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

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.

Study Overview

• Status: Completed
• Conditions: SARS-CoV2 Infection
• Intervention / Treatment: Dietary supplement: Vitamin D (cholecalciferol); Dietary supplement: Herbal oil

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 110
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Russian Federation
  • Moscow, Russian Federation, 115682
    • Federal Research Clinical Center of Federal Medical & Biological Agency

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Vit_D_suppl; 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); 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.
Placebo Comparator: Vit_D_placebo; 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; 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.; Other Names: Placebo

What is the study measuring?

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
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
Mortality	The dead and survived patients ratio	60 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

Collaborators and Investigators

• Sponsor: Federal Research Clinical Center of Federal Medical & Biological Agency, Russia
• Investigators: Study Chair: Tatiana V Klypa, ScD, Federal Research Clinical Center of Federal Medical & Biological Agency

Publications and helpful links

General Publications

• Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. doi: 10.1056/NEJMoa2002032. Epub 2020 Feb 28.
• Bassatne A, Basbous M, Chakhtoura M, El Zein O, Rahme M, El-Hajj Fuleihan G. The link between COVID-19 and VItamin D (VIVID): A systematic review and meta-analysis. Metabolism. 2021 Jun;119:154753. doi: 10.1016/j.metabol.2021.154753. Epub 2021 Mar 24.
• Bychinin MV, Klypa TV, Mandel IA, Andreichenko SA, Baklaushev VP, Yusubalieva GM, Kolyshkina NA, Troitsky AV. Low Circulating Vitamin D in Intensive Care Unit-Admitted COVID-19 Patients as a Predictor of Negative Outcomes. J Nutr. 2021 Aug 7;151(8):2199-2205. doi: 10.1093/jn/nxab107.
• Kong J, Zhu X, Shi Y, Liu T, Chen Y, Bhan I, Zhao Q, Thadhani R, Li YC. VDR attenuates acute lung injury by blocking Ang-2-Tie-2 pathway and renin-angiotensin system. Mol Endocrinol. 2013 Dec;27(12):2116-25. doi: 10.1210/me.2013-1146. Epub 2013 Nov 6.
• Bychinin MV, Klypa TV, Mandel IA, Yusubalieva GM, Baklaushev VP, Kolyshkina NA, Troitsky AV. Effect of vitamin D3 supplementation on cellular immunity and inflammatory markers in COVID-19 patients admitted to the ICU. Sci Rep. 2022 Nov 3;12(1):18604. doi: 10.1038/s41598-022-22045-y.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2020
• Primary Completion (Actual): December 31, 2021
• Study Completion (Actual): January 31, 2022

Study Registration Dates

• First Submitted: October 22, 2021
• First Submitted That Met QC Criteria: October 22, 2021
• First Posted (Actual): October 25, 2021

Study Record Updates

• Last Update Posted (Actual): March 7, 2022
• Last Update Submitted That Met QC Criteria: February 18, 2022
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: Vitamin D; coronavirus disease 2019 (COVID-19); cholecalciferol; severe acute respiratory syndrome coronavirus 2 (SARS-CoV2); severe and extremely severe disease
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol
• Other Study ID Numbers: COVID-VIT

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No