Calcifediol in the Treatment of COVID 19

Study Overview
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Brief Summary
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Patients hospitalized with COVID-19 treated with calcifediol during the first outbreaks of the pandemic (until the first vaccinations) are compared with the aim of determining the therapeutic, clinical, functional, and biochemical variables that modify the response (admission to ICU or death) to calcifediol during hospitalization for COVID 19

Detailed Description
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The ongoing pandemic of coronavirus disease-19 (COVID-19), caused by the β-coronavirus SARS-CoV-2, is the greatest challenge ever faced by modern medicine and public health systems worldwide. In early outbreaks, approximately 20% progressed to severe symptomatology, of which 5% developed acute respiratory distress syndrome (ARDS), septic shock and multi-organ failure accompanied by a high risk of death. In this scenario, the scientific community employed strong social containment measures and developed vaccines effective in preventing severe clinical forms of COVID-19. Vaccines against the causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have shown a preventive effect against the occurrence and severity of COVID-19, and social and economic activities are gradually recovering worldwide. The rapid mutation rate of this virus family including multiple mutations in the receptor binding domain of the spike protein that have been associated with increased transmissibility and immune evasion after natural infection and vaccination, calls into question both the efficacy of vaccines and their long-term safety and the efficacy of monoclonal antibodies withdrawn for lack of effectiveness. Moreover, the cost/benefit of newly licensed oral antivirals for high-risk patients in higher-income countries remains inadequately documented. These data update the repositioning strategy employed since the beginning of the pandemic for the use of safe drugs, approved for another indication and reproposed to improve symptoms and clinical outcomes in COVID-19 patients. Numerous drugs have been investigated with this strategy and many studies have been published. Calcifediol (25OH vitamin D3) is one of them. Calcifediol is the prohormone of the vitamin D endocrine system (VDES). It requires hydroxylation to convert to calcitriol (1,25(OH)2 vitamin D3) , the active form that exerts its functions by activating the vitamin D receptor (VDR), which is expressed in the immune system and many other affected organs in COVID, including the lungs. Available data strongly suggest that treatment with calcifediol can decrease the severity of COVID-19, decreasing the need for intensive care unit (ICU) admissions and decreasing the risk of mortality. It is a cost-effective treatment, without major adverse effects, and widely available, which could have positive implications for the treatment of the disease worldwide. Another family of repositioned drugs has been the corticosteroids. Commonly used for decades for their immunosuppressive/anti-inflammatory properties by inhibiting the expression of multiple pro-inflammatory cytokines and chemokines, and the (in)activation of various immune cells. However, at the start of the pandemic in 2020, corticosteroid treatment in COVID-19 was formally contraindicated or not recommended. Corticosteroids had been widely used during outbreaks of severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV, but review of their use in those epidemics suggested that corticosteroid use could increase mortality and secondary infection rates by delaying viral clearance. Therefore, World Health Organization (WHO) interim guidance on the clinical management of severe acute respiratory infection when SARS-CoV-2 infection was suspected (published on 28 January 2020) advised against the use of corticosteroids unless otherwise indicated. For this reason, the three studies described that treated COVID with high-dose calcifediol and best available therapy did not use corticosteroids (except rarely and after a consensus clinical decision by the treating physicians). Thus, the results obtained did not have the confounding factor of modulation of innate and acquired immunity by corticosteroid treatment. Following the RECOVERY trial, one of the largest randomized controlled trials for COVID-19 treatment, clinical practice guidelines were modified worldwide to authorize the standard use of dexamethasone or other corticosteroids as the best available treatment in hospitalized patients with severe COVID-19 requiring intensive oxygen therapy. However, the appropriate time interval for corticosteroid administration is a matter of debate, and the response to treatment is also likely to be related to the natural history of each patient's clinical and biological evolution. In addition, it is unclear how long treatment should last; since prolonged corticosteroid treatment may not be safe, due to interference with clotting and metabolic pathways, disease symptoms and long-term persistence of COVID-19. Therefore, systemic glucocorticoids, included as the best available treatment, could, depending on the timing of their introduction, modify and/or confound the beneficial effect of calcifediol evidenced in the pre-corticoid stage of the pandemic. Other variables may also act as a confounding factor in the response to calcifediol treatment.

Official Title
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Calcifediol in the Treatment of COVID 19. Modification of Therapeutic Response by Best Available Treatment or Other Treatment or Clinical Variables

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Calcifediol
* Drug: Best available therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 and < 90 years. Diagnosis confirmed by positive polymerase chain reaction (PCR) for COVID-19. Radiological image compatible with pulmonary involvement by COVID-19. Admission to Reina Sofia university Hospital (HURS) Pneumology Department. Exclusion Criteria: Patients for whom electronic medical record data cannot be collected.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Calcifediol<br> | Drug: Calcifediol<br>* Subjects hospitalized with COVID-19 treated with calcifediol<br>|
| Best therapy available<br> | Drug: Best available therapy<br>* Subjects hospitalized with COVID-19 treated with Azithromycin, hydroxychloroquine, corticoids and others authorized treatments.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Need for ICU admission | Measure the need for ICU admission by differentiating the groups calcifediol yes/no; corticosteroids yes/no. | from hospitalization till discharge /death | 
| Mortality | Measure mortality by differentiating groups: calcifediol yes/no; corticosteroids yes/no. | from hospitalization till discharge /death | 
| Composite variable poor prognosis, (ICU&death) | Measure the composite variable poor prognosis, (ICU&death) by differentiating the groups calcifediol yes/no; corticosteroids yes/no. | from hospitalization till discharge /death | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| clinical variables that calcifediol response | To detect clinical variables that may modify the response to calcifediol. | from hospitalization till discharge /death | 
| drug modifying calcifediol response | To detect clinical variables that may modify the response to calcifediol. | from hospitalization till discharge /death |