Effect of Vitamin D3 Supplementation on Severe Asthma Exacerbations in Children With Asthma and Low Vitamin D Levels: The VDKA Randomized Clinical Trial

Abstract

Importance: Severe asthma exacerbations cause significant morbidity and costs. Whether vitamin D3 supplementation reduces severe childhood asthma exacerbations is unclear.

Objective: To determine whether vitamin D3 supplementation improves the time to a severe exacerbation in children with asthma and low vitamin D levels.

Design, setting, and participants: The Vitamin D to Prevent Severe Asthma Exacerbations (VDKA) Study was a randomized, double-blind, placebo-controlled clinical trial of vitamin D3 supplementation to improve the time to severe exacerbations in high-risk children with asthma aged 6 to 16 years taking low-dose inhaled corticosteroids and with serum 25-hydroxyvitamin D levels less than 30 ng/mL. Participants were recruited from 7 US centers. Enrollment started in February 2016, with a goal of 400 participants; the trial was terminated early (March 2019) due to futility, and follow-up ended in September 2019.

Interventions: Participants were randomized to vitamin D3, 4000 IU/d (n = 96), or placebo (n = 96) for 48 weeks and maintained with fluticasone propionate, 176 μg/d (6-11 years old), or 220 μg/d (12-16 years old).

Main outcomes and measures: The primary outcome was the time to a severe asthma exacerbation. Secondary outcomes included the time to a viral-induced severe exacerbation, the proportion of participants in whom the dose of inhaled corticosteroid was reduced halfway through the trial, and the cumulative fluticasone dose during the trial.

Results: Among 192 randomized participants (mean age, 9.8 years; 77 girls [40%]), 180 (93.8%) completed the trial. A total of 36 participants (37.5%) in the vitamin D3 group and 33 (34.4%) in the placebo group had 1 or more severe exacerbations. Compared with placebo, vitamin D3 supplementation did not significantly improve the time to a severe exacerbation: the mean time to exacerbation was 240 days in the vitamin D3 group vs 253 days in the placebo group (mean group difference, -13.1 days [95% CI, -42.6 to 16.4]; adjusted hazard ratio, 1.13 [95% CI, 0.69 to 1.85]; P = .63). Vitamin D3 supplementation, compared with placebo, likewise did not significantly improve the time to a viral-induced severe exacerbation, the proportion of participants whose dose of inhaled corticosteroid was reduced, or the cumulative fluticasone dose during the trial. Serious adverse events were similar in both groups (vitamin D3 group, n = 11; placebo group, n = 9).

Conclusions and relevance: Among children with persistent asthma and low vitamin D levels, vitamin D3 supplementation, compared with placebo, did not significantly improve the time to a severe asthma exacerbation. The findings do not support the use of vitamin D3 supplementation to prevent severe asthma exacerbations in this group of patients.

Trial registration: ClinicalTrials.gov Identifier: NCT02687815.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Bacharier reported receiving grants from the National Heart, Lung, and Blood Institute (NHLBI) during the conduct of the study and personal fees from AstraZeneca, GlaxoSmithKline, Sanofi, Regeneron, Novartis, Genentech, Boeringher Ingelheim, Vectura, DBV Technologies, Circassia, Merck, Teva, Medscape, and Rockpointe outside the submitted work, as well as receiving royalties as associate editor from Elsevier (Journal of Allergy and Clinical Immunology). Dr Phipatanakul reported serving as a consultant for GlaxoSmithKline, Genentech, Novartis, Regeneron, Sanofi, and Teva; receiving clinical trial support or medications from Genentech, Novartis, Regeneron, Sanofi, Circassia, Monaghen, Thermo Fisher, Alk Abello, Lincoln Diagnostics, GlaxoSmithKline, Kaleo, and Merck; and funding to the institution by Genentech, Regeneron, Novartis, and the National Institutes of Health (NIH)—all for projects unrelated to the current work. Dr Guilbert reported receiving personal fees from GlaxoSmithKline, TEVA, Novartis, and the American Board of Pediatrics (pediatric pulmonary subboard); grants and personal fees from Sanofi/Regeneron; grants from AstraZeneca and Novartis; and royalties from UpToDate outside the submitted work. Dr Cabana reported serving as a member of the United States Preventive Services Task Force (USPSTF); this manuscript does not necessarily represent the views of the USPSTF. Dr Ross reported receiving grants from the NIH during the conduct of the study and grants and nonfinancial support from TEVA, nonfinancial support from Merck, and grants from Flamel, the NHLBI, AstraZeneca, and Novartis outside the submitted work. Dr Covar reported receiving grants from GlaxoSmithKline during the conduct of the study. Dr Gern reported receiving personal fees from AstraZeneca outside the submitted work. Dr Rosser reported receiving grants from the NIH/National Center for Advancing Translational Sciences during the conduct of the study. Dr Celedón reported receiving nonfinancial support from Pharmavite and GlaxoSmithKline during the conduct of the study and nonfinancial support (Asmanex) for an NIH-funded study from Merck outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Selection of Study Participants

FEV1 indicates forced expiratory volume in the first second of expiration. aSum is greater than 376 because potential participants could fail screening more than once and could fail for more than 1 reason. bSum is greater than 27 because participants could enter run-in more than once and could fail for more than 1 reason.

Figure 2.. Vitamin D Levels During Trial Period by Treatment Group

Boxes represent median and interquartile ranges with error bars indicating the highest and lowest values within 1.5 times the interquartile range; dots represent outlying data.

Figure 3.. Results of the Analysis of Time to a First Severe Asthma Exacerbation

Vertical bars represent single censored events. The adjusted hazard ratio for time from randomization to a first severe exacerbation was 1.13 (95% CI, 0.69-1.85) for the vitamin D3 vs placebo treatment groups (P = .63). Models were stratified by study site, sex, and race/ethnicity. The median observation time was 274.5 days (interquartile range [IQR], 163-333) in the vitamin D3 group and 321 days (IQR, 196.5-334) in the control group.