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ABSTRACT & COMMENTARY
By Traci Pantuso, ND, MS
Adjunct Faculty, Bastyr University, Seattle, WA
Dr. Pantuso reports no financial relationships relevant to this field of study.
SYNOPSIS: Vitamin D3 supplementation in patients with persistent asthma and low serum vitamin D (25(OH)D) did not show improvement in the clinical efficacy of inhaled corticosteroids.
SOURCE: Castro M, et al. Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels. The VIDA randomized clinical trial. JAMA 2014;311:2083-2091.
Forty-five percent of patients with persistent asthma do not respond to inhaled corticosteroids. Studies indicate a relationship between responsiveness to inhaled corticosteroids and vitamin D status. Vitamin D3 serum levels of < 30 ng/mL in adults and children with asthma have been associated with decreased responsiveness to corticosteroids, hyperresponsive airways, and increased exacerbation frequency. The Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma (VIDA) trial investigators sought to further understand the role of vitamin D in asthma, particularly in patients with persistent asthma who are considered non-responders to corticosteroids.
Participants. Participants were screened between April 2011 and May 2013. Eligible participants were ≥ 18 years with a serum vitamin D (25-hydroxy vitamin D; [25(OH)D]) < 30 ng/mL with asthma. Asthma was diagnosed with evidence of either bronchodilator reversibility FEV1 or airway hyperresponsiveness with methacholine challenge where FEV1 decreased by 20%.
Phases of the Trial. There were a number of phases to this 28-week trial including a run-in phase, an inhaled corticosteroid stabilization phase, and two inhaled corticosteroid taper-down phases (see Figure 1). During the four-week run in period, patients discontinued their previous asthma medication and were given ciclesonide and levalbuterol. To determine the corticosteroid responder status, each participant received 40 mg/day of prednisone for 1 week at the end of the run-in phase. FEV1 was then calculated; a change in FEV1 of 5% was considered significant and the participant a responder.
After the run-in phase, participants were randomized to placebo or high-dose vitamin D3 with 100,000 IU once followed by 4000 IU/day for 28 weeks added to an inhaled steroid ciclesonide (320 ug/day; 2 puffs twice daily) and levalbuterol. Randomization was computer generated and stratified by body mass index (BMI), clinical center, and race. Placebo vitamin D capsules were matched in appearance to the vitamin D3 capsules.
Participants entered into a 12-week inhaled corticosteroids (ciclesonide 320 mg/day) stability phase after randomization. The stability phase was then followed by two phases where the inhaled corticosteroids were tapered to 160 mg/day for 8 weeks and then 80 mg/day for another 8 weeks if the participant’s asthma symptoms were controlled.
Participants who had more than two treatment failures or exacerbations were withdrawn from the study. To evaluate adherence to ciclesonide and vitamin D capsules, the VIDA study measured adherence electronically. Peak expiratory flows and the asthma symptom diary were recorded on electronic device (Spirotel [Medical International Research]).
Primary Endpoint. The time to the first asthma treatment failure was the primary endpoint measured. A treatment failure in this study was defined as one or more of the following:
Figure 1. Trial Design
Secondary Outcomes. Fourteen secondary outcomes were measured but only nine were analyzed and presented in the article.
Asthma Symptoms. Participants completed an electronic diary of asthma symptoms in the morning and in the evening of each day. Asthma symptoms evaluated were shortness of breath, chest tightness, wheezing, cough, and phlegm or mucus. The grading scale was zero indicating no symptoms, one indicating mild symptoms and no interference with activity, two indicating moderate symptoms and interference with normal activity, and three representing severe symptoms that prevented normal activity. The asthma symptom utility index, which is scored on a zero to one point axis with one indicating better asthma control, was also used to evaluate asthma symptoms.
Statistical Analysis. The Cox proportional hazards regression model was used to analyze the intent-to-treat hypothesis. Power analysis was performed based on data from the Asthma Clinical Research Network Salmeterol or Corticosteroids and Salmeterol ± Inhaled Corticosteroids trials. The authors calculated that 400 participants were needed to detect a 90% power to detect hazard ratio for treatment failures of 0.56 (a reduction from 40%) in the placebo group and 24.5% in the vitamin D3 group. To analyze secondary outcomes, repeated measures analysis of covariance models were used and adjustments of BMI, clinical center, and race were made.
Enrollment. Out of 1523 participants initially screened for eligibility, 455 were excluded because they did not meet the eligibility requirements. The other 1068 eligible participants entered the run-in phase of the trial; 660 participants were excluded during the run-in phase. The remaining 408 participants were randomized to the two groups: 201 were randomized to the vitamin D3 group and 207 to the placebo group. Baseline characteristics between the two groups were similar at baseline.
Completion Rate. The completion rate between the two groups was similar with 89% (95% confidence interval [CI], 85-93%) in the vitamin D3 group vs 87% (95% CI, 83-92%) in the placebo group. The median duration of follow up was 28.1 weeks.
Vitamin D3. The mean baseline serum 25(OH)D levels were 18.8 ng/mL (95% CI, 18.2-19.5 ng/mL). Fifty-three percent of all participants had 25(OH)D levels < 20 ng/mL (see Table 1). Eighty-two percent of participants in the vitamin D3 group achieved a 25(OH)D serum level of ≥ 30 ng/mL (see Table 2).
In the placebo group, 25(OH)D mean serum levels continued to be < 20 ng/mL. However, 9% of participants in the placebo group demonstrated 25(OH)D levels of ≥ 30 at 12 weeks (4.4-52.2 ng/mL). One confounding variable was found at the end of the trial when 13% of the vitamin D group and 15% of the placebo group reported taking supplements containing vitamin D at the end of the trial; this is the only explanation the authors offer for the elevated 25(OH)D serum levels in 9% of the placebo group at 12 weeks.
In the vitamin D group, baseline serum 25(OH)D levels were associated with serum 25(OH)D levels 30 ng/mL at 12 weeks (odds ratio, 2.1; 95%CI, 1.2-3.8 for each 10-ng/mL increment).
Primary Outcome. The addition of vitamin D3 to the inhaled corticosteroid ciclesonide did not demonstrate a decrease in time to first treatment failure rate compared to placebo. The treatment failure rate for vitamin D3 group was 28% (95% CI, 21-34%) and 29% (95% CI, 23-35%) for the placebo group. The adjusted HR was 0.9 (95% CI, 0.6-1.3; P = 0.54).
Overall, the actual number of treatment failures in the vitamin D3 group was 63 compared to the 83 treatment failure events in the placebo group, and these differences were not statistically significant (P = 0.17).
The most frequent causes of treatment failure were due to the increased need for inhaled or systemic steroids (58%) or by experiencing an exacerbation (46%). 25(OH)D serum level at baseline was not associated with treatment failure (HR, 0.9 per 10 ng/mL increment; 95% CI, 0.7-1.1 per 10 ng/mL increment; P = 0.32).
Secondary Outcomes. None of the secondary outcome results were significantly different between the placebo and vitamin D groups. When the authors investigated the change in 25(OH)D serum levels between baseline and 12-week levels, they found a significant relationship with the rate of treatment failures and exacerbations. For example, there was a reduction in the rate of overall treatment failures with each 10 ng/mL increase in the 25(OH)D serum level (HR, 0.88; 95% CI, 0.78-0.99; P = 0.04) and overall rate of exacerbations (HR, 0.80; 95% CI, 0.67-0.96; P = 0.02).
Ideally, this study would have expanded on prior research showing an association between low 25(OH)D serum levels and asthma severity through symptomatic improvement with a controlled intervention. However, instead this study demonstrated that a one-time 100,000 IU plus 4000 IU per day of vitamin D3 with daily inhaled corticosteroids for 28 weeks does not decrease asthma exacerbations or treatment failure compared to daily inhaled corticosteroids and placebo. The findings do show that this dosing regimen is an effective method of obtaining 25(OH)D serum sufficiency. The lack of efficacy corroborates prior work, such as another double-blind, placebo-controlled study in pediatric asthma participants with low serum 25(OH)D that failed to find a difference in asthma symptoms.1 Experts are proposing a more complicated relationship between vitamin D3 levels and asthma than previously thought; it may be that the pathology of hypovitaminosis D and its relationship in the development and severity of asthma may be more complicated than just correcting low 25(OH)D serum levels.
Although it may be true that this intervention simply does not work in this population, there are also methodological limitations with this particular study that compromise drawing firm conclusions. For example, the authors mention that the control group had an event rate that was lower than they had previously thought, so the study may be underpowered to detect a smaller and significant difference between the vitamin D3 group and placebo. In addition, the wide range of 25(OH)D serum levels in both the vitamin D3 and placebo groups at the 12-week time point may have inhibited capturing an overall effect of the intervention. The authors point out that a larger number of participants and a longer trial period may be useful in understanding the clinical efficacy of vitamin D3 supplementation in asthma.
An issue that the authors failed to address in their study is the genetic variation in the vitamin D receptor, which is associated with asthma.2-5 Due to the vitamin D receptor variation, participants may have responded differently to vitamin D supplementation, affecting the results of the trial.
The relationship between vitamin D and the immune system in people with asthma is not well delineated, partly because of unknowns regarding the optimal level of vitamin D in the body for proper immune function. According to one researcher, it is not resolved whether there may be reasons unrelated to bone health to increase 25(OH)D plasma levels above those recommended for bone health.1 Another area of ongoing research that may be able to further elucidate the relationship between vitamin D3 and asthma is the role of 25(OH)D in fetal lung development. Low maternal 25(OH)D serum levels are associated with increased childhood wheezing and asthma.3
Despite the negative results of this study, supplementation with a reasonable dose of vitamin D3 is still recommended in people with asthma that have low, insufficient, or low sufficient levels, as vitamin D3 serum levels are associated with asthma and increased inflammatory responses.