Prevention of COVID-19 with oral vitamin D supplemental therapy in essential healthcare teams (PROTECT): protocol for a multicentre, triple-blind, randomised, placebo-controlled trial
Dr Francine Monique Ducharme, Cécile Tremblay, Shirin Golchi, Banafsheh Hosseini, Cristina Longo, John H White, Decio Coviello, Caroline Quach, Louis-Georges Ste-Marie, Robert W Platt
BMJ Open, doi:10.1136/bmjopen-2022-064058
Introduction In the COVID-19 pandemic, healthcare workers (HCWs) were at high risk of infection due to their exposure to COVID infections. HCWs were the backbone of our healthcare response to this pandemic; every HCW withdrawn or lost due to infection had a substantial impact on our capacity to deliver care. Primary prevention was a key approach to reduce infection. Vitamin D insufficiency is highly prevalent in Canadians and worldwide. Vitamin D supplementation has been shown to significantly decrease the risk of respiratory infections. Whether this risk reduction would apply to COVID-19 infections remained to be determined. This study aimed to determine the impact of high-dose vitamin D supplementation on incidence of laboratory-confirmed COVID-19 infection rate and severity in HCWs working in high COVID incidence areas. Methods and analysis PROTECT was a triple-blind, placebo-controlled, parallel-group multicentre trial of vitamin D supplementation in HCWs. Participants were randomly allocated in a 1:1 ratio in variable block size to intervention (one oral loading dose of 100 000 IU vitamin D 3 +10 000 IU weekly vitamin D 3 ) or control (identical placebo loading dose+weekly placebo). The primary outcome was the incidence of laboratory-confirmed COVID-19 infection, documented by RT-qPCR on salivary (or nasopharyngeal) specimens obtained for screening or diagnostic purposes, as well as self-obtained salivary specimens and COVID-19 seroconversion at endpoint. Secondary outcomes included disease severity; duration of COVID-19-related symptoms; COVID-19 seroconversion documented at endpoint; duration of work absenteeism; duration of unemployment support; and adverse health events. The trial was terminated prematurely, due to recruitment difficulty. Ethics and dissemination This study involves human participants and was approved by the Research Ethics Board (REB) of the Centre hospitalier universitaire (CHU) Sainte-Justine serving as central committee for participating institutions (#MP-21-2021-3044). Participants provided written informed consent to participate in the study before taking part. Results are being disseminated to the medical community via national/international conferences and publications in peer-reviewed journals. Trial registration number https://clinicaltrials.gov/ct2/ show/NCT04483635.
Open access Contributors FMD designed the study protocol, secured funding, and oversaw the overall conduct of the project. CT contributed to the protocol and amendments, directed the study implementation at the CHUM, and coordinated the prescription of study drug, pharmacy dispensation, as well as salivary sample reception and interpretation. SG conceived the statistical approach and sample size calculation and along with RWP, oversaw randomisation and statistical analysis. CL, JHW and CQ contributed to the study design and amendments. BH wrote the first manuscript draft. LGSM oversaw the safety assessment. DC is responsible for the work absenteeism analysis. All co-authors approved the manuscript. Authorship eligibility on resulting manuscripts will follow standard guidelines. Competing interests None declared. Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details. Patient consent for publication Consent obtained directly from patient(s). Provenance and peer review Not commissioned; externally peer reviewed. Data availability statement Data are available upon reasonable request. After publication of the primary results, the data sets used and analysed during the current study will be made available by the corresponding author on reasonable request. Supplemental material This content has been supplied by the author(s). It has not..
References
Brunvoll, Nygaard, Ellingjord-Dale, Prevention of COVID-19 and other acute respiratory infections with Cod liver oil supplementation, a low dose vitamin D supplement: Quadruple blinded, randomised placebo controlled trial, BMJ,
doi:10.1136/bmj-2022-071245
Burrer, CDC COVID-19 Response Team, CDC COVID-19 Response Team. CDC COVID-19 response team. characteristics of health care personnel with COVID-19 -United States, MMWR Morb Mortal Wkly Rep,
doi:10.15585/mmwr.mm6915e6
Castro, King, Kunselman, Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: The VIDA randomized clinical trial, JAMA,
doi:10.1001/jama.2014.5052
Denlinger, King, Cardet, Vitamin D supplementation and the risk of colds in patients with asthma, Am J Respir Crit Care Med,
doi:10.1164/rccm.201506-1169OC
Ducharme, Open access endocrine society position, BMJ Open
Gandy, Estimating the number of infections and the impact of nonpharmaceutical interventions on COVID-19 in 11 European countries
Goodall, Granados, Luinstra, Vitamin D3 and Gargling for the prevention of upper respiratory tract infections: A randomized controlled trial, BMC Infect Dis,
doi:10.1186/1471-2334-14-273
