High-dose vitamin D3 supplementation in the prevention of viral-induced asthma in high-morbidity preschoolers (DIVA): a randomised controlled trial in Canada

Background Systematic reviews have suggested a beneficial effect of vitamin D supplementation in reducing asthma exacerbations and respiratory infections, with an underrepresentation of individuals with severe asthma and preschoolers. We aimed to examine the efficacy and safety of high-dose vitamin D supplementation for reducing severe exacerbations in preschool-aged children with viral-induced, high-morbidity, and asthma. Methods In this randomised, placebo-controlled, parallel-group, triple-blind, multicentre trial, children aged 1–5 years with prior viral-induced exacerbations requiring oral corticosteroids (OCS) were enrolled across nine paediatric asthma centres in Canada. Participants were randomly assigned to receive either two oral boluses of 100,000 IU (3·5 months apart) with daily 400 IU vitamin D3, or placebo boluses and daily placebo, over 7 months. The primary outcome was the rate of exacerbations requiring rescue OCS during the 7-month follow-up, analysed by a negative binomial regression model. Secondary outcomes included laboratory-confirmed respiratory infections, health care utilisation, duration and severity of exacerbations, and safety. This trial was prospectively registered with ClinicalTrials.gov (NCT03365687). Findings Between Sept 18, 2018, and April 22, 2024, 1072 children were screened. Due to pandemic-related recruitment constraints, the trial enrolled 323 children, representing 37% of the planned sample size of 865 children. Participants had a mean age of 2·8 years (65% male) with a median of 2 (interquartile range: 1–3) oral corticosteroid courses in the prior year; at baseline, 48% had baseline serum 25-hydroxyvitamin D (25(OH)D) ≥75 nmol/L and 90% received GINA 2024 Step ≥3 therapy. Compared to placebo, there was no significant group difference in the rate of rescue OCS per child (0·67 ± 0·94 vs. 0·71 ± 1·02, incidence rate ratio [IRR] 0·95; 95% CI 0·70–1·30), laboratory-confirmed infections (1·73 ± 1·71 vs. 1·76 ± 1·55, IRR 0·99; 0·82–1·21), acute-care visits, duration and/or severity of exacerbations, and treatment-emergent or serious adverse events adverse events. The intervention was associated with a rapid and sustained rise in 25(OH)D. Interpretation In preschoolers with high-morbidity, viral-induced asthma, vitamin D3 supplementation did not significantly reduce severe exacerbation or respiratory viral infection rates, compared to placebo. No safety concerns were observed. With fewer participants than planned, the precision of estimates is limited and the results are inconclusive, thus deserve further exploration.