Vitamin D to Prevent Severe Asthma Exacerbations (Vit-D-Kids Asthma)

Results from experimental studies, observational studies, two small trials, and a recent
meta-analysis suggest that vitamin D reduces the risk of severe asthma exacerbations, and
that this protective effect may be due to immune modulation of viral illnesses and/or
increased response to inhaled corticosteroids (ICS).

On the basis of those findings, the investigators hypothesize that vitamin D reduces the
incidence of severe asthma exacerbations in high-risk school-aged children who have a serum
vitamin D level <30 ng/ml and who are being treated with ICS for persistent asthma. The
investigators further hypothesize that this protective effect results from reduced incidence
of common viral illnesses or enhanced response to ICS. These hypotheses will be tested in a
48-week randomized double-masked placebo-controlled trial of vitamin D3 supplementation to
prevent severe asthma exacerbations in 400 children aged 6 to 16 years who have vitamin D
insufficiency or deficiency (a serum 25(OH)D <30 ng/ml) and experienced a severe exacerbation
in the prior year (a marker of high risk for subsequent events), and who (after a run-in
period) are well controlled on medium-dose inhaled corticosteroids.

Our primary aim will determine whether vitamin D3 (4,000 IU/day) reduces the risk of severe
asthma exacerbations (our primary outcome) in participating children. Secondary aims will
determine the efficacy of vitamin D3 supplementation in: 1) preventing severe asthma
exacerbations due to viral infections, 2) reducing the daily and average cumulative dose of
inhaled corticosteroids.

Study participation involves 8-9 visits, with each visit lasting between 30-90 minutes.
Participation requires completion of study questionnaires, spirometry (breathing tests), and
collection of blood samples (to measure vitamin D levels) and urine samples (to measure
urinary calcium/creatinine ratios) at some study visits. Since the start of the study,
vitamin D levels and urinary calcium/creatinine ratios have been simultaneously measured, to
monitor for both vitamin D toxicity and high risk of severe vitamin D deficiency or rickets,
which (should they occur) would be managed by a pediatric endocrinologist or a pediatric
nephrologist, as appropriate.

All safety data for the study is regularly reviewed by a Data Safety Monitoring Board
appointed by the National Heart, Lung and Blood Institute, as well as by the Institutional
Review Board of each participating institution. Total study participation will last about one
year.

Inclusion Criteria:

- 6 to 16 years old

- Physician-diagnosed asthma for at least one year

- At least one severe asthma exacerbation in the previous year

- Use of asthma medications (daily controller medication [ICS or leukotriene inhibitor]
or inhaled β2-agonist [at least three days per week]) for at least six months in the
previous year

- Vitamin D insufficiency (i.e., serum vitamin D (25(OH)D level <30 ng/ml (75 nmol/L))

- FEV1 ≥70 % of predicted

- Positive bronchodilator response (i.e., increase in FEV1 ≥8% from baseline after
inhaled short acting beta agonist or increased airway responsiveness to methacholine
(PC20 ≤8 mg/ml if not on ICS or PC20 ≤16 mg/ml if on ICS)

- Study protocol (i.e., age-appropriate dose of Fluticasone and no other asthma
controller medications) approved by the child's regular doctor

- Parental consent and child's assent to participate in the study.

Additional inclusion criteria applied after the run-in period, to be eligible for
randomization:

- Adherence with ICS and study medication (≥75% use [at least 21 of 28 days]) during the
run-in period

- Willingness to be randomized and complete study

Exclusion Criteria:

- Serum calcium >10.8 mg/dl

- Serum 25(OH) D <14 ng/ml (35 nmol/L)

- Chronic respiratory disorder other than asthma

- Severe asthma (intubation for asthma at any time OR ≥3 hospitalizations for asthma in
previous year OR ≥6 severe asthma exacerbations in previous year)

- Hepatic/renal disease, rickets, malabsorption, or other diseases that would affect
vitamin D metabolism

- Current smoking, or former smoking if ≥5 pack-years

- Immune deficiency, cleft palate or Down's syndrome

- Treatment with anticonvulsants or ≥1,000 IU/day of vitamin D2 or D3

- Chronic oral corticosteroid therapy

- Inability to perform acceptable spirometry

- Use of investigational therapies or participation in trials 30 days before or during
the study

- Participant is currently breast feeding an infant

- Pregnancy

- Weight less than 10 kg

- Plans to move out of the study site area in the next year

Additional exclusion criteria applied after the run-in period:

- Any severe asthma exacerbation during the run-in period

- Need for asthma medications other than ICS and p.r.n. rescue inhalers during the
run-in period