Vitamin D₃ supplementation added to low-dose inhaled corticosteroids was not associated with longer time to asthma exacerbations among high-risk children with low baseline 25-hydroxyvitamin D levels, researchers reported.

The mean time to exacerbation was 240 days in children randomized to the vitamin D₃ supplementation group and 253 days in the placebo group (mean group difference -13.1 days [95% CI, — 42.6-16.4], adjusted hazard ratio 1.13 [95% CI 0.69-1.85], P=0.63), according to Juan Celedón, MD, DrPH, of Children’s Hospital of Pittsburgh, and colleagues.

Writing online in JAMA, they concluded that the findings therefore do not support vitamin D₃ supplementation as a treatment to delay the time to asthma exacerbation in at-risk children with low serum vitamin D levels.

The researchers noted that the negative findings could not be attributed to failure to achieve vitamin D sufficiency after supplementation, because close to 90% of the children in the vitamin D₃ treatment group achieved vitamin D levels of 30 ng/mL or greater during the trial, compared with less than 40% of children in the placebo arm.

Enrollment for the trial started in February 2016, with a goal of recruiting 400 participants. The trial was terminated early, in March 2019, with only 192 patients, due to futility, and follow-up ended in September 2019.

Nevertheless, Bruce L. Davidson, MD, a pulmonologist and vitamin D researcher at Providence Health System in Seattle, who was not involved in the study, said he believes supplementation can benefit children with severe vitamin D deficiency, as his own research has shown.

His 2017 study in CHEST, for example, also included children with asthma who were vitamin D deficient at enrollment, but the study had no placebo group. Instead, the team compared a maintenance dose of oral vitamin D (400 IU) with oral and rapid vitamin D repletion by injection. The team found that the oral plus injection supplementation significantly reduced unplanned visits for asthma exacerbations in children with very low vitamin D levels (3-11 ng/mL) at baseline.

“We found that in these children, the number of asthma attacks was reduced by roughly 50%,” Davidson told MedPage Today.

At the time, Davidson was a vocal opponent of one aspect of the trial design in the study by Celedón and co-authors: the inclusion of a placebo arm involving children who were vitamin D deficient, which Davidson called unethical. His concerns resulted in a redesign of the study midway through enrollment.

The trial was originally designed to include children with serum vitamin D levels of 10-29 ng/mL, but the lower level was increased to 14 ng/mL.

Davidson also protested the inclusion of children with serum vitamin D levels that approached the normal range, telling MedPage Today that it could have influenced the results.

“Vitamin D deficiency experts have long insisted that to see an effect, trials need to include only patients with very low levels,” he said. “But these researchers ignored that and instead seemed eager to prove that vitamin D prevents asthma attacks in a very broad range of children — all the way up to 30 ng/mL, which in adults is considered a normal vitamin D level.”

In their paper, Celedón and co-authors noted that previous observational studies have indicated a link between low serum 25-hydroxyvitamin D levels and asthma exacerbations and reduced response to corticosteroid treatments. It has been suggested that vitamin D supplementation could influence asthma through immune-modulatory and anti-inflammatory effects, including “regulatory T-cell induction, attenuation of Th2 and Th17 responses, enhancement of IL [interleukin]-10 production, and inhibition of airway smooth muscle hypertrophy and collagen deposition,” the team wrote.

The investigators recruited 192 children for the study — mean age of 9.8 years, 77 of whom were girls (40%), with 180 (93.8%) completing the trial.

In all, 36 participants (37.5%) in the vitamin D₃ group and 33 (34.4%) in the placebo group had at least one severe exacerbation during the study, but compared with placebo, vitamin D₃ supplementation did not significantly reduce the time to a severe exacerbation: The mean time to exacerbation was 240 days in the vitamin D₃ group and 253 days in the placebo group (mean group difference −13.1 days [95% CI −42.6-16.4], adjusted hazard ratio 1.13 [95% CI 0.69-1.85], P=0.63).

“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,” the researchers wrote.

Serious adverse events were similar in both groups (11 in the vitamin D3 group, nine in the placebo group).

Study limitations, the investigators said, included the lower than expected rate of exacerbations in both the vitamin D₃ and placebo groups (37.5% and 34.4%, respectively) and that the trial was not powered to determine whether this small difference was statistically significant. In addition, there was limited statistical power to determine whether supplementation reduced severe exacerbations in children with vitamin D levels less than 20 ng/mL due to the small number of participants with such levels.