Magnesium and Vitamin D Combination for Post-COVID Syndrome

Study Overview
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Brief Summary
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The goal of this double-blind randomized controlled clinical trial is to determine the efficacy of the administration of magnesium chloride + vitamin D as an adjuvant in the treatment of post-Coronavirus Disease (COVID) syndrome. The participants will be integrated: a) Intervention group that will receive 1 g of magnesium chloride (equivalent to 300 mg of elemental magnesium) + 4000 IU of vitamin D once a day, for four months. b) Control group that will receive inert placebo for four months. The outcome variable will be the improvement of the post-COVID syndrome. At the beginning and end of the study, blood samples will be taken to determine serum levels of vitamin D, total magnesium, ionic magnesium, calcium, fasting glucose and lipid profile. The evaluation of the efficacy and safety of the proposed intervention will be carried out by establishing the differences between the intervention and control groups.

Detailed Description
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More than 50 signs and symptoms have been described that characterize the post-COVID syndrome, among them the early presence of fatigue, shortness of breath, cough, joint and chest pain. Later, the signs and symptoms that may occur are muscle pain, headache, tachycardia, loss of smell or taste, memory and concentration problems, difficulty falling asleep, skin rashes and hair loss. Vitamin D is a fat-soluble vitamin whose best-known function is calcium and phosphate homeostasis, but it is also involved in multiple processes, including the regulation of the immune response. In vitro, vitamin D decreases viral replication, which is linked to its ability to stimulate innate immunity, increases the synthesis of cathelicidin and defensins, peptides that favor the preservation of the mucosa and enhance its protective effect against infection. In vivo, vitamin D decreases the expression of the cellular co-receptor dipeptidyl peptidase (DPP)-4/cluster of differentiation antigen 26 (CD26), which interacts with protein S, which decreases the penetration of the virus into the cell, contributes to the regulation of immunity, regulating excessive immune response, which is associated with an adverse prognosis, and interacts with the nuclear factor-kappa B (NF-kB) pathway, decreases the intensity of the Th1 response and the synthesis of proinflammatory cytokines, and increases the synthesis of anti-inflammatory cytokines. Magnesium, through its calcium channel blocking effect, decreases the inflammatory response produced by the NF-kB cascade, reduces the production of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) by monocytes and the expression of cytokines and inflammatory proteins. It influences both cell-mediated and humoral adaptive immunity, since it participates in the activation of leukocytes, the binding of antigens to macrophages, apoptotic regulation, and it reduces the production of superoxide anions. The pathophysiology of the post-COVID syndrome is not precisely known, although it has been established that it is a disorder with inflammatory components, endothelial damage, and thromboembolism. In this context, magnesium deficiency is associated with the development of the pro-inflammatory and pro-thrombotic response that generates a favorable microenvironment for the development of inflammation, endothelial damage and thromboembolism, components linked to the post-COVID syndrome. On the other hand, it has been described that patients with post-COVID present with vitamin D deficiency, a deficiency that contributes to the development of fatigue, anemia and chronic inflammation. In addition, there is interaction between magnesium and vitamin D, in such a way that the deficiency of the first contributes to the decrease in the synthesis of 25-hydroxy vitamin D and 1,25-hydroxy vitamin D and the number and activity of vitamin D receptors. Therefore, it is plausible to assume that both magnesium and vitamin D play an important role in the development of post-COVID syndrome. Goal. To determine the efficacy of the administration of magnesium chloride + vitamin D as an adjuvant in the treatment of post-COVID syndrome. Methods. Double-blind randomized controlled clinical trial to which subjects diagnosed with post-COVID syndrome will be integrated. The participants will be integrated: a) Intervention group that will receive 1 g of magnesium chloride (equivalent to 300 mg of elemental magnesium) + 4000 IU of vitamin D once a day, for four months. b) Control group that will receive inert placebo for four months. Men and women, aged 18 years or older, with a diagnosis of post-COVID syndrome, hypomagnesaemia and vitamin D insufficiency will be included. Having received magnesium or vitamin D supplements in the last 30 days, as well as treatment based on of steroids, will be exclusion criteria. The withdrawal of informed consent and adherence to the intervention less than 80% will be criteria for elimination. The outcome variable will be the improvement of the post-COVID syndrome. At the beginning and end of the study, blood samples will be taken to determine serum levels of vitamin D, total magnesium, ionic magnesium, calcium, fasting glucose and lipid profile. Statistic analysis. The evaluation of the efficacy and safety of the proposed intervention will be carried out by establishing the differences between the intervention and control groups, which will be estimated using the unpaired Student's t-test for analysis of the parametric variables (Mann-Whitney U for non-parametric variables) and Chi-Square (Fisher's exact test) for the analysis of categorical variables. Intragroup differences will be estimated using the paired Student's t-test. Even when it is assumed that the confounding variables will be controlled by the randomization process; Additionally, a stratified analysis will be carried out by those confounding variables that in the bivariate analysis show significant differences.

