Asthma
Conditions
Keywords
Vitamin D, severe asthma exacerbations, children
Brief summary
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
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.
Interventions
The vitamin D3 will be in oral gel cap form and contain 4000 International Units (IU) of cholecalciferol per gel cap.
DRUGPlacebo
The placebo is a gel cap that is indistinguishable from the vitamin D3 gel cap.
Sponsors
Pharmavite LLC
National Heart, Lung, and Blood Institute (NHLBI)
Juan Celedon, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to 16 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Days to a Severe Asthma Exacerbation | 48 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Days to Viral-induced Severe Exacerbation | 48 weeks | 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. |
| Proportion of Participants in Whom Fluticasone Dose Was Halved at Visit 6 | 24 weeks | 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 |
| Average Cumulative Prescribed Dose of ICS at the End of the Trial | 48 weeks | The average cumulative dose of inhaled corticosteroids (ICS) during the study period |
Countries
United States
Participant flow
Pre-assignment details
Of 595 participants assessed for eligibility, 192 finished run-in and were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Vitamin D3 Cholecalciferol (Vitamin D3) 4000 IU oral gel cap daily
vitamin D3 4000 IU: The vitamin D3 will be in oral gel cap form and contain 4000 International Units (IU) of cholecalciferol per gel cap. | 96 |
| Placebo placebo formulations will be in gel cap form and identical to the active drug
Placebo: The placebo is a gel cap that is indistinguishable from the vitamin D3 gel cap. | 96 |
| Total | 192 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 4 |
| Overall Study | Withdrawal by Subject | 2 | 4 |
Baseline characteristics
| Characteristic | Placebo | Vitamin D3 | Total |
|---|---|---|---|
| Age, Continuous | 9.7 years STANDARD_DEVIATION 2.5 | 9.9 years STANDARD_DEVIATION 2.5 | 9.8 years STANDARD_DEVIATION 2.5 |
| Asthma Control Test score | 21.3 units on a scale STANDARD_DEVIATION 3.6 | 22.0 units on a scale STANDARD_DEVIATION 3.2 | 21.7 units on a scale STANDARD_DEVIATION 3.4 |
| Asthma Control Test score >19 | 73 Participants | 76 Participants | 149 Participants |
| Body Mass Index z-score | 0.9 z-score STANDARD_DEVIATION 1.3 | 0.9 z-score STANDARD_DEVIATION 1.1 | 0.9 z-score STANDARD_DEVIATION 1.2 |
| Current household smoke exposure | 22 Participants | 25 Participants | 47 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 7 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 90 Participants | 89 Participants | 179 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| FEV1 | 90.6 % predicted STANDARD_DEVIATION 17.3 | 93.9 % predicted STANDARD_DEVIATION 15.8 | 92.2 % predicted STANDARD_DEVIATION 16.6 |
| FEV1/FVC | 89.6 % predicted STANDARD_DEVIATION 10.1 | 91.5 % predicted STANDARD_DEVIATION 9.3 | 90.6 % predicted STANDARD_DEVIATION 9.7 |
| Household smoke exposure before age 2 years | 32 Participants | 31 Participants | 63 Participants |
| No. of severe exacerbations in the previous year | 1 exacerbations | 1 exacerbations | 1 exacerbations |
| Parental Education Completed college | 32 Participants | 37 Participants | 69 Participants |
| Parental Education High school or less | 20 Participants | 21 Participants | 41 Participants |
| Parental Education Postgraduate education | 21 Participants | 14 Participants | 35 Participants |
| Parental Education Some college | 22 Participants | 22 Participants | 44 Participants |
| Race/Ethnicity, Customized Race Black | 49 Participants | 51 Participants | 100 Participants |
| Race/Ethnicity, Customized Race Other Race | 15 Participants | 18 Participants | 33 Participants |
| Race/Ethnicity, Customized Race White | 32 Participants | 27 Participants | 59 Participants |
| Region of Enrollment United States | 96 participants | 96 participants | 192 participants |
| Season of enrollment April-June | 26 Participants | 26 Participants | 52 Participants |
| Season of enrollment January-March | 25 Participants | 30 Participants | 55 Participants |
| Season of enrollment July-September | 22 Participants | 22 Participants | 44 Participants |
| Season of enrollment October-December | 23 Participants | 18 Participants | 41 Participants |
| Sex: Female, Male Female | 33 Participants | 44 Participants | 77 Participants |
| Sex: Female, Male Male | 63 Participants | 52 Participants | 115 Participants |
| Vitamin D | 22.8 ng/mL STANDARD_DEVIATION 4.6 | 22.5 ng/mL STANDARD_DEVIATION 4.6 | 22.6 ng/mL STANDARD_DEVIATION 4.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 96 | 0 / 96 |
| other Total, other adverse events | 5 / 96 | 4 / 96 |
| serious Total, serious adverse events | 9 / 96 | 7 / 96 |
Outcome results
Primary
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.
Time frame: 48 weeks
Population: Intent to treat population across the 48-week study period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin D3 | Days to a Severe Asthma Exacerbation | 240 Days | Standard Deviation 105.8 |
| Placebo | Days to a Severe Asthma Exacerbation | 253 Days | Standard Deviation 101.3 |
p-value: 0.6395% CI: [0.69, 1.85]Regression, Cox
Secondary
Average Cumulative Prescribed Dose of ICS at the End of the Trial
The average cumulative dose of inhaled corticosteroids (ICS) during the study period
Time frame: 48 weeks
Population: Intent to treat population across the 48-week study period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin D3 | Average Cumulative Prescribed Dose of ICS at the End of the Trial | 59.6 mg | Standard Deviation 22.9 |
| Placebo | Average Cumulative Prescribed Dose of ICS at the End of the Trial | 55.2 mg | Standard Deviation 14.5 |
p-value: 0.04995% CI: [0.001, 8.8]Regression, Linear
Secondary
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.
Time frame: 48 weeks
Population: In Vitamin D3 gorup, 82 with time to viral exacerbation were included in the analysis (14 first exacerbations not tested). In Placebo group, 83 with time to viral exacerbation were included in the analysis (13 first exacerbations not tested)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin D3 | Days to Viral-induced Severe Exacerbation | 272 Days | Standard Deviation 87.8 |
| Placebo | Days to Viral-induced Severe Exacerbation | 281 Days | Standard Deviation 83.6 |
p-value: 0.4695% CI: [0.63, 2.75]Regression, Cox
Secondary
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
Time frame: 24 weeks
Population: In the Vitamin D3 group, 91 subjects with data on reduction in the dose of inhaled corticosteroids (4 withdrew before 24 wk, 1 missed 24-wk visit). In the Placebo group, 91 subjects had data on reduction in the dose of inhaled corticosteroids (4 withdrew before 24 wk, 1 missed 24-wk visit)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamin D3 | Proportion of Participants in Whom Fluticasone Dose Was Halved at Visit 6 | 28 Participants |
| Placebo | Proportion of Participants in Whom Fluticasone Dose Was Halved at Visit 6 | 29 Participants |
p-value: 0.9995% CI: [0.66, 1.52]Regression, Logistic