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| ID | Type | Description | Link |
|---|---|---|---|
| U01HL119952 | U.S. NIH Grant/Contract | View source |
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Futility of vitamin D supplementation based on protocol threshold: <30% conditional power to detect pre-specified effect- 16% reduction in severe exacerbations.
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| Name | Class |
|---|---|
| Pharmavite LLC | INDUSTRY |
| National Heart, Lung, and Blood Institute (NHLBI) | NIH |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| vitamin D3 | Experimental | Cholecalciferol (Vitamin D3) 4000 IU oral gel cap daily |
|
| placebo | Placebo Comparator | placebo formulations will be in gel cap form and identical to the active drug |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| vitamin D3 4000 IU | Drug | The vitamin D3 will be in oral gel cap form and contain 4000 International Units (IU) of cholecalciferol per gel cap. |
|
| 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 |
| 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. |
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Inclusion Criteria:
Additional inclusion criteria applied after the run-in period, to be eligible for randomization:
Exclusion Criteria:
Additional exclusion criteria applied after the run-in period:
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| Name | Affiliation | Role |
|---|---|---|
| Juan C. Celedón, MD, DrPH | University of Pittsburgh | Principal Investigator |
| Stephen Wisniewski, PhD | University of Pittsburgh | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California - San Francisco | San Francisco | California | 94102 | United States | ||
| National Jewish Health |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34326185 | Derived | Han YY, Forno E, Bacharier LB, Phipatanakul W, Guilbert TW, Cabana MD, Ross K, Blatter J, Rosser FJ, Durrani S, Luther J, Wisniewski SR, Celedon JC. Vitamin D supplementation, lung function and asthma control in children with asthma and low vitamin D levels. Eur Respir J. 2021 Oct 28;58(4):2100989. doi: 10.1183/13993003.00989-2021. Print 2021 Oct. | |
| 32840597 | Derived | Forno E, Bacharier LB, Phipatanakul W, Guilbert TW, Cabana MD, Ross K, Covar R, Gern JE, Rosser FJ, Blatter J, Durrani S, Han YY, Wisniewski SR, Celedon JC. Effect of Vitamin D3 Supplementation on Severe Asthma Exacerbations in Children With Asthma and Low Vitamin D Levels: The VDKA Randomized Clinical Trial. JAMA. 2020 Aug 25;324(8):752-760. doi: 10.1001/jama.2020.12384. |
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Of 595 participants assessed for eligibility, 192 finished run-in and were randomized.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Intent to treat population across the 48-week study period | Posted | Mean | Standard Deviation | Days | 48 weeks |
|
48 weeks
A hospitalization for an asthma exacerbation was considered a serious adverse event.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hospitalization for asthma exacerbation | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fractures | Musculoskeletal and connective tissue disorders | Systematic Assessment | Fractures |
Limited statistical power to determine if vitamin D supplementation prolongs the time to a severe asthma exacerbation in children with vitamin D level <20 ng/ml.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Juan Celedón | University of Pittsburgh | (412) 692-8429 | juan.celedon@chp.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 19, 2018 | Oct 9, 2020 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D001249 | Asthma |
| ID | Term |
|---|---|
| D001982 | Bronchial Diseases |
| D012140 | Respiratory Tract Diseases |
| D008173 | Lung Diseases, Obstructive |
| D008171 | Lung Diseases |
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| ID | Term |
|---|---|
| D002762 | Cholecalciferol |
| ID | Term |
|---|---|
| D002782 | Cholestenes |
| D002776 | Cholestanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
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| Placebo | Drug | The placebo is a gel cap that is indistinguishable from the vitamin D3 gel cap. |
|
| 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):
| 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 |
| Denver |
| Colorado |
| 80206 |
| United States |
| Boston Children's Hospital | Boston | Massachusetts | 02115 | United States |
| Saint Louis Children's Hospital | St Louis | Missouri | 63110 | United States |
| Cincinnati Children's Hospital Medical Center | Cincinnati | Ohio | 45229 | United States |
| Rainbow Babies and Children's Hospital | Cleveland | Ohio | 44106 | United States |
| Children's Hospital of Pittsburgh of UPMC | Pittsburgh | Pennsylvania | 15224 | United States |
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.
