Cholecalciferol to Improve the Outcomes of COVID-19 Patients (CARED)

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

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.

Study Overview

• Status: Completed
• Conditions: COVID
• Intervention / Treatment: Drug: Vitamin D; Drug: Placebo

Detailed Description

See above.

• Study Type: Interventional
• Enrollment (Actual): 218
• Phase: Phase 4

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires
    • Florencio Varela, Buenos Aires, Argentina, 1888
      • Hospital De Alta Complejidad en Red El Cruce

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Vitamin D Study Group
• Collaborators: Agencia Nacional de Investigación y Desarrollo
• Investigators: Study Director: Walter Manucha, PhD, IMBECU, Univ Nac de Cuyo, Mendoza, Argentina; Principal Investigator: Carlos Tajer, MD, Hospital de Alta Complejidad El Cruce - Universidad Nacional Arturo Jauretche; Principal Investigator: Laura Antonietti, MD, Hospital de Alta Complejidad El Cruce - Universidad Nacional Arturo Jauretche; Principal Investigator: León Ferder, MD, Maimonides University; Principal Investigator: Felipe Inserra, MD, Universidad Maimónides - Hospital Universitario Austral; Principal Investigator: Javier Mariani, MD, Hospital de Alta Complejidad El Cruce - Universidad Nacional Arturo Jauretche

Publications and helpful links

General Publications

• Martin Gimenez VM, Inserra F, Tajer CD, Mariani J, Ferder L, Reiter RJ, Manucha W. Lungs as target of COVID-19 infection: Protective common molecular mechanisms of vitamin D and melatonin as a new potential synergistic treatment. Life Sci. 2020 Aug 1;254:117808. doi: 10.1016/j.lfs.2020.117808. Epub 2020 May 15.
• Mariani J, Antonietti L, Tajer C, Ferder L, Inserra F, Sanchez Cunto M, Brosio D, Ross F, Zylberman M, Lopez DE, Luna Hisano C, Maristany Batisda S, Pace G, Salvatore A, Hogrefe JF, Turela M, Gaido A, Rodera B, Banega E, Iglesias ME, Rzepeski M, Gomez Portillo JM, Bertelli M, Vilela A, Heffner L, Annetta VL, Moracho L, Carmona M, Melito G, Martinez MJ, Luna G, Vensentini N, Manucha W. High-dose vitamin D versus placebo to prevent complications in COVID-19 patients: Multicentre randomized controlled clinical trial. PLoS One. 2022 May 27;17(5):e0267918. doi: 10.1371/journal.pone.0267918. eCollection 2022.
• Mariani J, Tajer C, Antonietti L, Inserra F, Ferder L, Manucha W. High-dose vitamin D versus placebo to prevent complications in COVID-19 patients: A structured summary of a study protocol for a randomised controlled trial (CARED-TRIAL). Trials. 2021 Feb 1;22(1):111. doi: 10.1186/s13063-021-05073-3.

Study record dates

Study Major Dates

• Study Start (Actual): August 11, 2020
• Primary Completion (Actual): July 28, 2021
• Study Completion (Actual): July 28, 2021

Study Registration Dates

• First Submitted: May 26, 2020
• First Submitted That Met QC Criteria: May 31, 2020
• First Posted (Actual): June 2, 2020

Study Record Updates

• Last Update Posted (Actual): July 30, 2021
• Last Update Submitted That Met QC Criteria: July 28, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: SARS-CoV-2; Vitamin D; COVID; coronavirus; Cholecalciferol; Respiratory insufficiency
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol
• Other Study ID Numbers: 001 (NavyGHB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No