Clinical trial NCT03365687: Vitamin D In the Prevention of Viral-induced Asthma in Preschoolers
Official title: Vitamin D In the Prevention of Viral-induced Asthma in Preschoolers: a Randomized Controlled Multicenter Trial (DIVA)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Asthma
Asthma Exacerbations
Preschool Child
Vitamin D
Upper Respiratory Infection
Randomized Controlled Study
Symptoms
Bronchodilator Agents
Keywords: Children
Vitamin D
Respiratory viral infection
Randomized controlled trial
Asthma exacerbations
intervention
functional status
acute care visits
oral corticosteroids
hypercalciuria
hypercalcemia
Lead sponsor: St. Justine's Hospital
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: EURO-PHARM International Canada, Inc.
First posted: 2017-12-07
Enrollment: 323
Sex: ALL
Minimum age (years): 1
Maximum age (years): 5
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a randomised, triple-blind, placebo-controlled, parallel-group multicentre trial of vitamin D3 supplementation.
Primary purpose: PREVENTION

Brief summary: 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: 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 infections 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) and year around from 2022 onwards.

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.

Eligibility criteria: 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; or from the pandemic (2020) onwards, ≥1 asthma exacerbation requiring rescue oral corticosteroids (OCS) 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); or from the pandemic (2020) onwards, ≥ 2 URTIs in past 12 months
* 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

Primary outcomes:
measure: Number of asthma exacerbations per child treated with rescue oral corticosteroids
timeFrame: 7 months
Secondary outcomes:
measure: Laboratory-confirmed respiratory infections
timeFrame: 7 months
measure: Mean number of ED visits and hospital admissions for asthma exacerbations
timeFrame: 7 months
measure: De-intensification of preventive asthma therapy
timeFrame: 3.5 and 7 months
measure: Duration of asthma symptoms during asthma exacerbations
timeFrame: 7 months
measure: Duration of B2-agonist use during asthma exacerbations
timeFrame: 7 months
measure: Severity of asthma symptoms during asthma exacerbations
timeFrame: 7 months
measure: Intensity of use of rescue β2-agonists during asthma exacerbations
timeFrame: 7 months
measure: Parents' functional status during asthma exacerbations
timeFrame: 7 months
measure: Number of parental workdays lost
timeFrame: 7 months
measure: Parental productivity
timeFrame: 7 months
measure: Intervention cost-effectiveness
timeFrame: 7 months
Other outcomes:
measure: Hypercalcemia
timeFrame: 7 months
measure: Hypercalciuria
timeFrame: 7 months
measure: Elevated serum 25-hydroxyvitamin D
timeFrame: 7 months
measure: Adverse Health Events
timeFrame: 7 months
measure: Serious Adverse Health Events
timeFrame: 7 months
measure: Gene expression
timeFrame: 3.5 months
Locations:
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital
state: British Columbia
city: London
country: Canada
facility: Children's Hospital of London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: Children's Hospital of Eastern Ontario
state: Ontario
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: Montreal Children's Hospital
state: Quebec
city: Montreal
country: Canada
facility: CHU Sainte Justine
state: Quebec
city: Montreal
country: Canada
facility: Maisonneuve-Rosemont Hospital
state: Quebec
city: Québec
country: Canada
facility: CHU de Québec-Université Laval
state: Quebec
city: Sherbrooke
country: Canada
facility: CHU de Sherbrooke
state: Quebec
Study officials:
affiliation: Study Principal Investigator
name: Francine M Ducharme, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jensen ME, Ducharme FM, Alos N, Mailhot G, Masse B, White JH, Sadatsafavi M, Khamessan A, Tse SM, Alizadehfar R, Bock DE, Daigneault P, Lemire C, Yang C, Radhakrishnan D. Vitamin D in the prevention of exacerbations of asthma in preschoolers (DIVA): protocol for a multicentre randomised placebo-controlled triple-blind trial. BMJ Open. 2019 Dec 30;9(12):e033075. doi: 10.1136/bmjopen-2019-033075.