration of 25(OH)D <50 nmol/L ) at age 12 months determined by measuring blood taken at the 12 month clinic visit [ Time Frame: At 12 months of age ] The prevalence of vitamin D insufficiency (serum concentration of 25(OH)D <50 nmol/L ) at age 12 months determined by measuring blood taken at the 12 month clinic visit
4.	Allergy-related healthcare utilisation within the first 12 months of life [ Time Frame: Within the first 12 months of life ] Allergy-related healthcare utilisation within the first 12 months of life
5.	Infection episodes within the first 12 months of life [ Time Frame: Within the first 12 months of life ] Infection episodes within the first 12 months of life
6.	Measure of height at 12 months of age [ Time Frame: At 12 months of age ] Measure of height at 12 months of age
7.	Measure of weight at 12months of age [ Time Frame: At 12 months of age ] Measure of weight at 12months of age
8.	Wheeze episodes within the first 12 months of life [ Time Frame: Within the first 12 months of life ] Wheeze episodes within the first 12 months of life
9.	The occurrence of food sensitisation at 6 years of age determined by SPT positive [ Time Frame: At 6 years of age ] The occurrence of food sensitisation at 6 years of age determined by SPT positive
10.	The occurrence of asthma in the first 6 years of life [ Time Frame: At 6 years of age ] The occurrence of asthma at 6 years of age
11.	The occurrence of eczema in the first 6 years of life [ Time Frame: Within first 6 years of life ] The occurrence of eczema in the first 6 years of life
12.	The prevalence of vitamin D insufficiency (serum concentration of 25(OH)D <50 nmol/L ) at age 6 years determined by measuring blood taken at the 6 year clinic visit [ Time Frame: At 6 years of age ] The prevalence of vitamin D insufficiency (serum concentration of 25(OH)D <50 nmol/L ) at age 6 years determined by measuring blood taken at the 6 year clinic visit
13.	Allergy-related healthcare utilisation in the first 6 years of life [ Time Frame: Within first 6 years of life ] Allergy-related healthcare utilisation in the first 6 years of life by data linkage from MBS and PBS
14.	Measure of height at 6 years of age [ Time Frame: At 6 years of age ] Measure of height at 6 years of age
15.	Measure of Waist circumference at 6 years of age [ Time Frame: At 6 years of age ] Measure of Waist circumference at 6 years of age
16.	Measure of Hip circumference at 6 years of age [ Time Frame: At 6 years of age ] Measure of Hip circumference at 6 years of age
17.	Lung function at 6 years of age [ Time Frame: At 6 years of age ] Lung function: bronchial responsiveness is measured using the percent change from baseline and absolute changes in forced expiratory volume (FEV) in 1 second and/or forced vital capacity (FVC) at 6 years of age
18.	The occurrence of rhinitis in the first 6 years of life [ Time Frame: Within first 6 years of life ] The occurrence of rhinitis in the first 6 years of life
19.	Psychosocial Distress at 6 years of age [ Time Frame: At 6 years of age ] Psychosocial health at 6 years of age by Kessler Psychological Distress Scale-10 (K-10) for parents The K10 scale involves 10 questions about emotional states each with a five-level response scale. Each item is scored from one 'none of the time' to five 'all of the time'. Scores of the 10 items are then summed, yielding a minimum score of 10 and a maximum score of 50. Low scores indicate low levels of psychological distress and high scores indicate high levels of psychological distress.
20.	Psychosocial health at 6 years of age [ Time Frame: At 6 years of age ] Psychosocial health at 6 years of age by Strengths and Difficulties Questionnaire (SDQ) for child SDQ ask about 25 attributes, some positive and others negative.bThese 25 items are divided between 5 scales: emotional symptoms (5 items) } 1) to 4) added together to generate a total difficulties score (based on 20 items) conduct problems (5 items) hyperactivity/inattention (5 items) peer relationship problems (5 items) prosocial behaviour (5 items)
21.	Quality of life at 6 years of age [ Time Frame: At 6 years of age ] Quality of life (QL) at 6 years of age by Child Health Utility 9D (CHU9D, parent proxy version; PedsQL Parent Report for Young Children ages 5-7) The questionnaire has 9 questions with 5 response levels per question. The CHU9D allows the analyst to obtain quality adjusted life years (QALYs) directly for use in cost utility analysis.
22.	Quality of life regarding Food Allergy at 6 years of age [ Time Frame: At 6 years of age ] Quality of life (QL) at 6 years of age by Food Allergy Quality of Life Questionnaires-Parent Form (FAQLQ-PF) All items are scored on a 7-point Likert scale from 0 (not at all troubled) to 6 (extremely troubled) [22]. The total scores are divided by the number of items answered, giving a range of scores from 0 to 6, with higher values indicating a poorer quality of life
23.	Cardiovascular health (vascular function) at 6 years of age [ Time Frame: At 6 years of age ] Cardiovascular health at 6 years of age determined by assessing vascular function through a pulse doppler recording of the blood flow
24.	Cardiovascular health (Carotid and aortic Intima-Media Thickness) at 6 years of age [ Time Frame: At 6 years of age ] Cardiovascular health (Carotid and aortic Intima-Media Thickness) at 6 years of age by acquiring images with simultaneous ECG gating
25.	Cardiovascular health (Blood pressure) at 6 years of age [ Time Frame: At 6 years of age ] Cardiovascular health (Brachial and central blood pressure ) at 6 years of age will be measured using the SphygmoCor® XCEL system.
26.	Cardiovascular health (Arterial stiffness) at 6 years of age [ Time Frame: At 6 years of age ] Cardiovascular health (Arterial stiffness ) at 6 years of age will be assessed by central and peripheral pulse wave velocity (PWV) and pressure waveform analysis (PWA) using a cuff for the femoral artery and tonometer pressure sensor for the carotid artery.
27.	Dental health at 6 years of age [ Time Frame: At 6 years of age ] Dental health at 6 years of age: A registered oral health professional will examine the participant's mouth and teeth, checking for cavities/dental decay as well as developmental mark on the teeth. In addition, a 3D scan and/or photographs of the participant's teeth will be taken to document findings.
28.	Hearing health at 6 years of age [ Time Frame: At 6 years of age ] Hearing health at 6 years of age by using SHOEBOX® Audiometry Professional Edition to measure hearing threshold

Minimum Age:

6 Weeks

Maximum Age:

12 Weeks

Sex:

All

Gender Based:

Accepts Healthy Volunteers:

Yes

Criteria:

Inclusion Criteria:

Each participant must meet the following criteria to be included in this study:

Healthy, term (born no earlier than 2 weeks before estimated date of delivery), predominantly breastfeeding infants aged 6 to 12 weeks (inclusive) who are expected to be predominantly breastfed for at least 6-months. This will be determined by answering yes/no to question 'do you intend/wish to breastfeed until your infant is at least 6 months of age.' Up to one bottle (approx. 120mL) of formula per 24 hours at the time of screening is acceptable, as this will contain <100 IU vitamin D.
Has a parent/legally acceptable representative (LAR) capable of understanding the informed consent document and providing consent on the subject's behalf,
The parent must expect to be able to complete 4 online questionnaires over the infant's first 12 months of life and for the infant to be available for skin prick testing (+/- food challenge) at The Royal Children's Hospital at 12 months of age.

Exclusion Criteria:

Participants meeting any of the following criteria will be excluded from the study:

Infants who are currently receiving vitamin D supplementation
Infants on medication that interferes with vitamin D metabolism
Poor health due to a current or past significant disease state or congenital abnormality.
Prematurity <37 weeks/low birth weight <2500 g/Small for gestational age (SGA)
Unable to provide consent without the aid of an interpreter.
Women at high risk of vitamin D deficiency with infants on vitamin D supplementation.

Citations:

Allen KJ, Koplin JJ, Ponsonby AL, Gurrin LC, Wake M, Vuillermin P, Martin P, Matheson M, Lowe A, Robinson M, Tey D, Osborne NJ, Dang T, Tina Tan HT, Thiele L, Anderson D, Czech H, Sanjeevan J, Zurzolo G, Dwyer T, Tang ML, Hill D, Dharmage SC. Vitamin D insufficiency is associated with challenge-proven food allergy in infants. J Allergy Clin Immunol. 2013 Apr;131(4):1109-16, 1116.e1-6. doi: 10.1016/j.jaci.2013.01.017. Epub 2013 Feb 27. PubMed 23453797

Allen KJ, Panjari M, Koplin JJ, Ponsonby AL, Vuillermin P, Gurrin LC, Greaves R, Carvalho N, Dalziel K, Tang ML, Lee KJ, Wake M, Curtis N, Dharmage SC. VITALITY trial: protocol for a randomised controlled trial to establish the role of postnatal vitamin D supplementation in infant immune health. BMJ Open. 2015 Dec 16;5(12):e009377. doi: 10.1136/bmjopen-2015-009377. PubMed 26674499

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