Official Title
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Efficacy and Security of the Magnesium and Vitamin D Combination as Adjuvant Treatment of Post-COVID Syndrome. A Randomised Double-blind Clinical Trial

Conditions
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Post-COVID-19 Syndrome, Long COVID, Vitamin D Deficiency, Magnesium Deficiency

Intervention / Treatment
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* Dietary Supplement: Magnesium chloride
* Dietary Supplement: Vitamin D
* Dietary Supplement: Inert placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women aged 18 or older. Previous diagnosis of COVID-19, confirmed by Real Time Polymerase Chain Reaction (RT-PCR) for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Diagnosis of post-COVID syndrome Hypomagnesemia Vitamin D deficiency Exclusion Criteria: Subjects who have received magnesium and/or vitamin D supplements in the last 30 days

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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
Interventional Model Description: Study groups: Intervention group that will receive 1.2 g of magnesium chloride (equivalent to 360 mg of magnesium elemental) + 4000 IU of vitamin D once a day, for four months. Control group that will receive inert placebo for four months.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention group<br>Will receive 1.2 g of magnesium chloride (equivalent to 360 mg of magnesium elemental) + 4000 IU of vitamin D once a day, for four months. | Dietary Supplement: Magnesium chloride<br>* Each 650 mg capsule contains 340 mg of magnesium chloride, which must be ingested twice a day with aliments.<br>* Other names: Magnesium;Dietary Supplement: Vitamin D<br>* Each tablet contains 4000 IU of vitamin D, and must be ingested a pill per night.<br>* Other names: Cholecalciferol;|
| Placebo Comparator: Control group.<br>Will receive inert placebo for four months. | Dietary Supplement: Inert placebo<br>* Instead of dietary supplements, sodium bicarbonate as inert placebo will be administered twice a day in 650 mg capsules.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline Post-COVID syndrome symptoms at 4 months | The presence of two or more of the following signs and/or symptoms will be considered a suspicion of post-COVID syndrome: Fatigue, shortness of breath, cough, joint pain, chest pain, muscle pain, headache, tachycardia, arrhythmias, loss of smell, loss of taste, memory problems, concentration problems, depression, anxiety, insomnia, skin rashes, hair loss. | First control date, and four months after treatment initiation. | 
| Change from Baseline Post-COVID Functional Status at 4 months | Post-COVID Functional Status Scale | First control date, and four months after treatment initiation. | 
| Change from Baseline Serum vitamin D levels at 4 months | Recovery of serum vitamin D levels from deficiency (< 30 ng/mL) to normally (30 - 100 ng/mL). The serum concentration of the 25 OH vitamin D fraction will be determined by the enzyme-linked immunosorbent assay (ELISA) method, the serum levels of magnesium and calcium by colorimetric techniques (A15 Clinical Analyzer, Biosystems, USA). | First control assessment, and four months after treatment initiation. | 
| Change from Baseline Serum Magnesium levels at 4 months | Recovery of serum magnesium levels from deficiency (< 2.0 mg/dL) to normally (2.0 - 2.5 mg/dL). | First control assessment, and four months after treatment initiation. | 
| Change from Baseline Mental State levels at 4 months | Mini Mental State Examination | First control date, and four months after treatment initiation. | 
| Change from Baseline Anxiety Symptoms at 4 months | Beck Anxiety Inventory | First control date, and four months after treatment initiation. | 
| Change from Baseline Depression Symptoms at 4 months | Beck Depression Inventory | First control date, and four months after treatment initiation. | 
| Change from Baseline Post-traumatic Stress Symptoms at 4 months | Severity of Post-traumatic Stress Symptoms | First control date, and four months after treatment initiation. | 
| Change from Baseline Dyspnea Symptoms at 4 months | modified Medical Research Council (mMRC) dyspnea scale | First control date, and four months after treatment initiation. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline Fasting Blood Glucose levels at 4 months | Normal values: 70 - 100 mg/dL | First control assessment, and four months after treatment initiation. | 
| Change from Baseline Serum Lipid Profile at 4 months | Normal values: total cholesterol 100 - 200 mg/dL; HDL-cholesterol 40 - 60 mg/dL; triglycerides 50 - 150 mg/dL. | First control assessment, and four months after treatment initiation. | 
| Change from Baseline Serum Calcium levels at 4 months | Normal values: 8.4 - 10.2 mg/dL | First control assessment, and four months after treatment initiation. | 
| Change from Baseline Serum Creatinine levels at 4 months | Normal values: 0.5 - 1.2 mg/dL | First control assessment, and four months after treatment initiation. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Post-COVID syndrome, Long COVID, Vitamin D, Magnesium