Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial

Abstract

Importance: In asthma and other diseases, vitamin D insufficiency is associated with adverse outcomes. It is not known if supplementing inhaled corticosteroids with oral vitamin D3 improves outcomes in patients with asthma and vitamin D insufficiency.

Objective: To evaluate if vitamin D supplementation would improve the clinical efficacy of inhaled corticosteroids in patients with symptomatic asthma and lower vitamin D levels.

Design, setting, and participants: The VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma) randomized, double-blind, parallel, placebo-controlled trial studying adult patients with symptomatic asthma and a serum 25-hydroxyvitamin D level of less than 30 ng/mL was conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institute's AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by January 2014. After a run-in period that included treatment with an inhaled corticosteroid, 408 patients were randomized.

Interventions: Oral vitamin D3 (100,000 IU once, then 4000 IU/d for 28 weeks; n = 201) or placebo (n = 207) was added to inhaled ciclesonide (320 µg/d). If asthma control was achieved after 12 weeks, ciclesonide was tapered to 160 µg/d for 8 weeks, then to 80 µg/d for 8 weeks if asthma control was maintained.

Main outcomes and measures: The primary outcome was time to first asthma treatment failure (a composite outcome of decline in lung function and increases in use of β-agonists, systemic corticosteroids, and health care).

Results: Treatment with vitamin D3 did not alter the rate of first treatment failure during 28 weeks (28% [95% CI, 21%-34%] with vitamin D3 vs 29% [95% CI, 23%-35%] with placebo; adjusted hazard ratio, 0.9 [95% CI, 0.6-1.3]). Of 14 prespecified secondary outcomes, 9 were analyzed, including asthma exacerbation; of those 9, the only statistically significant outcome was a small difference in the overall dose of ciclesonide required to maintain asthma control (111.3 µg/d [95% CI, 102.2-120.4 µg/d] in the vitamin D3 group vs 126.2 µg/d [95% CI, 117.2-135.3 µg/d] in the placebo group; difference of 14.9 µg/d [95% CI, 2.1-27.7 µg/d]).

Conclusions and relevance: Vitamin D3 did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency. These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma.

Trial registration: clinicaltrials.gov Identifier: NCT01248065.