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Race abd ethnicity were ascertained per parental report. "Other race" includes American Indian, Alaskan Native, mixed, and other reported as "other". | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Parental Education | 2 participants from the Vitamin D3 group and 1 participant from the placebo group did not have information on parental education | Count of Participants | Participants |
|
| Household smoke exposure before age 2 years | 2 participants from Vitamin D3 group and 2 participants from Placebo gorup did not have information on household smoke expousre before age 2 years | Count of Participants | Participants |
|
| Current household smoke exposure | 3 participants from Vitamin D3 group and 3 participants from Placebo group did not have information on household smoke exposure during the study | Count of Participants | Participants |
|
| Season of enrollment | Count of Participants | Participants |
|
| Asthma Control Test score >19 | The Asthma Control Test (ACT) was administered to participants aged 12 years or older, and the Childhood Asthma Control Test (C-ACT) was administered to participants aged 6 to 11 years. The ACT is calculated based on 5 self-administered questions and has a score ranges of 5 to 25. The C-ACT is calculated based on 7 questions (3 answered by the parent and 4 answered with the child's input) and has a score range of 0 to 27. For both, a higher score indicates better symptom control, and a score greater than 19 indicates well-controlled asthma symptoms. | Count of Participants | Participants |
|
| Body Mass Index z-score | A body mass index z-score is a measure of relative weight adjusted for the child's age and sex. BMI z-scores were calculated using US Centers for Disease Control and Prevention (CDC) equations that create z-scores and percentiles for a child's sex and age. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values are indicative of higher weight. | 1 participant in the Vitamin D3 group did not have a valid BMI z-score | Mean | Standard Deviation | z-score |
|
| No. of severe exacerbations in the previous year | A severe asthma exacerbation was defined as the occurrence of either (1) use of systemic corticosteroids (tablets, suspension, or injection) for at least 3 days or (2) a hospitalization or ED visit because of asthma, requiring systemic corticosteroids | 8 participants in the Vitamin D3 group and 10 participants in the placebo group did not have such information | Median | Inter-Quartile Range | exacerbations |
|
| Vitamin D | Mean | Standard Deviation | ng/mL |
|
| FEV1 | Forced Expiratory Volume in the first second (FEV1) refers to the maximum amount of air that the subject can forcibly expel during the first-second following maximal inhalation. All participants performed spirometry following American Thoracic Society/European Respiratory Society guidelines. Calculated using reference values from the third National Health and Nutrition Examination Survey. Values 80% of predicted or greater are considered normal. | Mean | Standard Deviation | % predicted |
|
| FEV1/FVC | FEV1/FVC is the ratio of the forced expiratory volume in the first one second (FEV1) to the forced vital capacity (FVC, the total amount of air exhaled) of the lungs. A reduced FEV1/FVC represents obstruction of airflow. All participants performed spirometry following American Thoracic Society/European Respiratory Society guidelines. Calculated using reference values from the third National Health and Nutrition Examination Survey. Values 80% of predicted or greater are considered normal. | Mean | Standard Deviation | % predicted |
|
| Asthma Control Test score | For participants aged ≥12 years, asthma control was assessed using the Asthma Control Test (ACT [score range, 5-25]. For participants aged <12 (6-11) years, asthma control was assessed using Childhood ACT (C-ACT [score range,0-27]. For both tests, higher scores mean better symptom control, and more than 19 points is considered well controlled asthma. | Mean | Standard Deviation | units on a scale |
|
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. |
|
|
|
| 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. | 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) | Posted | Mean | Standard Deviation | Days | 48 weeks |
|
|
|
|
| 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):
| 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) | Posted | Count of Participants | Participants | 24 weeks |
|
|
|
|
| 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 | Intent to treat population across the 48-week study period | Posted | Mean | Standard Deviation | mg | 48 weeks |
|
|
|
|
| 0 |
| 96 |
| 9 |
| 96 |
| 5 |
| 96 |
| EG001 | 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. | 0 | 96 | 7 | 96 | 4 | 96 |
| eosinophilia | Blood and lymphatic system disorders | Systematic Assessment |
|
| severe neutropenia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Pneumonia/otitis/hives | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Depression | Psychiatric disorders | Non-systematic Assessment |
|
|
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| D012130 |
| Respiratory Hypersensitivity |
| D006969 | Hypersensitivity, Immediate |
| D006967 | Hypersensitivity |
| D007154 | Immune System Diseases |
| D011083 |
| Polycyclic Compounds |
| D013261 | Sterols |
| D014807 | Vitamin D |
| D012632 | Secosteroids |
| D008563 | Membrane Lipids |
| D008055 | Lipids |
| Unknown or Not Reported |
|
| Other Race |
|
| Completed college |
|
| Postgraduate education |
|
| July-September |
|
| October-December |
|