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
Background
Vitamin 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 findings
This 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 
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.
Conclusions
In 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 registration
ClinicalTrials.gov NCT04344041.
Author summary
Why was this study done?
Preclinical data suggest that vitamin D may attenuate the effects of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by exerting anti-inflammatory effects and by regulating the renin–angiotensin system, thus potentially preventing the cytokine storm and its lethal consequences.
Observational studies have reported that, while accounting for confounders, participants with lower 25-hydroxyvitamin D (25(OH)D) concentrations were more likely to progress to severe forms of Coronavirus Disease 2019 (COVID-19) and to die from COVID-19.
Observational studies have also found that vitamin D3 supplementation prior to or during COVID-19 was associated with improved survival in older adults with COVID-19.
Clinical trials to evaluate the impact on survival of high-dose vitamin D supplementation in COVID-19 patients have yet not been performed.
What did the researchers do and find?
In this multicenter, open-label, randomized controlled trial (RCT), we randomly assigned 254 at-risk older adults with COVID-19 to a single oral high-dose (400,000 IU) or standard-dose (50,000 IU) vitamin D3 administered within 72 hours after the diagnosis of COVID-19, with 14-day survival as the primary outcome.
We found that the early administration of 400,000 IU versus 50,000 IU vitamin D3 to at-risk older patients with COVID-19 was associated with reduced overall mortality at day 14. The protective effect was not sustained at 28 days.
High-dose cholecalciferol did not result in more frequent adverse effects compared to the standard dose.
What do these findings mean?
In the absence of toxicity and given the benefits of high-dose vitamin D found on 14-day mortality, a combination therapy with both standard treatments for COVID-19 and high doses of vitamin D3 may be proposed to at-risk older patients with COVID-19 within the first hours of the infection.
The lack of protection after 28 days should encourage examination of the possible benefit of a continuous daily (or weekly) vitamin D supplementation following the initial loading dose.
Our study was not designed to determine whether vitamin D supplementation helps with prevention of SARS-CoV-2 infection.
