Lessening Organ Dysfunction With VITamin C - COVID-19

Study Overview
=================
Brief Summary
-----------------
LOVIT-COVID is a multicentre concealed-allocation parallel-group blinded randomized controlled trial to ascertain the effect of high-dose intravenous vitamin C compared to placebo on mortality or persistent organ dysfunction at 28 days in hospitalized COVID-19 patients.

Detailed Description
-----------------
Background. Research suggests that vitamin C is potentially lifesaving in the intense inflammatory cascade such as that associated with COVID-19. Inflammation and oxidative stress are among the main mechanisms underlying COVID-19-associated acute hypoxemic respiratory failure. Previous evidence had also already established that a dysregulated inflammatory cascade may distinguish patients who transition from a relatively mild viral pneumonitis to acute respiratory distress syndrome and multiorgan failure. As such, adjunct immune modulation therapies may improve outcomes of COVID-19 patients who are hospitalized. Numerous preclinical studies have shown that, in addition to direct scavenging of oxygen radicals, vitamin C limits their production and restores endothelial function. As the majority of hospitalized patients with COVID-19 are not critically ill, avoiding clinical deterioration and subsequent intensive care unit admission is a high priority. Participation in research should be offered before patients become critically ill, at which time many perceive that treatment may be too late. It is important to ensure that as many COVID-19 patients as possible are offered the opportunity to participate to research since that is generally the only means to access investigational therapies. The proposed trial will address this gap, by evaluating the efficacy of intravenous vitamin C in hospitalized patients with confirmed COVID-19. Objectives. The overarching objective, which is identical to the objective of the parent LOVIT trial (NCT 03680274), is to determine whether intravenous vitamin C, compared to placebo, reduces morbidity and mortality in patients hospitalized with COVID-19. To ascertain the volume of distribution, clearance, and plasma concentration over a course of 96 hours of intravenous vitamin C 50 mg/kg of weight every 6 hours or matching placebo (pharmacokinetic (PK) substudy). Methods. Patients will be randomly assigned to vitamin C (intravenous, 50 mg/kg every 6h) or placebo (0.9% NaCl or dextrose 5% in water) for 96 hours. Study personnel at the clinical sites will document the composite of death or persistent organ dysfunction at day 28. Daily assessments will occur for organ function, on days 1, 3, 7 for inflammation, infection, and endothelial injury biomarkers, at baseline for vitamin C level, and at 6 months for mortality and HRQoL. The LOVIT-COVID Trial will be conducted in Canadian and possibly international sites. For the PK substudy: Blood samples will be drawn around the 8th dose at time 0 and then after administration at times 1h, 2h, 4h and 6h (the 6h level will be immediately prior to the next dose). The PK substudy will be conducted with 100 participants in some of the participating centers. Relevance. A growing body of evidence suggests that vitamin C, an inexpensive and readily available intervention, is potentially lifesaving in sepsis and may also be beneficial in COVID-19. LOVIT-COVID will constitute rigorous assessments of the effect of vitamin C monotherapy on patient-important outcomes. If proven effective, vitamin C could be used worldwide and drastically change outcomes in high- and low-income settings alike.

Official Title
-----------------
Lessening Organ Dysfunction With VITamin C - COVID

Conditions
-----------------
Vitamin C, COVID-19, Hospitalized Patients

Intervention / Treatment
-----------------
* Drug: Vitamin C
* Drug: Control


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmed diagnosis of COVID-19; Admitted to hospital (ward or intensive care unit). Exclusion Criteria: Receiving or has received vasopressors during the current hospitalization; More than 24 hours has elapsed since receipt of non-invasive ventilatory support (high-flow nasal cannula or continuous positive airway pressure or non-invasive ventilation) or invasive mechanical ventilation; Patient is expected to be discharged from the hospital in the next 24 hours; More than 14 days have elapsed since the commencement of hospital admission with respiratory illness; Known glucose-6-phosphate dehydrogenase (G6PD) deficiency; Known sickle cell anemia Pregnancy or breastfeeding; Known allergy to vitamin C; Known kidney stones within the past 1 year; Received any intravenous vitamin C during this hospitalization unless incorporated in parenteral nutrition; Expected death or withdrawal of life-sustaining treatments within 48 hours; Previously enrolled in this study; Previously enrolled in a trial for which co-enrolment is not allowed (co- enrolment to be determined case by case). The trial has broad eligibility criteria and includes all COVID-19 patients admitted to the hospital (e.g. hospital ward or the intensive care unit) who are not receiving vasopressors.

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized controlled trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vitamin C<br>Vitamin C: 50 mg/kg of weight administered intravenously every 6 hours for 96 hours (16 doses). | Drug: Vitamin C<br>* Intravenous vitamin C administered in bolus doses of 50 mg/kg mixed in a 50-ml solution of either normal saline (0.9% NaCl) or dextrose 5% in water (D5W) during 30 to 60 minutes, every 6 hours for 96 hours (i.e. 200 mg/kg/day and 16 doses in total).<br>* Other names: Ascorbic acid;|
| Placebo Comparator: Control<br>Normal saline (0.9% NaCl) or dextrose 5% in water (D5W) in a volume to match the vitamin C. | Drug: Control<br>* Dextrose 5% in water of normal saline (0.9% NaCL) in a volume to match vitamin C.<br>* Other names: Placebo;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death or persistent organ dysfunction | Number of deceased participants or with persistant organ dysfunction (dependency on mechanical ventilation, new renal replacement therapy, or vasopressors). | Both assessed at 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of intensive care unit-free days | Number of whole and part study days for which the patient is alive and not admitted to an intensive care unit | Assessed at 21 days | 
| Persistent organ dysfunction-free days in ICU | