The Efficacy of Vitamin D Supplementation in Patients With Severe and Extremely Severe COVID-19

Study Overview
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Brief Summary
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Despite the successful treatment of patients with moderate coronavirus disease 2019 (COVID-19), outcomes for patients with severe disease remain unsatisfactory. In this category of patients, the course of the disease is complicated by the development of acute respiratory distress syndrome (ARDS) and the need for mechanical ventilation in the intensive care unit (ICU). Mortality in this category of patients reaches 85%. The lack of effective treatment for COVID-19 has prompted scientists to look for new strategies to reduce the incidence and severity of COVID-19, disease progression, and mortality. Disease severity and mortality rates due to COVID-19 infection are greater in the elderly and chronically ill patients, populations at high risk for vitamin D deficiency. Vitamin D plays an important role in immune function and inflammation. A number of experimental studies have shown that stimulation of vitamin D receptors can improve the course of ARDS due to inhibition of the hyperimmune inflammatory response, regulation of the renin-angiotensin system, modulation of neutrophil activity, maintenance of the integrity of the pulmonary epithelial barrier and stimulation of epithelial repair, as well as by reducing hypercoagulation. Several studies on ICU patients have reported that low vitamin D (25(OH)D) concentrations are associated with a higher risk of negative outcomes such as death, organ failure, prolonged mechanical ventilation, a higher rate of ventilation-associated pneumonia, and sepsis. While the available evidence to-date, from largely poor-quality observational studies, may be viewed as showing a trend for an association between low serum 25(OH)D levels and COVID-19 related health outcomes, this relationship was not found to be statistically significant. Calcifediol supplementation may have a protective effect on COVID-19 related ICU admissions.

Detailed Description
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The aim of the study is to evaluate the efficacy of vitamin D (cholecalciferol) supplementation in patients with severe and extremely severe disease caused by the SARS-CoV-2 virus, admitted to an ICU of the COVID-center on the first day and in dynamics until discharge from the hospital or death. Patients with vitamin D deficiency [25-hydroxyvitamin D (25(OH)D) ≤ 30 ng/ml] will be randomized to two groups: 1 - patients will receive 60,000 IU of cholecalciferol supplementation; 2 - patients will receive matched placebo. The demographic and clinical data will be collected. Laboratory data (hemoglobin, lymphocytes, neutrophil to lymphocyte ratio, D-dimer level, Interleukin-6, procalcitonin, ferritin, glucose level, high-sensitive troponin Т, vitamin D level (25(OH)D), acid-base balance, signs of a secondary bacterial infection, immunogram, Von Willebrand factor antigen and Instrumental data (CT-scan, Electrocardiography, echocardiography, arterial and venous ultrasound investigation) will be analysed. The frequency of complications, duration of mechanical ventilation, length of stay in the ICU and in the hospital, and mortality will be evaluated. This study is single-centre prospective randomized placebo-controlled trial.

Official Title
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The Efficacy of Vitamin D Supplementation in Patients With Severe and Extremely Severe COVID-19

Conditions
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SARS-CoV2 Infection

Intervention / Treatment
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* Dietary Supplement: Vitamin D (cholecalciferol)
* Dietary Supplement: Herbal oil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: all patients with COVID-19 admitted to the ICU with vitamin D deficiency [25-hydroxyvitamin D (25(OH)D) ≤ 30 ng/ml] Exclusion Criteria: less than 24 hours in ICU by any reason chronic decompensated disease with extrapulmonary organ dysfunction (tumour progression, liver cirrhosis, congestive heart failure) with a life expectancy of less than 48 hours atonic coma allergic reaction on cholecalciferol or herbal oil

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Vit_D_suppl<br>Patients will receive 60,000 IU of cholecalciferol dissolved in 45 ml herbal oil orally or via feeding tube weekly followed by 5,000 IU of cholecalciferol (two drops) daily until discharge or death. | Dietary Supplement: Vitamin D (cholecalciferol)<br>* Patients will receive 60,000 IU of cholecalciferol dissolved in 45 ml herbal oil orally or via feeding tube after serum Vitamin D concentrations measurement followed by the same dose of cholecalciferol weekly and 5,000 IU of cholecalciferol (two drops) daily until discharge or death.<br>|
| Placebo Comparator: Vit_D_placebo<br>Patients will receive 45 ml of herbal oil orally or via feeding tube followed by 45 ml of herbal oil weekly followed by two drops of herbal oil daily until discharge or death. | Dietary Supplement: Herbal oil<br>* Patients will receive 45 ml of herbal oil orally or via feeding tube after serum Vitamin D concentrations measurement followed by the same dose of pure herbal oil weekly and two drops of herbal oil daily until discharge or death.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Сomplete blood count | Сomplete blood count | Change from baseline on day 5 during ICU treatment | 
| Сomplete blood count dynamics 1 | Сomplete blood count | Change from baseline on day 10 during ICU treatment | 
| Сomplete blood count dynamics 2 | Сomplete blood count | Change from baseline on day 15 during ICU treatment | 
| Сomplete blood count dynamics 3 | Сomplete blood count | Change from baseline on day 21 during ICU treatment | 
| C-reactive protein | Concentration of C-reactive protein | Change from baseline on day 5 during ICU treatment | 
| C-reactive protein 1 | Concentration of C-reactive protein | Change from baseline on day 10 during ICU treatment | 
| C-reactive protein 2 | Concentration of C-reactive protein | Change from baseline on day 15 during ICU treatment | 
| C-reactive protein 3 | Concentration of C-reactive protein | Change from baseline on day 21 during ICU treatment | 
| Von Willebrand factor antigen | Concentration of Von Willebrand factor antigen | Change from baseline on day 7 during ICU treatment | 
| Thrombotic complications | Arterial or venous thrombotic complications | 60 days | 
| Immunogram | The amount of NKT cells (CD3+CD56+CD16+), NK cells (CD3-CD56+CD16+) | Change from baseline on day 7 during ICU treatment | 
| Proinflammatory marker | Concentration of D-dimer | Change from baseline on day 5 during ICU treatment | 
| Proinflammatory marker 1 | Concentration of D-dimer | on day 10 during ICU treatment | 
| Proinflammatory marker 2 | Concentration of D-dimer | on day 15 during ICU treatment | 
| Proinflammatory marker 3 | Concentration of D-dimer | on day 21 during ICU treatment | 
| inflammatory marker | Concentration of Interleukin-6 | Change from baseline on day 5 during ICU treatment | 
| inflammatory marker 1 | Concentration of Interleukin-6 | Change from baseline on day 10 during ICU treatment | 
| inflammatory marker 2 | Concentration of Interleukin-6 | Change from baseline on day 15 during ICU treatment | 
| inflammatory marker 3 | Concentration of Interleukin-6 | Change from baseline on day 21 during ICU treatment | 
| Infection marker | Concentration of Procalcitonin | Change from baseline on day 5 during ICU treatment | 
| Infection marker 1 | Concentration of Procalcitonin | Change from baseline on day 10 during ICU treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | The dead and survived patients ratio | 60 days | 
| Mechanical ventilation duration | The amount of mechanical ventilation days | 30 days | 
| Non-invasive Mechanical ventilation duration | The amount of Non-invasive mechanical ventilation days | 30 days | 
| Length of stay in the ICU | The amount of day of ICU treatment | 60 days | 
| Length of stay in the hospital | The amount of day of hospital treatment | 60 days | 
| Infection complications | The amount of Infection complications | 60 day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), coronavirus disease 2019 (COVID-19), severe and extremely severe disease, Vitamin D, cholecalciferol