Conflict of interest statement

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Castro reported receiving grants from the National Institutes of Health, Boston Scientific, Amgen, Ception/Cephalon/Teva, Genetech, Medimmune, Merck, Novartis, GlaxoSmithKline, sanofi-aventis, Vectura, NextBio, and KaloBios; and receiving personal fees from Asthmatx, Boston Scientific, IPS/Holaria, Genentech, Merck, GlaxoSmithKline, Genentech, Boehringer Ingelheim, Elsevier, and Sparo Inc. Dr King reported receiving personal fees from KaloBios and Pearl Therapeutics. Ms Kunselman reported receiving grants from the National Heart, Lung, and Blood Institute and the National Institutes of Health. Drs Cabana, Holguin, Sorkness, Hundal, Naureckas, Phipatanakul, Que, Sheshardri, and Sullivan-Vedder reported no disclosures. Dr Denlinger reported receiving grants from the National Institutes of Health and personal fees from Novartis. Dr Kazani reported receiving income from Novartis Institutes for Biomedical Research. Drs Moore and Moy reported receiving grants from the National Institutes of Health. Drs Avila and Lazarus reported receiving grants from the National Heart, Lung, and Blood Institute and the National Institutes of Health. Dr Bacharier reported receiving personal fees from Aerocrine, AstraZeneca, Genentech/Novartis, GlaxoSmithKline, Merck, Schering, and Teva. Dr Bleecker reported receiving grants from the National Heart, Lung, and Blood Institute and the National Institutes of Health; and personal fees from AstraZeneca, Boehringer Ingelheim-Pfizer, Janssen-Johnson & Johnson, Genentech-Novartis, GlaxoSmithKline, Merck, sanofi/Regeneron, Amgen, AstraZeneca-MedImmune, Boehringer Ingelheim-Pfizer, Cephalon, Forest, Genentech-Roche, Novartis, and Pearl. Dr Boushey reported receiving a grant from Genentech. Dr Chmiel reported receiving personal fees from Genentech, Boehringer Ingelheim, CSL Behring, Gilead Sciences, KaloBios Pharmaceuticals, the American College of Chest Physicians, and the American Board of Pediatrics; and receiving grants from the National Institutes of Health and the Cystic Fibrosis Foundation. Dr Fitzpatrick reported receiving personal fees from MedImmune Inc Consulting, Merck, GlaxoSmithKline, Genentech, and Boehringer Ingelheim. Dr Gentile reported receiving personal fees from Teva and Merck. Dr Israel reported receiving personal fees from Cowen & Co, Infinity Pharmaceuticals, Merck, Regeneron Pharmaceuticals, Teva Specialty Pharmaceuticals, and UpTable 1ToDate; and receiving grants from Amgen and i3 Research (Biota). Dr Kraft reported receiving grants from the National Institutes of Health, GlaxoSmithKline, Chiesi, AstraZeneca, and Genentech. Dr Krishnan reported receiving a grant and support for travel from the National Heart, Lung, and Blood Institute. Dr LaForce reported receiving personal fees from Novartis Pharmaceuticals Corp. Dr Lemanske reported receiving grants from the National Heart, Lung, and Blood Institute and Pharmaxis; receiving grants, board membership, and personal fees from the University of Wisconsin; and receiving personal fees from Merck, Sepracor, SA Boney and Associates, GlaxoSmithKline, the American Institute of Research, Genentech, Double Helix Development, Boerhinger Ingelheim, Michigan Public Health, Allegheny General Hospital, American Academy of Pediatrics, West Allegheny Health, California Chapter 4, Colorado Allergy Society, Pennsylvania Allergy Society, Howard Pilgrim Health, California Society of Allergy, NYC Allergy Society, World Allergy Organization, Asia Pacific Association of Pediatric Allergy, Respirology and Immunology, Western Society of Allergy, Asthma, and Immunology, American Academy of Allergy, Asthma and Immunology, Elsevier, and UpToDate. Dr Lugogo reported receiving a grant from the National Institutes of Health. Dr Martin reported receiving grants from the National Institutes of Health and MedImmune; personal fees and nonfinancial support from Teva; and personal fees from UpToDate. Dr Mauger reported receiving grants from the National Heart, Lung, and Blood Institute; nonfinancial support from Sunovion and Teva; and personal fees and nonfinancial support from GlaxoSmithKline, Merck, and Boehringer Ingelheim. Dr Peters reported receiving grants from the National Institutes of Health and the National Heart, Lung, and Blood Institute; other from Johns Hopkins University and the American Lung Association-Asthma Clinical Research Center; personal fees from AstraZeneca, Aerocrine, Airsonett AB, Boehringer Ingelheim, GlaxoSmithKline, Merck, Novartis, Ono Pharmaceuticals, Pfizer, PPD Development, Quintiles, Sunovion, Targacept, Teva, Integrity CE, Merck, and UpToDate; and personal fees and other from Respiratory Medicine for serving as an associate editor in respiratory research, the Journal of Allergy for serving as an associate editor in case reports in medicine, and as an associate editor in US respiratory disease for the Journal of Pulmonary Respiratory Medicine, Clinical Experimental Medical Sciences, and the Journal of Allergy and Clinical Immunology: In Practice. Dr Smith reported receiving grants from the National Heart, Lung, and Blood Institute and the National Institutes of Health and other support from Merck. Dr Solway reported receiving grants from the National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, the National Institutes of Health, and AstraZeneca; nonfinancial support from Sunovion Pharmaceuticals Inc; personal fees from PulmOne Advanced Medical Devices, Hollister Inc, Cytokinetics Inc, Novartis Institute for Biomedical Research, and Boston Scientific; and holds US patent Nos. 6 090 618, 6 114 311, 6 284 743, 6 291 211, 6 297 221, 6 331 527, and 7 169 764. Dr Sumino reported receiving grants and speaker fees from the National Institues of Health. Dr Wechsler reported receiving grants from the National Heart, Lung, and Blood Institute; and personal fees from GlaxoSmithKline, Novartis, Cephalon/Teva, Sepracor/Sunovion, NKT Therapeutics, Asthmatx/Boston Scientific, Genzyme, MapPharma, Genentech, Boehringer Ingelheim, Merck, Regeneron, and MedImmune. Dr Wenzel reported receiving personal fees from AstraZeneca, Gilead, Boeringer Ingelheim, Teva, Sterna, and ICON Medical Imaging; grants and personal fees from GlaxoSmithKline, Amgen, Merck, and MedImmune; and grants from sanofi-aventis and Array. Dr White reported receiving grants from the National Heart, Lung, and Blood Institute and the National Institute of Allergy and Infectious Diseases; and personal fees from Boehringer Ingelheim and GlaxoSmithKline. Dr Sutherland reported being a current employee of sanofi; however, all trial-related activities were performed and completed while he was an employee of National Jewish Health.

Figures

Figure 1. Participant Flow of VIDA Trial

VIDA indicates Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma. Postrandomization dropouts were included in the analysis as censored observations. a Details for those screened but ineligible were not collected. bThe most common reasons were predicted forced expiratory volume in the first second of expiration (FEV1) greater than 90% (n = 286; a subsequent protocol modification removed this criteria), did not have a provocative concentration of methacholine at which FEV1 decreased by 20% or did not qualify for challenge (n = 60), too few symptoms (n = 52), and predicted FEV1 of less than 50% (n =41).

Figure 2. Primary Treatment Failure Outcome

Vertical bars represent censored events. The adjusted hazard ratio for time from randomization to first treatment failure was 0.9 (95% CI, 0.6–1.3) for the vitamin D3 vs placebo treatment groups (P = .54).

Figure 3. Secondary Exacerbation Outcome

The first data point corresponds to the number of exacerbations that occurred during the first 4 weeks of treatment. The adjusted hazard ratio for cumulative number of exacerbations that occurred over the course of the trial was 0.63 (95% CI, 0.39–1.01; P = .05).