Cholecalciferol to Improve the Outcomes of COVID-19 Patients

Study Overview
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Brief Summary
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The recent inception of the coronavirus SARS-CoV-2, responsible for the coronavirus disease (COVID-19), has caused thousands of deaths globally. The most frequently reported complications among COVID-19 patients are from respiratory involvement. Vitamin D has immunomodulatory effects that could protect against COVID-19 infection. Indeed, there is good evidence from randomized clinical trials suggesting that high doses of vitamin D administered during cold seasons prevent viral respiratory infections in at risk individual, and more recently, observational studies suggested that the mortality rate from COVID-19 is inversely correlated with levels of serum 25(OH)vitamin D. The hypothesis of the study is that a high dose of vitamin D given orally to patients admitted to the hospital for COVID-19 will prevent the occurrence of respiratory deragement and other adverse clinical events. To evaluate the aforementioned hypothesis, a randomized, controlled, double-blind, clinical trial comparing a 500.000 UI dose of vitamin D versus placebo among COVID-19 patients at moderate risk, requiring hospitalization but without requirements of critical care at admission was designed. The intervention will be one dose of 500.000 UI given orally or matching placebo. The trial has a sequential design with two steps: The first step, projected to include 200 patients, will assess the effects of the intervention on the respiratory SOFA; and If there is a detectable effects, the second step, projected to include 1264 patients, will assess the effects on a combined event that includes need of high dose of oxygen or mechanical ventilation. All study outcomes will be measured during the index hospitalization.

Detailed Description
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See above.

Official Title
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Randomized Controlled Trial of High Dose of Vitamin D as Compared With Placebo to Prevent Complications Among COVID-19 Patients

Conditions
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COVID

Intervention / Treatment
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* Drug: Vitamin D
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: SARS-CoV-2 confirmed infection; Admission to a hospital; Expected hospitalization in the center for at least for 24 hs; Oxygen Saturation >90% breathing without oxygen supplement; Age at least 45 years or the presence of one of the followings risk factors: Hypertension; Diabetes (type I o II); At least moderate COPD or Asthma; Cardiovascular disease (history of myocardial infarction, coronary angioplasty, coronary artery bypass grafting or valve replacement surgery); Body Mass Index >=30; Signed Written consent. Exclusion Criteria: <18 years old; Women in childbearing age; >= 72 hs since current admission; Requirement for high dose of oxygen (>5 liters/minute) or mechanical ventilation (non-invasive or invasive); History of Chronic kidney disease requiring hemodialysis or chronic liver failure; Inability for oral intake; Previous treatment with pharmacological vitamin D; History of: previous treatment with anticonvulsants; sarcoidosis; malabsorption syndrome; Known hypercalcemia. Life expectancy less than 6 months; Known allergy to the study medication; Any condition impeding to bring informed consent.

