The coronavirus disease-19 (COVID-19) pandemic, caused by the severe acute respiratory
syndrome β-coronavirus (SARS-CoV-2), is one of the greatest challenges facing modern
medicine and public health systems worldwide. Since its appearance in December 2019, it
has caused nearly 7 million deaths, recognized, and confirmed worldwide, with high acute
and post-acute morbidity, making it one of the deadliest in human history, with a
devastating impact on national economies worldwide.

In the first outbreaks of COVID-19, although 80% were asymptomatic or had mild symptoms,
20% of patients developed severe symptoms, and 5% presented acute respiratory distress
syndrome (ARDS), septic shock and accompanied multi-organ organ failure, with a high risk
of death. Numerous risk factors have been described that influence the poor outcome of
these patients, such as age, sex, high blood pressure, chronic obstructive pulmonary
disease, diabetes, obesity, chronic lung and digestive diseases, asthma, chronic heart
disease, cancer, D-dimer greater than 1000, or a high SOFA (Sequential Organ Failure
Assessment Score). It has also been observed that patients with no a priori risk factors
may have a poor outcome.

The scientific community immediately proposed strong social containment measures, quickly
developed effective vaccines to prevent the appearance of severe clinical forms of
COVID-19, and developed new treatments against all aspects of the disease: antiviral
agents, anti-inflammatory agents, antithrombotic therapies, therapies against hypoxemic
acute respiratory failure, therapies with anti-SARS-CoV-2 antibodies (neutralizing),
modulators of the renin-angiotensin-aldosterone system and vitamins, so that social and
economic activity has gradually recovered worldwide.

However, at the current time, there are some indications that hospital admissions for
COVID-19 are on the rise again, so the pandemic seems far from over and future waves of
infection are likely. These indications update and highlight again the repositioning
strategy used since the beginning of the pandemic for the use of safe drugs, approved for
another indication, and redirected to improve symptoms and clinical outcomes in patients
with COVID-19. Various drugs have been investigated under this strategy and many studies
have been published, some of them successful.

In this sense, during the first months of the pandemic, on the basis of biological
plausibility, the investigators thought that the activation of the vitamin D receptor
(VDR) signaling pathway of the vitamin D endocrine system (VDES) could produce beneficial
effects in COVID-19. These effects were achieved by improving innate antiviral effector
mechanisms, facilitating the induction of antimicrobial peptides/autophagy, mitigating
the subsequent reactive hyperinflammatory phase of the host, decreasing the
cytokine/chemokine storm, modulating the expression of the renin angiotensin system
(RAAS) and neutrophil activity, maintaining the integrity of the pulmonary/intestinal
epithelial barrier, stimulating epithelial repair and directly and indirectly reducing
the increase in coagulability and prothrombotic tendency associated with a severe course
of COVID-19 and its complications. Available evidence suggests that VDES/VDR stimulation,
while maintaining optimal serum 25-hydroxyvitamin D [(25(OH)D)] status, in patients with
SARS-CoV-2 infection may significantly reduce the risk of distress syndrome, acute
respiratory distress syndrome (ARDS) and the development of severe COVID-19.

The investigators decided to use calcifediol, which is a prohormone (and cornerstone of
the VDES) and substrate for the synthesis of the system's hormone, calcitriol. The poor
availability of calcifediol described in the general population, most marked in patients
affected by COVID, means that the potential protection that VDR/VDES stimulation confers
against various aspects of the disease is lost.

Calcifediol provides pharmacokinetic advantages, which give it a certain functional
superiority over native vitamin D3 and even over the hormonal form of VDES, calcitriol,
for its use in COVID-19. It is very hydrophilic and, therefore, after oral ingestion, it
is absorbed through the portal venous system and does not require hydroxylation at the 25
position, immediately increasing optimal circulating concentrations of 25(OH)D3.
Therefore, even if administered orally, it is available at high concentrations within a
few hours, and in a stable manner, to be a substrate for calcitriol synthesis at the
kidney and other target organs in COVID-19.

The clinical trial pilot study and several observational intervention studies using
relatively high doses of calcifediol (0.532 µg on day 1 and 0.266 µg on days 3, 7, 14, 21
and 28) decreased the severity of the disease, dramatically reducing the need for ICU
admission, severity, and mortality rate.

Therefore, using calcifediol at the doses described for rapid correction of 25(OH)D
deficiency in all patients in the early stages of COVID-19, in association with the best
available therapy, was assessed as a good option for the treatment of COVID-19. For this
reason, on January 24, 2021, the CHUA incorporated calcifediol into the protocol
"Recommendations for action and treatment of the coronavirus SARS-CoV-2 disease"
(COVID-19) version 11.1".