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Effect of Vitamin D3 Supplementation on Severe Asthma Exacerbations in Children With Asthma and Low Vitamin D LevelsThe VDKA Randomized Clinical Trial

Educational Objective
To learn whether vitamin D3 supplementation improves the time to a severe exacerbation in children with asthma and low vitamin D levels.
1 Credit CME
Key Points

Question  In high-risk children with persistent asthma and low vitamin D levels, does vitamin D3 supplementation prolong the time to a severe asthma exacerbation?

Findings  In this randomized clinical trial that included 192 children, vitamin D3 supplementation, compared with placebo, did not significantly improve the time to a severe asthma exacerbation (adjusted hazard ratio, 1.13).

Meaning  The findings from this trial do not support the use of vitamin D3 supplementation to improve the time to a severe asthma exacerbation in children with asthma and low serum vitamin D levels.

Abstract

Importance  Severe asthma exacerbations cause significant morbidity and costs. Whether vitamin D3 supplementation reduces severe childhood asthma exacerbations is unclear.

Objective  To determine whether vitamin D3 supplementation improves the time to a severe exacerbation in children with asthma and low vitamin D levels.

Design, Setting, and Participants  The Vitamin D to Prevent Severe Asthma Exacerbations (VDKA) Study was a randomized, double-blind, placebo-controlled clinical trial of vitamin D3 supplementation to improve the time to severe exacerbations in high-risk children with asthma aged 6 to 16 years taking low-dose inhaled corticosteroids and with serum 25-hydroxyvitamin D levels less than 30 ng/mL. Participants were recruited from 7 US centers. Enrollment started in February 2016, with a goal of 400 participants; the trial was terminated early (March 2019) due to futility, and follow-up ended in September 2019.

Interventions  Participants were randomized to vitamin D3, 4000 IU/d (n = 96), or placebo (n = 96) for 48 weeks and maintained with fluticasone propionate, 176 μg/d (6-11 years old), or 220 μg/d (12-16 years old).

Main Outcomes and Measures  The primary outcome was the time to a severe asthma exacerbation. Secondary outcomes included the time to a viral-induced severe exacerbation, the proportion of participants in whom the dose of inhaled corticosteroid was reduced halfway through the trial, and the cumulative fluticasone dose during the trial.

Results  Among 192 randomized participants (mean age, 9.8 years; 77 girls [40%]), 180 (93.8%) completed the trial. A total of 36 participants (37.5%) in the vitamin D3 group and 33 (34.4%) in the placebo group had 1 or more severe exacerbations. Compared with placebo, vitamin D3 supplementation did not significantly improve the time to a severe exacerbation: the mean time to exacerbation was 240 days in the vitamin D3 group vs 253 days in the placebo group (mean group difference, −13.1 days [95% CI, −42.6 to 16.4]; adjusted hazard ratio, 1.13 [95% CI, 0.69 to 1.85]; P = .63). Vitamin D3 supplementation, compared with placebo, likewise did not significantly improve the time to a viral-induced severe exacerbation, the proportion of participants whose dose of inhaled corticosteroid was reduced, or the cumulative fluticasone dose during the trial. Serious adverse events were similar in both groups (vitamin D3 group, n = 11; placebo group, n = 9).

Conclusions and Relevance  Among children with persistent asthma and low vitamin D levels, vitamin D3 supplementation, compared with placebo, did not significantly improve the time to a severe asthma exacerbation. The findings do not support the use of vitamin D3 supplementation to prevent severe asthma exacerbations in this group of patients.

Trial Registration  ClinicalTrials.gov Identifier: NCT02687815

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Article Information

Corresponding Author: Juan C. Celedón, MD, DrPH, Division of Pulmonary Medicine, UMPC Children’s Hospital of Pittsburgh, 4401 Penn Ave, Pittsburgh, PA 15224 (juan.celedon@chp.edu).

Accepted for Publication: June 25, 2020.

Correction: This article was corrected online on June 2, 2021, to fix the numbers of patients who did not complete the trial in Figure 1.

Author Contributions: Drs Celedón and Wisniewski had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Wisniewski, Celedón.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Forno, Bacharier, Phipatanakul, Durrani, Wisniewski, Celedón.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Blatter, Wisniewski.

Obtained funding: Cabana, Celedón.

Administrative, technical, or material support: Forno, Phipatanakul, Guilbert, Covar, Gern, Rosser, Blatter, Durrani, Han, Celedón.

Supervision: Forno, Bacharier, Phipatanakul, Ross, Covar, Rosser, Wisniewski, Celedón.

