Vitamin D In the Prevention of Viral-induced Asthma in Preschoolers

Study Overview
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Brief Summary
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In this 7-month randomized controlled trial, children aged 1 to less than 6 years, with recurrent asthma attacks triggered mostly by colds, will receive a high dose of vitamin D or a placebo every 3.5 months during their usual clinic visit, and a daily supplement of vitamin D or a placebo. This study will test whether children in vitamin D group have less frequent and less severe asthma exacerbations compared with those receiving placebo.The study will also document the safety profile of this strategy.

Detailed Description
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This is a multicenter triple-blind randomized parallel-group, placebo-controlled trial of vitamin D3 supplementation. Children aged 1-5 (<6) years with physician-diagnosed asthma predominantly triggered by upper respiratory tract infection will be screened for enrolment in paediatric asthma, respiratory or allergy clinics and the ED departments and randomized between Sept 1 to January 31, annually (4 recruitment years). Using a computer-generated random list, stratified by site, children will be allocated (1:1) using permuted block randomisation method to enhance concealment. Children will be followed for 7 months, with 3 visits every 3.5 months with repeated urine (for calcium:creatinine ratio) and blood samples. In addition, ten (10) days after each bolus, urine will be sampled for urinary calcium:creatinine ratio. In case of elevated urine calcium:creatinine ratio, a blood sample may be needed primarily for markers of calcium metabolism and exploratory outcomes. Only patients enrolled at CHU Sainte-Justine and Montreal Children's Hospital will receive a systematic home visit 10 days after first bolus for both urine and blood samples. There will be 6 follow-up phone calls, at week 1 and then monthly, to inquire about exacerbations and URTIs, remind parents to complete questionnaires and to collect a nasal swab at each exacerbation and screen for adverse events. The main outcome is the number of courses of rescue oral corticosteroids (OCS) per child during the study period. Several secondary outcomes will be documented using biological samples and validated questionnaires to ascertain laboratory-confirmed respiratory infections, intensity and severity of exacerbations, mean number of ED visits, parents' functional status during exacerbations, de-intensification of preventive asthma therapy, cost effectiveness, and safety profile. A sample of 432 children (400+7,5% attrition) per arm will provide 80% power with a two-tailed alpha of 5% to detect a 25% relative reduction in the mean number of exacerbations requiring OCS per child. An intention-to-treat (ITT) analysis will be carried out with all randomised children.

Official Title
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Vitamin D In the Prevention of Viral-induced Asthma in Preschoolers: a Randomized Controlled Multicenter Trial (DIVA)

Conditions
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Asthma

Intervention / Treatment
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* Dietary Supplement: Vitamin D
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 1-5 years Physician-diagnosed asthma (as per the 2015 Canadian Position Paper on the diagnosis of preschool asthma) ≥1 asthma exacerbation requiring rescue oral corticosteroids (OCS) in the past 6 months or ≥2 in the past 12 months (as documented by pharmacy/medical records) ≥4 upper respiratory tract infections (URTIs) in the past 12 months (as per parental report) URTIs as the main asthma trigger (as per parental report) Exclusion Criteria: Intake > 400 IU/day of vitamin D3 supplements or fish oil in the past 3 months Intention to use > 400 IU/day of vitamin D3 supplements or fish oil in the fall and winter Extreme prematurity (< 28 week gestation) No vitamin D supplementation (if breast-fed in the last 6 months) Vitamin D restrictive diets, that is, minimal intake of vitamin D fortified milk (<250 mL/day for 1-3 years or <375 mL/day for 4-6 years AND no other (or <200 IU/day) vitamin D supplement Recent immigrants from regions at high risk of rickets (in the past 12 months) Recent refugees (in the past 12 months) Undernourished children Other chronic respiratory disease (e.g. Cystic fibrosis, Bronchopulmonary dysplasia) or chronic kidney, gastrointestinal, endocrinological or cardiac diseases, or sickle cell anemia? History of bone disorder disease (e.g. rickets, osteomalacia) Intake of oral anti-epileptic, diuretic or anti-fungal medications Anticipated difficulty with follow-up or with adherence to the intervention or the procedures

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a randomised, triple-blind, placebo-controlled, parallel-group multicentre trial of vitamin D3 supplementation.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Vitamin D<br>Vitamin D supplement (100,000 IU) orally at baseline and at 3.5 months with daily 400 IU vitamin D for 7 months | Dietary Supplement: Vitamin D<br>* 2 mL of 50,000 IU/mL at baseline and at 3.5 months with a daily dose of 1 mL (400 IU/mL) for 7 months<br>* Other names: Cholecalciferol;|
| Placebo Comparator: Placebo<br>Placebo orally at baseline and at 3.5 months with daily placebo during 7 months | Dietary Supplement: Placebo<br>* 2 mL of placebo at baseline and at 3.5 months with a daily dose of placebo (1 mL) for 7 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of asthma exacerbations per child treated with rescue oral corticosteroids | Group difference in the mean number of exacerbations treated with rescue oral corticosteroids/child | 7 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Laboratory-confirmed respiratory infections | Group difference in mean number of laboratory-confirmed respiratory infections during asthma exacerbations | 7 months | 
| Severity of asthma symptoms during asthma exacerbations | Group difference in the mean severity of asthma symptoms documented on the 'Asthma Flare-up Diary for Young Children' | 7 months | 
| Duration of asthma symptoms during asthma exacerbations | Group difference in the mean duration of asthma symptoms documented on the validated 'Asthma Flare-up Diary for Young Children' | 7 months | 
| Intensity of use of rescue β2-agonists during asthma exacerbations | Group difference in the mean cumulative use of rescue β2-agonists during exacerbations documented on the validated 'Asthma Flare-up Diary for Young Children' | 7 months | 
| Parents' functional status during asthma exacerbations | Group difference in the mean parents' functional status during exacerbation as documented on the validated 'Effect of a child's asthma flare-up on parents questionnaire' | 7 months | 
| Mean number of ED visits for asthma exacerbations | Group difference in mean number of ED visits for asthma exacerbations | 7 months | 
| De-intensification of preventive asthma therapy | Group difference in proportion of children with de-intensification of preventive asthma therapy | 7 months | 
| Intervention cost-effectiveness | Cost of intervention vs. cost (family expenses and health care) of exacerbations | 7 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vitamin D, Children, Respiratory viral infection, Randomized controlled trial, Asthma exacerbations