Harrell, Statistical design and analysis plan for randomized trial of hydroxychloroquine for treatment of COVID-19: ORCHID, Can J Stat,
doi:10.1002/cjs.11699
Herr, Greulich, Koczulla, The role of vitamin D in pulmonary disease: COPD, asthma, infection, and cancer, Respir Res,
doi:10.1186/1465-9921-12-31
Hosseini, El Abd, Ducharme, Effects of vitamin D supplementation on COVID-19 related outcomes: A systematic review and meta-analysis,
doi:10.3390/nu14102134
Hosseini, Tremblay, Longo, Oral vitamin D supplemental therapy to attain a desired serum 25-Hydroxyvitamin D concentration in essential Healthcare teams, Trials,
doi:10.1186/s13063-022-06944-z
Ilie, Stefanescu, Smith, The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality
Jafarzadeh, Chauhan, Saha, Contribution of monocytes and Macrophages to the local tissue inflammation and cytokine storm in COVID-19: Lessons from SARS and MERS, and potential therapeutic interventions, Life Sci,
doi:10.1016/j.lfs.2020.118102
Jensen, Mailhot, Alos, Vitamin D intervention in Preschoolers with viral-induced asthma (DIVA): A pilot randomised controlled trial, Trials,
doi:10.1186/s13063-016-1483-1
Jolliffe, Holt, Greenig, Effect of a test-and-treat approach to vitamin D supplementation on risk of all cause acute respiratory tract infection and COVID-19: Phase 3 randomised controlled trial (CORONAVIT), BMJ,
doi:10.1136/bmj-2022-071230
Kearns, Alvarez, Tangpricha, Large, single-dose, oral vitamin D supplementation in adult populations: A systematic review, Endocr Pract,
doi:10.4158/EP13265.RA
Maghbooli, Sahraian, Ebrahimi, Vitamin D sufficiency, a serum 25-Hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection, PLoS One,
doi:10.1371/journal.pone.0239799
Manaseki-Holland, Maroof, Bruce, Effect on the incidence of pneumonia of vitamin D supplementation by quarterly bolus dose to infants in Kabul: A randomised controlled superiority trial, Lancet,
doi:10.1016/S0140-6736(11)61650-4
Manaseki-Holland, Qader, Masher, Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: A randomised controlled trial, Trop Med Int Health,
doi:10.1111/j.1365-3156.2010.02578.x
Martineau, James, Hooper, Vitamin D3 supplementation in patients with chronic obstructive pulmonary disease (Vidico): A Multicentre, double-blind, randomised controlled trial, Lancet Respir Med,
doi:10.1016/S2213-2600(14)70255-3
Martineau, Jolliffe, Greenberg, Vitamin D supplementation to prevent acute respiratory infections: Individual participant data meta-analysis, Health Technol Assess,
doi:10.3310/hta23020
Martineau, Jolliffe, Hooper, Vitamin D supplementation to prevent acute respiratory tract infections: Systematic review and meta-analysis of individual participant data, BMJ,
doi:10.1136/bmj.i6583
Martineau, all co-authors of the original study. Vitamin D supplementation to prevent asthma exacerbations -authors' reply, Lancet Respir Med,
doi:10.1016/S2213-2600(18)30199-1
Nguyen, Drew, Graham, Risk of COVID-19 among front-line health-care workers and the general community: A prospective cohort study, Lancet Public Health,
doi:10.1016/S2468-2667(20)30164-X
Pérez-Castrillón, Dueñas-Laita, Brandi, Calcifediol is superior to Cholecalciferol in improving vitamin D status in postmenopausal women: A randomized trial, J Bone Miner Res,
doi:10.1002/jbmr.4387
Ran, Chen, Wang, Risk factors of Healthcare workers with Coronavirus disease 2019: A retrospective cohort study in a designated hospital of Wuhan in China, Clin Infect Dis,
doi:10.1093/cid/ciaa287
Schwalfenberg, A review of the critical role of vitamin D in the functioning of the immune system and the clinical implications of vitamin D deficiency, Mol Nutr Food Res,
doi:10.1002/mnfr.201000174
Sosa Henríquez, De, Romero, Cholecalciferol or Calcifediol in the management of vitamin D deficiency, Nutrients,
doi:10.3390/nu12061617
Vieth, Holick, Chapter 57B -the IOM-endocrine society controversy on recommended vitamin D targets: In support of the on May 27, 2023 by guest. Protected by copyright,
doi:10.1136/bmjopen-2022-064058on25
Villasis-Keever, López-Alarcón, Miranda-Novales, Efficacy and safety of vitamin D supplementation to prevent COVID-19 in frontline Healthcare workers. A randomized clinical trial, Arch Med Res,
doi:10.1016/j.arcmed.2022.04.003
Zosky, Berry, Elliot, Vitamin D deficiency causes deficits in lung function and alters lung structure, Am J Respir Crit Care Med,
doi:10.1164/rccm.201010-1596OC
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'DOI': '10.1038/s41591-020-0916-2'},
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'unstructured': 'Vieth R , Holick MF . Chapter 57B - the IOM—endocrine society '
'controversy on recommended vitamin D targets: In support of the '
'endocrine society position. In: Feldman D , ed. Vitamin D (Fourth '
'Edition). Academic Press, 2018: 1091–107.',
'DOI': '10.1016/B978-0-12-809965-0.00059-8'},
{ 'key': '2023052510251620000_13.5.e064058.34',
'unstructured': 'Harrell FL C . Statistical design and analysis plan for randomized trial '
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'Available: http://hbiostat.org/proj/covid19/bayesplan.html'},
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'Calcifediol in the management of vitamin D deficiency. Nutrients '
'2020;12:1617. doi:10.3390/nu12061617',
'DOI': '10.3390/nu12061617'},
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