Asthma
Conditions
Keywords
Asthma, Vitamin D, Corticosteroids, Treatment failure
Brief summary
The purpose of the study is to find out if taking vitamin D in addition to an asthma controller medication helps to prevent worsening of asthma symptoms and asthma attacks.
Detailed description
This is a randomized, double-blind parallel group trial that will enroll individuals who have vitamin D insufficiency and asthma with persistent symptoms despite low-dose inhaled corticosteroid. Participants on low-dose inhaled corticosteroid will be randomized to add-on therapy with either placebo or high-dose vitamin D for a 28-week period. During the inhaled corticosteroid-stable phase, participants will remain on low-dose inhaled corticosteroid. During the inhaled corticosteroid-taper phase, participants will taper their inhaled corticosteroid by 50% at two time-points post-randomization. The investigators will determine if the addition of vitamin D reduces the likelihood of treatment failure when compared to placebo during both the inhaled corticosteroid-stable and inhaled corticosteroid-taper phases of the study. Given the high prevalence of both vitamin D insufficiency and asthma, this trial has high potential to impact daily asthma management.
Interventions
DRUGVitamin D3
vitamin D (100,000 IU loading dose followed by 4,000 IU/day)
DRUGCiclesonide
Low dose inhaled corticosteroid (80 mcg/puff two puffs twice daily)
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Milton S. Hershey Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men and women 18 years of age and older * Physician-diagnosed asthma for at least previous 12 months * Asthma confirmed by: (a) β-agonist reversibility of forced expiratory volume in 1 second (FEV1) ≥12 % following 180 mcg (4 puffs) levalbuterol at visit 1 OR (b) methacholine provocative concentration causing a 20% fall in FEV1 (PC20) ≤ 8 mg/ml if not receiving an inhaled corticosteroid or ≤ 16 mg/ml if receiving an inhaled corticosteroid at visit 2. Source documentation for PC20 from an AsthmaNet methacholine challenge completed within 6 months of visit 2 will be accepted. * Stable asthma controller therapy (inhaled corticosteroid or leukotriene modifier only) dose for past 2 weeks * FEV1 ≥ 50% of predicted at visit 1 * Vitamin D level of less than 30 ng/ml at visit 0 * Experienced no more than one treatment failure in the VIDA run-in or oral corticosteroid (OCS) response periods on previous enrollments * For women of childbearing potential: not pregnant, non-lactating, and agree to practice an adequate birth control method for the duration of the study
Exclusion criteria
* Taking vitamin D supplements containing \> 1000 IU/day of vitamin D * Taking \>2500 mg/day calcium supplements * Chronic oral corticosteroid therapy * Chronic inhaled corticosteroid therapy \> 1,000 mcg of fluticasone daily or the equivalent * History of physician-diagnosed nephrolithiasis * Use of concomitant medications that alter vitamin D metabolism - phenytoin, phenobarbital, cardiac glycosides; or absorption - orlistat, cholestyramine, colestipol; or those that interfere with study endpoints * Impaired renal function (GFR \< 30 ml/min) * Asthma exacerbation within past 4 weeks requiring systemic corticosteroids * Respiratory tract infection within past 4 weeks * Chronic diseases (other than asthma) * History of cigarette smoking within the past 1 year or \> 10 pack years total * Serum calcium greater than 10.2 mg/dl on entry * Urine calcium/creatinine ratio greater than 0.37 (urinary Ca and Creat in mg)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Failure | Twenty-eight week intervention period from randomization until end of trial. | Treatment failure is a well-defined asthma outcome reflecting overall asthma control that has been used previously in multiple clinical trials. Treatment failure as defined in the current proposal and prior trials is consistent with the American Thoracic Society (ATS)/European Respiratory Society(ERS) definition of a moderate exacerbation - a deterioration in symptoms and/or lung function with increased rescue bronchodilator use that lasts 2 days or more. The percentages of participants experiencing a treatment failure are Kaplan-Meier estimates of failure rate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Lung Function Change From Baseline | Change is measured as value at 28 weeks minus baseline value. | FEV1 (liters) and methacholine PC20 will be evaluated. Changes are measured as 28 weeks minus baseline. |
| Exacerbations | Overall exacerbation rate during 28-week trial | Outcome defined as number of exacerbations per person-year. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ciclesonide + Placebo Ciclesonide: Low dose inhaled corticosteroid (80 mcg/puff two puffs twice daily) | 207 |
