Vitamin D Supplementation and Clinical Outcomes in Severe COVID-19 Patients

Study Overview
=================
Brief Summary
-----------------
Single center, open label randomized clinical trial. Study location: tertiary hospital center (University Hospital Split, Croatia). All COVID-19 patients with positive PCR test admitted to ICU and in need for respiratory support will be eligible for inclusion in this study. Patients admitted to ICU with severe COVID-19 disease and in need for invasive or non-invasive respiratory support with low levels of vitamin D (<50 nmol/l) measured on admission. All patients are older than 18 years and have confirmed COVID-19 disease with PCR test. Intervention: All patients included in this study will receive standard of care. Patients randomized into intervention group will be receiving 10 000 IU of cholecalciferol daily. Supplement will be administered orally or via gastric tube during ICU stay or for at least 14 days in case of ICU discharge before day 14. Supplementation will begin within 48 hours of admission to ICU. Supplement will be prepared and administered by experienced nursing staff. For patients receiving supplementation, vitamin D levels will be checked on days 7 and 14. In case that vitamin D levels are > 150 nmol/l or if the calcium levels are consistently > 2.6 mmol/l, further supplementation will be stopped. Outcomes: Primary outcome is number of days spent on ventilator. Secondary outcomes: all-cause mortality on day 28, all-cause mortality on day 60, mortality at hospital discharge, clinical improvement at day 28 (WHO clinical progression scale), days spent in ICU, days spent in hospital after discharge from ICU, need for dialysis at day 28, bacterial superinfections, neutrophile to lymphocyte ratio, disease severity (CRP levels, PaO2/FiO2 ratio, D-dimer levels, fibrinogen, ferritin, PCT), adverse outcomes. Hypothesis: patients receiving Vitamin D supplementation will have shorter number of days spent on mechanical ventilation.

Official Title
-----------------
Vitamin D Supplementation and Clinical Outcomes in Severe COVID-19 Patients - Randomized Controlled Trial

Conditions
-----------------
Covid-19, Respiratory Distress Syndrome, Vitamin D Deficiency

Intervention / Treatment
-----------------
* Dietary Supplement: cholecalciferol


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients admitted to ICU with severe COVID-19 disease and in need for invasive or non-invasive respiratory support with low levels of vitamin D (<50 nmol/l) measured on admission. All patients are older than 18 years and have confirmed COVID-19 disease with PCR test. Exclusion Criteria: Patients will be excluded from study in case of calcium levels that are consistently above normal serum range (> 2.6 mmol/L, > 10.5 mg/dL) or if vitamin D levels are > 150 nmol/L.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>Patients with low levels of Vitamin D on admission to ICU randomized to receive vitamin D supplementation | Dietary Supplement: cholecalciferol<br>* daily supplementation of cholecalciferol, 10 000 IU, during 14 days<br>|
| No Intervention: Control<br>Patients with low levels of Vitamin D on admission to ICU not receiving vitamin D supplementation | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| number of days on mechanical ventilation | Number of days spent on mechanical ventilation for each patient | Daily, through study completion, on average 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality on day 28 | Number of patients alive on day 28 | day 28 | 
| All-cause mortality on day 60 | Number of patients alive on day 60 | day 60 | 
| clinical improvement at day 28 | World Health Organization Clinical progression scale. Values are from 0 to 10 with higher score meaning worse clinical status | day 28 | 
| Number of days spent in ICU | Number of days spent in Intensive care unit for each patient | Daily, through study completion, on average 6 months | 
| Number of days spent in hospital after ICU discharge | Number of days spent in hospital for each patient | Daily, through study completion, on average 6 months | 
| Acute renal failure | Number of patients with need for renal replacement therapy | Day 28 | 
| bacterial superinfections | Number of patients with bacterial superinfections during hospitalization | Daily, through study completion, on average 6 months | 
| CRP levels (mg/ml) | blood tests will be taken daily during hospital stay | Daily, through study completion, on average 6 months | 
| prokalcitonin levels (ng/ml) | blood tests will be taken daily during hospital stay | Daily, through study completion, on average 6 months | 
| fibrinogen levels (g/L) | blood tests will be taken daily during hospital stay | Daily, through study completion, on average 6 months | 
| D-dimer levels (mg/l) | blood tests will be taken daily during hospital stay | Daily, through study completion, on average 6 months | 
| adverse outcomes | Number of patients with elevated serum calcium levels | Daily, through study completion, on average 6 months |