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: Two parallel arms randomized controlled trial. A sequential design will be used with the first primary outcome being the primary outcome for the first step. This step will include 200 patients. After reach this point, a review of the primary outcome (change in respiratory SOFA) will be done. According to these results, the Executive committee will decide to proceed the second step of the study and include the remaining 1064 patients to evaluate the second primary outcome (need for high dose of oxygen supplementation or mechanical ventilation).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vitamin D<br>5 capsules containing 100.000 UI of vitamin D each. The intervention will be 5 capsules given in one-time oral intake. | Drug: Vitamin D<br>* 5 capsules of 100.000 UI Vitamin D orally given all at once. One dose.<br>* Other names: Cholecalciferol;|
| Placebo Comparator: Placebo<br>5 capsules containing placebo. The intervention will be 5 capsules given in one-time oral intake. | Drug: Placebo<br>* 5 capsules of containing placebo orally given all at once. One dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Respiratory SOFA. | Is the respiratory component of the sequential organ failure assessment score (SOFA score). It is a 4 points scale, each point indicate a deeper respiratory impairment. The score is based on the relationship between the arterial pressure of oxygen (PaO2) and inspired fraction of oxygen (FiO2), as the ratio of both (PaFi). In the cases were arterial blood gas are not measured, the pulse oximetry will be used instead. The respiratory SOFA is as follows: 1: PaO2/FiO2 >=300; 2: PaO2/FiO2 >=200 and <300; 3: PaO2/FiO2 >=100 and <200; 4: PaO2/FiO2 <100. The minimum respiratory SOFA score will be record on daily basis during first week or to death or discharge, whichever occur first. This outcome is the primary outcome of the first study phase. | One week | 
| Need of a high dose of oxygen or mechanical ventilation. | The start of oxygen supplementation at FiO2 >40% or the initiation of invasive through orotracheal intubation) or non-invasive ventilation (Continuous positive airway pressure or Bilevel positive airway ventilation). This outcome will be recorded during hospitalization to 30 days, the death or discharge, whichever occur first. This is the primary outcome of the second study phase. | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in oxygen saturation. | Difference between the oxygen saturation at study entry and the lowest oxygen saturation measured during the first week, the death or discharge, whichever occur first. The oxygen saturation will be measured by pulse oximetry using commercially available devices. | One week | 
| Oxygen desaturation. | Oxygen saturation equal or less than 90% in any moment during the hospitalization. This outcome will be measured by pulse oximetry using commercially available devices. The outcome will be measured during the first week, the death or hospital discharge, whichever occur first. | One week | 
| Change in Quick SOFA score. | The difference between the Quick SOFA score at study entry and the highest value recorded during the hospitalization. The outcome will be measured during the hospitalization until 30 days, the death or discharge whichever occur first. | 30 days. | 
| Myocardial infarction. | Myocardial infarction is defined as suspicious symptoms with new Q waves in the EKG and enzymatic elevations compatible with the Fourth MI Definition. The outcome will be measured during the hospitalization until 30 days, the death or discharge whichever occur first. | 30 days | 
| Stroke. | Stroke is defined as a focal neurological loss lasting >24 hs as reported by treating physician. The outcome will be measured during the hospitalization until 30 days, the death or discharge whichever occur first. | 30 days | 
| Acute kidney injury. | Acute kidney injury is defined as an increase of at least 50% in serum creatinine levels (as compared with any previous value during the hospitalization). The outcome will be measured during the hospitalization until 30 days, the death or discharge whichever occur first. | 30 days | 
| Pulmonary thromboembolism. | Pulmonary thromboembolism is defined as the presence of suspicious symptoms (i.e. dyspnea) confirmed with objective evidence of a thrombus in the pulmonary tree by CT or MRI or Pulmonary Angiography. The outcome will be measured during the hospitalization until 30 days, the death or discharge whichever occur first. | 30 days | 
| Combined endpoint (stroke, myocardial infarction, acute kidney injury and pulmonary thromboembolism. | Combined outcome of the aforementioned events, Stroke is defined as a focal neurological loss lasting >24 hs as reported by treating physician. Myocardial infarction is defined as suspicious symptoms with new Q waves in the EKG and enzymatic elevations compatible with the Fourth MI Definition. Pulmonary thromboembolism is defined as the presence of suspicious symptoms (i.e. dyspnea) confirmed with objective evidence of a thrombus in the pulmonary tree by CT or MRI or Pulmonary Angiography. Acute kidney injury is defined as an increase of at least 50% in serum creatinine levels (as compared with any previous value during the hospitalization). The outcome will be measured during the hospitalization until 30 days, the death or discharge whichever occur first. | 30 days | 
| Admission to ICU. | Admission to Intensive Care Unit due to clinical deterioration as judged by the treating physician. The outcome will be measured during the hospitalization until 30 days, the death or discharge whichever occur first. | 30 days | 
| Invasive Mechanical Ventilation. | The start of mechanical ventilation invasive during the hospitalization until 30 days, the death or discharge whichever occur first. | 30 days | 
| Hospital Length of Stay. | Total duration of initial hospital stay in days. The outcome will be measured during the hospitalization until 30 days, the death or discharge whichever occur first. In the cases with hospital stays longer than 30 days, it will considered as 30 days. | 30 days. | 
| ICU length of stay. | Total duration of initial ICU stay in days. The outcome will be measured during the hospitalization until 30 days, the death or discharge whichever occur first. In the cases with ICU stays longer than 30 days, it will considered as 30 days. | 30 days | 
| Death | Death of any cause during the hospitalization until 30 days or discharge whichever occur first. | 30 days. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID, coronavirus, SARS-CoV-2, Vitamin D, Cholecalciferol, Respiratory insufficiency