| Ciclesonide + Vitamin D Vitamin D3: vitamin D (100,000 IU loading dose followed by 4,000 IU/day)
Ciclesonide: Low dose inhaled corticosteroid (80 mcg/puff two puffs twice daily) | 201 |
| Total | 408 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 0 |
| Overall Study | Lost to Follow-up | 3 | 5 |
| Overall Study | Other | 3 | 5 |
| Overall Study | Third treatment failure event | 3 | 1 |
| Overall Study | Withdrawal by Subject | 14 | 11 |
Baseline characteristics
| Characteristic | Ciclesonide + Placebo | Total | Ciclesonide + Vitamin D |
|---|---|---|---|
| Age, Continuous | 39.5 years STANDARD_DEVIATION 12.7 | 39.7 years STANDARD_DEVIATION 12.9 | 39.9 years STANDARD_DEVIATION 13.1 |
| Body mass index | 31.5 kg/m^2 STANDARD_DEVIATION 9.5 | 31.8 kg/m^2 STANDARD_DEVIATION 8.9 | 32.0 kg/m^2 STANDARD_DEVIATION 8.2 |
| Duration of asthma | 25.0 years STANDARD_DEVIATION 12.8 | 25.0 years STANDARD_DEVIATION 13.2 | 24.9 years STANDARD_DEVIATION 13.5 |
| FEV1 before albuterol use (L) | 2.62 liters STANDARD_DEVIATION 0.83 | 2.63 liters STANDARD_DEVIATION 0.8 | 2.63 liters STANDARD_DEVIATION 0.78 |
| FEV1 before albuterol use (% predicted) | 80.5 % predicted STANDARD_DEVIATION 14.2 | 80.6 % predicted STANDARD_DEVIATION 14 | 80.7 % predicted STANDARD_DEVIATION 13.8 |
| Level of 25-hydroxyvitamin D | 18.8 ng/mL | 19.2 ng/mL | 19.9 ng/mL |
| Methacholine PC20 (mg/mL) | 1.85 mg/mL STANDARD_DEVIATION 1.67 | 1.95 mg/mL STANDARD_DEVIATION 1.65 | 2.05 mg/mL STANDARD_DEVIATION 1.61 |
| Race/Ethnicity, Customized Asian/Pacific Islander | 7 participants | 14 participants | 7 participants |
| Race/Ethnicity, Customized Black | 68 participants | 131 participants | 63 participants |
| Race/Ethnicity, Customized Hispanic | 19 participants | 39 participants | 20 participants |
| Race/Ethnicity, Customized Other | 2 participants | 8 participants | 6 participants |
| Race/Ethnicity, Customized White | 111 participants | 216 participants | 105 participants |
| Sex: Female, Male Female | 141 Participants | 278 Participants | 137 Participants |
| Sex: Female, Male Male | 66 Participants | 130 Participants | 64 Participants |
| Sputum eosinophils (%) | 0.40 % of eosinophils | 0.40 % of eosinophils | 0.30 % of eosinophils |
| Symptom score (afternoon and evening) | 0.43 Avg score of 5 sx: 0=absent to 3=severe STANDARD_DEVIATION 0.4 | 0.43 Avg score of 5 sx: 0=absent to 3=severe STANDARD_DEVIATION 0.37 | 0.44 Avg score of 5 sx: 0=absent to 3=severe STANDARD_DEVIATION 0.35 |
| Symptom score (morning) | 0.41 Avg score of 5 sx: 0=absent to 3=severe STANDARD_DEVIATION 0.36 | 0.41 Avg score of 5 sx: 0=absent to 3=severe STANDARD_DEVIATION 0.35 | 0.41 Avg score of 5 sx: 0=absent to 3=severe STANDARD_DEVIATION 0.34 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 157 / 207 | 168 / 201 |
| serious Total, serious adverse events | 9 / 207 | 6 / 201 |
Outcome results
Primary
Treatment Failure
Treatment failure is a well-defined asthma outcome reflecting overall asthma control that has been used previously in multiple clinical trials. Treatment failure as defined in the current proposal and prior trials is consistent with the American Thoracic Society (ATS)/European Respiratory Society(ERS) definition of a moderate exacerbation - a deterioration in symptoms and/or lung function with increased rescue bronchodilator use that lasts 2 days or more. The percentages of participants experiencing a treatment failure are Kaplan-Meier estimates of failure rate.
Time frame: Twenty-eight week intervention period from randomization until end of trial.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ciclesonide + Placebo | Treatment Failure | 29 Percentage of participants |
| Ciclesonide + Vitamin D | Treatment Failure | 28 Percentage of participants |
Secondary
Exacerbations
Outcome defined as number of exacerbations per person-year.
Time frame: Overall exacerbation rate during 28-week trial
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ciclesonide + Placebo | Exacerbations | 0.40 Exacerbations/person-year |
| Ciclesonide + Vitamin D | Exacerbations | 0.26 Exacerbations/person-year |
Secondary
Lung Function Change From Baseline
FEV1 (liters) and methacholine PC20 will be evaluated. Changes are measured as 28 weeks minus baseline.
Time frame: Change is measured as value at 28 weeks minus baseline value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ciclesonide + Placebo | Lung Function Change From Baseline | -0.04 Liters |
| Ciclesonide + Vitamin D | Lung Function Change From Baseline | -0.07 Liters |