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

Vitamin D to Prevent Severe Asthma Exacerbations

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.

Study Overview

• Status: Terminated
• Conditions: Asthma
• Intervention / Treatment: Drug: vitamin D3 4000 IU; Drug: 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.

• Study Type: Interventional
• Enrollment (Actual): 192
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94102
      • University of California - San Francisco
  • Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Health
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Saint Louis Children's Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44106
      • Rainbow Babies and Children's Hospital
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 16 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Juan Celedon, MD
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Pharmavite LLC
• Investigators: Principal Investigator: Stephen Wisniewski, PhD, University of Pittsburgh; Principal Investigator: Juan C. Celedón, MD, DrPH, University of Pittsburgh

Publications and helpful links

General Publications

• 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.
• 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. Erratum In: JAMA. 2021 Jul 6;326(1):90.

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2016
• Primary Completion (Actual): September 17, 2019
• Study Completion (Actual): September 17, 2019

Study Registration Dates

• First Submitted: February 11, 2016
• First Submitted That Met QC Criteria: February 16, 2016
• First Posted (Estimate): February 22, 2016

Study Record Updates

• Last Update Posted (Actual): August 12, 2021
• Last Update Submitted That Met QC Criteria: August 10, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Vitamin D, severe asthma exacerbations, children
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol
• Other Study ID Numbers: PRO12020541; U01HL119952 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO