High-dose versus standard-dose vitamin D supplementation in older adults with COVID-19 (COVIT-TRIAL): A multicenter, open-label, randomized controlled superiority trial

Abstract

BackgroundVitamin D supplementation has been proposed as a treatment for Coronavirus Disease 2019 (COVID-19) based on experimental data and data from small and uncontrolled observational studies. The COvid19 and VITamin d TRIAL (COVIT-TRIAL) study was conducted to test whether a single oral high dose of cholecalciferol (vitamin D3) administered within 72 hours after the diagnosis of COVID-19 improves, compared to standard-dose cholecalciferol, the 14-day overall survival among at-risk older adults infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).Methods and findingsThis multicenter, randomized, controlled, open-label, superiority trial involved collaboration of 9 medical centers in France. Patients admitted to the hospital units or living in nursing homes adjacent to the investigator centers were eligible if they were ≥65 years, had SARS-CoV-2 infection of less than 3 days, and at least 1 COVID-19 worsening risk factor (among age ≥75 years, SpO2 ≤94%, or PaO2/FiO2≤300 mm Hg). Main noninclusion criteria were organ failure requiring ICU, SpO2 ≤92% despite 5 L/min oxygen, life expectancy <3 months, vitamin D supplementation >800 IU/day during the preceding month, and contraindications to vitamin D supplements. Eligible and consenting patients were randomly allocated to either a single oral high-dose (400,000 IU) or standard-dose (50,000 IU) cholecalciferol administered under medical supervision within 72 hours after the diagnosis of COVID-19. Participants and local study staff were not masked to the allocated treatment, but the Steering Committee and the Data and Safety Monitoring Board were masked to the randomization group and outcome data during the trial. The primary outcome was 14-day overall mortality. Between April 15 and December 17, 2020, of 1,207 patients who were assessed for eligibility in the COVIT-TRIAL study, 254 met eligibility criteria and formed the intention-to-treat population. The median age was 88 (IQR, 82 to 92) years, and 148 patients (58%) were women. Overall, 8 (6%) of 127 patients allocated to high-dose cholecalciferol, and 14 (11%) of 127 patients allocated to standard-dose cholecalciferol died within 14 days (adjusted hazard ratio = 0.39 [95% confidence interval [CI], 0.16 to 0.99],P= 0.049, after controlling for randomization strata [i.e., age, oxygen requirement, hospitalization, use of antibiotics, anti-infective drugs, and/or corticosteroids] and baseline imbalances in important prognostic factors [i.e., sex, ongoing cancers, profuse diarrhea, and delirium at baseline]). The number needed to treat for one person to benefit (NNTB) was 21 [NNTB 9 to ∞ to number needed to treat for one person to harm (NNTH) 46]. Apparent benefits were also found on 14-day mortality due to COVID-19 (7 (6%) deaths in high-dose group and 14 (11%) deaths in standard-dose group; adjusted hazard ratio = 0.33 [95% CI, 0.12 to 0.86],P= 0.02). The protective effect of the single oral high-dose administration was not sustained at 28 days (19 (15%) deaths in high-dose group and 21 (17%) deaths in standard-dose group; adjusted hazard ratio = 0.70 [95% CI, 0.36 to 1.36],P= 0.29). High-dose cholecalciferol did not result in more frequent adverse effects compared to the standard dose. The open-label design and limited study power are the main limitations of the study.ConclusionsIn this randomized controlled trial (RCT), we observed that the early administration of high-dose versus standard-dose vitamin D3 to at-risk older patients with COVID-19 improved overall mortality at day 14. The effect was no longer observed after 28 days.Trial registrationClinicalTrials.govNCT04344041.

Linkages between COVID-19, solar UV radiation, and the Montreal Protocol

“…In contrast, a pilot trial in Spain, in which 76 hospitalised patients were randomised to control (usual care) or supplementation with 0.532 mg of 25(OH)D (calcifediol) on the day of admission, 7 day 3, and day 7, followed by a weekly dose of 0.266 mg until discharge, observed reduced admission to intensive care in the supplemented group (2% vs 50%; p < 0.001) [91]. An open-label trial 8 in France, in which 254 hospitalised patients aged ≥ 65 years were randomised to a single oral dose of 400,000 IU or 50,000 IU of vitamin D 3 , found reduced deaths at 14 days in the high-dose group (6%) compared with the lower-dose group (11%) (p = 0.049) [92]. In addition to the inconsistency in the findings, and some limitations related to trial design in some studies, all used very large bolus doses (i.e.…”

The interplay between hypovitaminosis D and the immune dysfunction in the arteriovenous thrombotic complications of the sever coronavirus disease 2019 (COVID-19) infection

“…Numerous studies have shown that VitD can reduce the risk of acute viral respiratory tract infections and pneumonia. However, the significance of VitD in the treatment of the acquired infections, such as COVID-19, needs to be further investigated particularly in people with low VitD levels at baseline [ 35 ]. VitD opposes the attachment of the virus to the ACE-2 receptors in the pulmonary epithelium [ 36 ].…”

Potential Benefit of Vitamin D Supplementation in COVID-19

“…Since the completion of the aforementioned meta-analysis, a number of interventional studies evaluating the impact of vitamin D supplementation on COVID-19 outcomes have been published. [18][19][20][21][22][23][24] All but two of the studies 23,24 found benefits to vitamin D supplementation in patients hospitalized with COVID-19. Of note, bolus dosing was used in both studies that found no benefit, and in the Mariani et al study, baseline 25(OH)VitD levels >30 ng/mL.…”