Conflict of Interest Disclosures: Dr Bacharier reported receiving grants from the National Heart, Lung, and Blood Institute (NHLBI) during the conduct of the study and personal fees from AstraZeneca, GlaxoSmithKline, Sanofi, Regeneron, Novartis, Genentech, Boeringher Ingelheim, Vectura, DBV Technologies, Circassia, Merck, Teva, Medscape, and Rockpointe outside the submitted work, as well as receiving royalties as associate editor from Elsevier (Journal of Allergy and Clinical Immunology). Dr Phipatanakul reported serving as a consultant for GlaxoSmithKline, Genentech, Novartis, Regeneron, Sanofi, and Teva; receiving clinical trial support or medications from Genentech, Novartis, Regeneron, Sanofi, Circassia, Monaghen, Thermo Fisher, Alk Abello, Lincoln Diagnostics, GlaxoSmithKline, Kaleo, and Merck; and funding to the institution by Genentech, Regeneron, Novartis, and the National Institutes of Health (NIH)—all for projects unrelated to the current work. Dr Guilbert reported receiving personal fees from GlaxoSmithKline, TEVA, Novartis, and the American Board of Pediatrics (pediatric pulmonary subboard); grants and personal fees from Sanofi/Regeneron; grants from AstraZeneca and Novartis; and royalties from UpToDate outside the submitted work. Dr Cabana reported serving as a member of the United States Preventive Services Task Force (USPSTF); this manuscript does not necessarily represent the views of the USPSTF. Dr Ross reported receiving grants from the NIH during the conduct of the study and grants and nonfinancial support from TEVA, nonfinancial support from Merck, and grants from Flamel, the NHLBI, AstraZeneca, and Novartis outside the submitted work. Dr Covar reported receiving grants from GlaxoSmithKline during the conduct of the study. Dr Gern reported receiving personal fees from AstraZeneca outside the submitted work. Dr Rosser reported receiving grants from the NIH/National Center for Advancing Translational Sciences during the conduct of the study. Dr Celedón reported receiving nonfinancial support from Pharmavite and GlaxoSmithKline during the conduct of the study and nonfinancial support (Asmanex) for an NIH-funded study from Merck outside the submitted work. No other disclosures were reported.

Funding/Support: This study was funded by grant HL119952 from the US NIH. The project was also supported by the Pediatric Clinical and Translational Research Center (PCTRC) at University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh through NIH grant UL1TR001857. Pharmavite LLC provided the vitamin D and placebo capsules for the study, and GlaxoSmithKline provided the Flovent given to study participants.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The VDKA group members include the following: University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh and University of Pittsburgh: design of the study: John M. Brehm, MD, MPH. Collection of the data: Jonathan D. Finder, MD, Mark E. Dovey, MD, Jonathan E. Spahr, MD, David M. Orenstein, MD, Geoffrey Kurland, MD, Daniel J. Weiner, MD, Gregory Burg, MD, Sandeep Puranik, MD, Allyson Larkin, MD, Hiren Muzumdar, MD, Deborah Albright, MD, Hey Chong, MD, PhD, David Nash, MD, Todd Green, MD, Natalie Baldauff, DO, Robert W. Hickey, MD, John Broyles, MS, CRNP, Lori Holt, MSN, CRNP, Rose Lanzo, Jamie Adams, Elizabeth Hartigan, RN, MPH, Cynthia Granny, and Pamela Vincent. Data management and data analysis: Zachary Doyle, Heather Eng, and Jim Luther.

Boston Children’s Hospital: Data collection: Jonathan Gaffin, MD, MMSc, Perdita Permaul, MD, Margee Louisias, MD, MPH, Marissa Hauptman, MD, MPH, Nicole Akar-Ghibril, MD, Elizabeth Burke Roberts, RN, PNP, Sachin Baxi, MD, Lisa Bartnikas, MD, William Sheehan, MD, Britanny Esty MD, David Kantor MD, PhD, Peggy Lai, MD, MPH, Michelle Maciag, MD, Elena Crestani, MD, Mehtap Haktanir-Abul, MD, Amparito Cunningham MD, MPH, Anna Cristina Vasquez-Muniz, BA, Nicole Adler, BS, Reid Mathews, BS, Brian Volonte, BS, John Pacheco, BA, Anna Ramsey, BS, Vanessa Konzelmann, BS, Aiza Zia, BS, Julianne Saia, BS, Alma Castillo-Hernandez, BS, Benjamin Peterson, BS, Jennifer Rooney, MS, and Robert Rega, BS.

Cincinnati Children’s Hospital Medical Center: Data collection: Cassie Shipp, MD, Carolyn Kercsmar, MD, Karen McDowell, MD, Stephanie (Logsdon) Ward, MD, Nancy Lin, MD, Alisha George, MD, Will Corwin, Grant Geigle, Alisha Hartmann, and John Broderick.

Rainbow Babies and Children’s Hospital: Data collection: Laurie Logan, RN, Laura Veri, Daniel Craven MD, Ben Gaston MD, Amy DiMarino MD, Erica Roesch MD, and Ross Myers, MD.

Washington University at St Louis: Data collection: Wanda Caldwell, Tina Norris, and Roseanne Donato.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We thank all study participants and their families; the research coordinators and research teams at each of the study sites and the data coordinating center; the data and safety monitoring board; and the clinical trials specialist (Julie Bamdad, MSE) and program officer (Patricia Noel, PhD) for the project at the federal agency that funded the study (the National Heart, Lung, and Blood Institute) for monitoring the study progress.

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