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

Study Overview
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Brief Summary
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This study will determine whether vitamin D3 prevents severe asthma attacks in children who have a serum vitamin D (25(OH)D) level <30 ng/ml and who are being treated with inhaled corticosteroids for asthma. Half the participants will receive vitamin D3 at a dose of 4,000 IU/day, and the other half will receive placebo.

Detailed Description
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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.

Official Title
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Vitamin D to Prevent Severe Asthma Exacerbations

Conditions
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Asthma

Intervention / Treatment
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* Drug: vitamin D3 4000 IU
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: vitamin D3<br>Cholecalciferol (Vitamin D3) 4000 IU oral gel cap daily | Drug: vitamin D3 4000 IU<br>* The vitamin D3 will be in oral gel cap form and contain 4000 International Units (IU) of cholecalciferol per gel cap.<br>* Other names: Cholecalciferol;|
| Placebo Comparator: placebo<br>placebo formulations will be in gel cap form and identical to the active drug | Drug: Placebo<br>* The placebo is a gel cap that is indistinguishable from the vitamin D3 gel cap.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days to a Severe Asthma Exacerbation | A severe asthma exacerbation is defined as an exacerbation that meets either of these criteria: 1) Use of systemic corticosteroids (tablets, suspension, or injection), or an increase from a stable maintenance dose, for at least 3 days OR 2) A hospitalization or ER visit because of asthma, requiring systemic corticosteroids. | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days to Viral-induced Severe Exacerbation | A severe viral asthma exacerbation is defined as a severe asthma exacerbation [defined as an exacerbation that meets either of these criteria: 1) Use of systemic corticosteroids (tablets, suspension, or injection), or an increase from a stable maintenance dose, for at least 3 days OR 2) A hospitalization or ER visit because of asthma, requiring systemic corticosteroids] along with a positive respiratory viral panel from a nasal blow collected within 72 hours of the exacerbation. | 48 weeks | 
| Proportion of Participants in Whom Fluticasone Dose Was Halved at Visit 6 | In the absence of moderate or severe asthma exacerbations, participants may have their dose of inhaled corticosteroids (ICS) reduced by 50% if the following criteria are met at visit 6 (halfway through the Trial Phase): Asthma Control Test (ACT) score greater than 19 Both pre-bronchodilator FEV1 and FEV1/FVC ≥80% of predicted Use of ≤4 puffs of a rescue inhaler per week ≤1 day per month with asthma symptoms preventing full participation in usual daily activities Clinician's judgment regarding adequate asthma control | 24 weeks | 
| Average Cumulative Prescribed Dose of ICS at the End of the Trial | The average cumulative dose of inhaled corticosteroids (ICS) during the study period | 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vitamin D, severe asthma exacerbations, children