400,000 IU of vitamin D 3 days after COVID symptoms reduced 14 day mortality by 3X – Annweiler RCT May 2022

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 <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]).

Apparently had to give ~$40 of vitamin D to save one life

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.
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Discussion

In this multicenter open-label RCT, the administration of high-dose versus standard-dose cho-lecalciferol supplementation to infected older adults within 72 hours after the diagnosis of COVID-19 was associated with reduced overall mortality at day 14. High-dose cholecalciferol was safe and did not result in more frequent adverse effects compared to the standard dose. Some benefits were also found on the 14-day mortality due to COVID-19 as well as on the overall mortality between day 6 and day 14, a critical period in COVID-19, during which inflammatory lung damage is particularly frequent and severe [6]. In contrast, there was no evidence that the single high-dose vitamin D3 administered early in COVID-19 provided any benefit on overall mortality for up to 28 days.

The possibility of a beneficial role of vitamin D supplementation in COVID-19 has been the matter of extensive discussion since the start of the pandemic based on previous meta-analyses of RCT reporting protective effect on respiratory tract infections [23,24]. While our trial was being conducted, 4 other RCT aimed at determining whether vitamin D supplementation improves COVID-19 outcomes have been published. In the SHADE study (India), which randomly assigned 40 middle-aged adults with COVID-19 and vitamin D deficiency to 50,000 IU vitamin D3 per day for 7 days or placebo, the proportion of negative conversion of SARS-COV-2 by 21 days was higher with vitamin D than with placebo (63% versus 21%, P = 0.02) [25]. In a RCT conducted in Saudi Arabia among 69 mild-to-moderate COVID-19 middle-aged patients with suboptimal vitamin D status, the assignment to 5,000 IU daily oral vitamin D3 supplementation for 2 weeks reduced the time to recovery for cough (6.2 ± 0.8 days versus 9.1 ± 0.8 days, P = 0.04) and ageusia (11.4 ± 1.0 versus 16.9 ± 1.7 days, P = 0.035) compared to 1,000 IU daily supplementation [26]. In a RCT conducted in Spain, which randomly assigned 76 middle-aged adults hospitalized for COVID-19 to standard care and oral calcifediol (0.532 mg at baseline followed by 0.266 mg at day 3 and day 7) or standard care alone, the proportion of individuals who needed ICU treatment was lower with calcifediol than in the control group (2% versus 50%, P < 0.001) [27]. Finally, a RCT conducted in Brazil, which randomly assigned 240 middle-aged participants hospitalized for moderate-to-severe COVID-19 to 200,000 IU vitamin D3 supplementation or placebo administered 10.3 days after symptoms onset on average, did not find any effect of supplementation on the length of hospital stay [28]. These previous studies did not investigate as a primary outcome the effect of vitamin D supplementation on the survival of patients with COVID-19.

Our trial has several strengths and fundamental differences in design from previous RCT which helped elucidate the potential benefits of vitamin D supplementation on survival in COVID-19. We included older participants at high risk of both vitamin D insufficiency and COVID-19 worsening. All participants received the intervention (except for the participant who died immediately after randomization in the high-dose vitamin D3 group). Overall use of outside-of-trial vitamin D supplements was low. The loading high dose of oral vitamin D3 administered early in the disease resulted from the first week in a large difference in 25(OH)D concentrations between the trial groups. In this regard, the cumulative mortality curve (Fig 2) and the landmark-based predictions suggest that high-dose vitamin D3 supplementation administered early in COVID-19 is unlikely to improve ongoing organic failures and to prevent deaths in the first days of the infection, but is more likely to prevent secondary worsening of COVID-19 related to the uncontrolled inflammatory chain reaction that characterizes the cytokine storm and contributes to inflammatory lung damages and acute respiratory distress syndrome [6,29]. These results are consistent with the well-known anti-inflammatory properties of vitamin D [3] and its ability to regulate the renin-angiotensin system [4,5], which could help curb the cytokine storm and the risk of severe and fatal forms of COVID-19.

