High Dose Vitamin-D Substitution in Patients With COVID-19: a Randomized Controlled, Multi Center Study

Study Overview
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Brief Summary
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The world is currently facing a pandemic with the coronavirus (SARS-CoV-2) which leads to the disease of COVID-19. Risk factors for a poor outcome of COVID-19 have so far been identified as older age and co-morbidity including chronic respiratory conditions such as chronic obstructive pulmonary disease (COPD) and current smoking status. Previous studies found, that vitamin D deficiency is more prevalent among patients with these risk factors. There are observational studies reporting independent associations between low serum concentrations of 25-hydroxyvitamin D (the major circulating vitamin D metabolite) and susceptibility to acute respiratory tract infection. Vitamin D substitution in patients with COVID-19 who show a vitamin D deficiency should therefore be investigated for efficacy and safety. The study is designed as a randomized, placebo-controlled, double blind study. The objective of the study is to test the hypothesis that patients with vitamin D deficiency suffering from COVID-19 treated under standardized conditions in hospital will recover faster when additionally treated with a single high dose of vitamin D compared to standard treatment only.

Detailed Description
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The world is currently experiencing a coronavirus (SARS-CoV-2) pandemic. The disease caused by infection with this virus is known as COVID-19. Risk factors for a poor outcome of COVID-19 have so far been found to include, older age and co-morbidity including chronic respiratory conditions and current smoking status. Previous studies found, that vitamin D deficiency is more prevalent among patients with these risk factors. There are observational studies reporting independent associations between low serum concentrations of 25-hydroxyvitamin D (the major circulating vitamin D metabolite) and susceptibility to acute respiratory tract infection. 25-hydroxyvitamin D supports induction of antimicrobial peptides in response to both viral and bacterial stimuli suggesting a potential mechanism by which vitamin D inducible protection against respiratory pathogens might be mediated. The clear functions of vitamin D in the immune system are difficult to define because the immune response is not a static process. The vitamin-D-receptor, which has also been detected in immunological cells, suggests that vitamin D can regulate some processes related to immunity. A further argument which supports a potential antiviral activity of vitamin D is the modulation of the inflammatory response. The release of pro-inflammatory cytokines by the influenza virus appeared to correlate with the severity of illness. The use of vitamin D as a prophylactic for influenza has shown promise in prevention of illness and reduction of secondary asthma in children. Inadequate vitamin D status is associated with susceptibility to upper respiratory infections in patients with chronic obstructive pulmonary disease (COPD). In the ViDiCo-trial vitamin D supplementation protected against moderate or severe exacerbation, but not upper respiratory infection, in patients with COPD. A further study retrospectively examined data from 108 patients with acute respiratory distress syndrome (ARDS) for whom a vitamin D status was available at the time of diagnosis revealed that over 95% of these patients had vitamin D deficiency. When examined according to quarterly of serum 25- hydroxyvitamin D, a consistent inverse relationship between serum 25-hydroxyvitamin D and length of hospital and ICU stay among survivors was observed. Vitamin D substitution in patients with COVID-19 who show a vitamin D deficiency should therefore be investigated for efficacy and safety. For this purpose the investigators designed a randomized, placebo controlled double blind trial to test the hypothesis hypothesis that a single high dose of vitamin D in addition to standard treatment improves the recovery period positively in patients with COVID-19 and vitamin D deficiency compared to standard treatment only. That means, that the time of recovery is shorter in the single high dose vitamin D group relative to standard treatment group only.

Official Title
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High Dose Vitamin-D Substitution in Patients With COVID-19: a Randomized Controlled, Multi Center Study

Conditions
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Covid19, Vitamin D Deficiency, Corona Virus Infection, ARDS, Coronavirus, SARS-CoV Infection

Intervention / Treatment
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* Drug: Single high dose vitamin D
* Drug: Placebo
* Drug: Treatment as usual vitamin D


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed Consent as documented by signature Hospitalized Patient Ongoing COVID-19 infection Vitamin D deficiency defined as a serum 25-hydroxyvitamin D concentration ≤ 50nmol/l( ≤20ng/ml) > 18 years of age Exclusion Criteria: Known hypersensitivity to one of the used products of vitamin D or indigents in the drug's composition Active malignancy Hypercalcemia Granulomatous disease such as sarcoidosis History of renal stones within the past year Pregnancy/breastfeeding, as evaluated through screening, Previous enrollment into the current study, Enrollment of the investigator, his/her family members, employees and other dependent persons,

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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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
Interventional Model Description: one group receives a single high dose of vitamin D in addition to treatment as usual (TAU) the other group receives a single dose of placebo in addition to TAU
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High Dose Vitamin D<br>Patient will receive a single high dose of vitamin D (140'000) in addition to daily 800 IU of vitamin D. The medication be administered orally | Drug: Single high dose vitamin D<br>* Patient receives either one dose orally of 140'000 IU (7 ml) of this drug once as an intervention treatment additionally to TAU or the patient receives 7 ml of the placebo Solution (7 ml) in addition to TAU<br>* Other names: VITAMIN D3 oil 500 IU/drop;Drug: Treatment as usual vitamin D<br>* Both groups receive the treatment as usual after the single high dose or the placebo which will be 800 IU per day<br>* Other names: Vitamin D3 solution 4000 IU/ml;|
| Placebo Comparator: Placebo<br>Patient will receive a single dose of placebo, orally administered and then treatment as usual (daily 800 IU of vitamin D, orally administered) | Drug: Placebo<br>* Patient receives a single dose of a placebo solution<br>* Other names: Oily placebo solution;Drug: Treatment as usual vitamin D<br>* Both groups receive the treatment as usual after the single high dose or the placebo which will be 800 IU per day<br>* Other names: Vitamin D3 solution 4000 IU/ml;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length of hospitalization | Overall duration of the hospitalization from day of admission until the day of discharge or fatality | Administration to Discharge from hospital care (mean duration is between 14 and 22 days for Patients with COVID 19) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Need of intensive care | Did the patient need a intensive care treatment during the hospitalization (yes/no) | Until discharge or fatality (mean duration is between 14 and 22 days for Patients with COVID-19) | 
| Lenght of the Intensive Care Treatment | Day of admission to ICU until discharge or fatality | Until discharge or fatality (mean duration is between 14 and 22 days for Patients with COVID-19) | 
| Overall mortality | Percentage of patient died during hospitalization | During the length of hospitalisation (mean duration is between 14 and 22 days for Patients with COVID-19) | 
| Development of vitamin D levels | percentage of patients with 25-hydroxyvitamin D > 50nmol/L (>20ng/mL) at day 7 - The values of calcium, phosphorus, 24-hydroxyvitamin D, 1.25-dihydroxyvitamin D, parathyroid hormone. | Day 1 (Baseline) and Day 7 after the first administration of the high dose vitamin D or the placebo and at discharge (mean hospital stay is between 14 and 22 days for Patients with COVID-19) | 
| Development of sepsis | percentage of patients developing a sepsis | During the length of hospitalization (mean duration is between 14 and 22 days for Patients with COVID-19) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Covid19, Vitamin D Deficiency, ARDS, Corona Virus, High dose vitamin D