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

• Sponsor: Juan Celedon, MD (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02687815
• Collaborator: Pharmavite LLC (Industry), National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 192
• Locations: 7
• Arms: 2
• Actual Duration (Months): 42.8
• Patients Per Site: 27.4
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: vitamin D3 4000 IU; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 192 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Vitamin D to Prevent Severe Asthma Exacerbations
• Actual Study Start Date: Feb 22, 2016
• Actual Primary Completion Date: Sep 17, 2019
• Actual Study Completion Date: Sep 17, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: vitamin D3 Cholecalciferol (Vitamin D3) 4000 IU oral gel cap daily	Drug: 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.; Other Names: Cholecalciferol
Placebo Comparator: placebo placebo formulations will be in gel cap form and identical to the active drug	Drug: Placebo; The placebo is a gel cap that is indistinguishable from the vitamin D3 gel cap.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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

3. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 16 Years
• Sexes Eligible for Study: All
• Accepts 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 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California - San Francisco	San Francisco	California	United States	94102
2	National Jewish Health	Denver	Colorado	United States	80206
3	Boston Children's Hospital	Boston	Massachusetts	United States	02115
4	Saint Louis Children's Hospital	Saint Louis	Missouri	United States	63110
5	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
6	Rainbow Babies and Children's Hospital	Cleveland	Ohio	United States	44106
7	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224

Sponsors and Collaborators

• Juan Celedon, MD
• Pharmavite LLC
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Juan C. Celedón, MD, DrPH, University of Pittsburgh
• Principal Investigator: Stephen Wisniewski, PhD, University of Pittsburgh

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 19, 2018

More Information

Publications

None provided.

• Responsible Party: Juan Celedon, MD, Niels K. Jerne Professor of Pediatrics, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT02687815
• Other Study ID Numbers: PRO12020541; U01HL119952
• First Posted: Feb 22, 2016
• Last Update Posted: Aug 12, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Juan Celedon, MD, Niels K. Jerne Professor of Pediatrics, University of Pittsburgh: Vitamin D, severe asthma exacerbations, children
• Additional relevant MeSH terms: Asthma; Vitamin D; Cholecalciferol

Study Results

Participant Flow

Pre-assignment Detail	Of 595 participants assessed for eligibility, 192 finished run-in and were randomized.

Arm/Group Title	Vitamin D3	Placebo
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	96	96
COMPLETED	92	88
NOT COMPLETED	4	8

Baseline Characteristics

Arm/Group Title	Vitamin D3	Placebo	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	96	96	192
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	9.9 (2.5)	9.7 (2.5)	9.8 (2.5)
Sex: Female, Male (Count of Participants)
Female	44 45.8%	33 34.4%	77 40.1%
Male	52 54.2%	63 65.6%	115 59.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	7 7.3%	6 6.3%	13 6.8%
Not Hispanic or Latino	89 92.7%	90 93.8%	179 93.2%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	27 28.1%	32 33.3%	59 30.7%
Black	51 53.1%	49 51%	100 52.1%
Other Race	18 18.8%	15 15.6%	33 17.2%
Region of Enrollment (participants) [Number]
United States	96 100%	96 100%	192 100%
Parental Education (Count of Participants)
High school or less	21 21.9%	20 20.8%	41 21.4%
Some college	22 22.9%	22 22.9%	44 22.9%
Completed college	37 38.5%	32 33.3%	69 35.9%
Postgraduate education	14 14.6%	21 21.9%	35 18.2%
Household smoke exposure before age 2 years (Count of Participants)
Count of Participants [Participants]	31 32.3%	32 33.3%	63 32.8%
Current household smoke exposure (Count of Participants)
Count of Participants [Participants]	25 26%	22 22.9%	47 24.5%
Season of enrollment (Count of Participants)
January-March	30 31.3%	25 26%	55 28.6%
April-June	26 27.1%	26 27.1%	52 27.1%
July-September	22 22.9%	22 22.9%	44 22.9%
October-December	18 18.8%	23 24%	41 21.4%
Asthma Control Test score >19 (Count of Participants)
Count of Participants [Participants]	76 79.2%	73 76%	149 77.6%
Body Mass Index z-score (z-score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [z-score]	0.9 (1.1)	0.9 (1.3)	0.9 (1.2)
No. of severe exacerbations in the previous year (exacerbations) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [exacerbations]	1	1	1
Vitamin D (ng/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ng/mL]	22.5 (4.6)	22.8 (4.6)	22.6 (4.6)
FEV1 (% predicted) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [% predicted]	93.9 (15.8)	90.6 (17.3)	92.2 (16.6)
FEV1/FVC (% predicted) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [% predicted]	91.5 (9.3)	89.6 (10.1)	90.6 (9.7)
Asthma Control Test score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	22.0 (3.2)	21.3 (3.6)	21.7 (3.4)

Outcome Measures

1. Primary Outcome

Title	Days to a Severe Asthma Exacerbation
Description	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

Outcome Measure Data

Analysis Population Description

Intent to treat population across the 48-week study period

Arm/Group Title	Vitamin D3	Placebo
Arm/Group Description	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.	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.
Measure Participants	96	96
Mean (Standard Deviation) [Days]	240 (105.8)	253 (101.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vitamin D3, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.63
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.13
	Confidence Interval	(2-Sided) 95%; 0.69 to 1.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Days to Viral-induced Severe Exacerbation
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Vitamin D3	Placebo
Arm/Group Description	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.	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.
Measure Participants	82	83
Mean (Standard Deviation) [Days]	272 (87.8)	281 (83.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vitamin D3, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.46
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.32
	Confidence Interval	(2-Sided) 95%; 0.63 to 2.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Proportion of Participants in Whom Fluticasone Dose Was Halved at Visit 6
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Vitamin D3	Placebo
Arm/Group Description	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.	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.
Measure Participants	91	91
Count of Participants [Participants]	28 29.2%	29 30.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vitamin D3, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.99
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.52
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Average Cumulative Prescribed Dose of ICS at the End of the Trial
Description	The average cumulative dose of inhaled corticosteroids (ICS) during the study period
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

Intent to treat population across the 48-week study period

Arm/Group Title	Vitamin D3	Placebo
Arm/Group Description	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.	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.
Measure Participants	96	96
Mean (Standard Deviation) [mg]	59.6 (22.9)	55.2 (14.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vitamin D3, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.049
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.40
	Confidence Interval	(2-Sided) 95%; 0.001 to 8.80
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	48 weeks
Adverse Event Reporting Description	A hospitalization for an asthma exacerbation was considered a serious adverse event.
Arm/Group Title	Vitamin D3		Placebo
Arm/Group Description	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.		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.
All Cause Mortality
	Vitamin D3		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/96 (0%)		0/96 (0%)
Serious Adverse Events
	Vitamin D3		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/96 (9.4%)		7/96 (7.3%)
Blood and lymphatic system disorders
eosinophilia	1/96 (1%)	1	0/96 (0%)	0
severe neutropenia	1/96 (1%)	1	0/96 (0%)	0
Psychiatric disorders
Depression	0/96 (0%)	0	2/96 (2.1%)	3
Respiratory, thoracic and mediastinal disorders
Hospitalization for asthma exacerbation	6/96 (6.3%)	8	6/96 (6.3%)	6
Pneumonia/otitis/hives	1/96 (1%)	1	0/96 (0%)	0
Other (Not Including Serious) Adverse Events
	Vitamin D3		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/96 (5.2%)		4/96 (4.2%)
Musculoskeletal and connective tissue disorders
Fractures	5/96 (5.2%)	5	4/96 (4.2%)	4

Limitations/Caveats

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.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.