The open-label design of the COVIT-TRIAL study represents a risk of bias in the interpretation of the results. Such design was chosen to improve feasibility in accordance with a full-scale validation test [30]. This limitation is probably of very little consequence due to the hard outcome (survival), and we consider it unlikely that the placebo effect of taking open-label high-dose vitamin D3 might have prevented death in COVID-19 patients. Moreover, no influence of the open-label design was expected on the declaration of all-cause mortality at day 14 (primary outcome), which has the merit of being an objective and indisputable outcome. Likewise, the same treatments known to improve survival in COVID-19 were used in both groups during the follow-up, whether regarding corticosteroids, oxygen therapy, or intubation. This absence of interference in care strategies according to the assignment to the trial groups was expected as the efficacy of high-dose vitamin D3 was not demonstrated at the time of the trial.

As a second limitation, it is plausible that our trial was underpowered because of the lack of preliminary data in the early stage of the COVID-19 pandemic that would have allowed an accurate power calculation. Our starting hypothesis expecting a 12% mortality reduction in the high-dose versus standard-dose vitamin D3 group might have been too optimistic, with consequently a greater beta risk. Moreover, it is likely that the power suffered from the fact that the comparator group received a standard dose of vitamin D3 rather than a placebo. However, not supplementing older adults would not have been deemed ethical since this population is particularly at risk of vitamin D insufficiency [22]. Moreover, the use here of covariates adjustment was able to offset this limitation, allowed an increase in statistical power, and, thus, provided conclusions more appropriate to the clinical context [21].

We used very high doses of vitamin D3 in this trial, although 2 previous meta-analyses reported significant efficacy of daily low doses of vitamin D in preventing acute respiratory tract infections [23,24]. Our trial was, however, not aimed at preventing the onset of COVID-19 but at improving survival during the acute phase of the disease. As devised by Binkley and colleagues [31], vitamin D supplementation with physiologic doses to achieve widely accepted 25(OH)D levels considered adequate may not be the same as large pharmacologic doses. In this regard, it is plausible that high-dose vitamin D might have effects as a “drug” that are not observed with “supplementation” doses. Thus, to provide the greatest chance of finding benefit in life-threatening COVID-19, the dose regimen in our trial was designed to result in rapid attainment and maintenance of serum levels that were as high as safely possible [32]. There is concern that 25(OH)D concentrations above 125 nmol/L maybe associated with adverse effects [33]. In our trial, the administration of 400,000 IU vitamin D3 resulted in a median 25 (OH)D concentration of 150 nmol/L at day 7 without any differences compared to 50,000 IU vitamin D3 regarding the protocol-specified adverse events of interest (Table 3). In line with recent large RCTs that administered for several years 2,000 to 4,000 IU vitamin D3 per day to participants with a very satisfactory baseline vitamin D status [34,35], our study reveals that the risks associated with high-dose vitamin D3 supplementation are minimal during the study period. The clinical implication is that, in the absence of toxicity and given the benefits of high-dose vitamin D on 14-day mortality, a combination therapy with both standard treatments for COVID-19 and high doses of vitamin D3 maybe proposed to at-risk older patients with COVID-19 within the first hours of the infection.

Appears to need a booster dose of Vitamin D ~14 days

However, the lack of protection after 28 days questions the single administration of vitamin D3 at the very beginning of the disease. Since the half-life of 25(OH)D is about 2.5 weeks, which implies that 25(OH)D at day 28 would be about half that at day 14, a continuous daily (or weekly) vitamin D supplementation following the loading dose [23] might be required to improve late survival at 28 days, but this deserves further studies especially since the serum 25(OH)D concentrations at day 14 and/or day 28 were not measured here. Similarly, our study was not designed to determine whether vitamin D3 supplementation can help prevent SARS-CoV-2 infection.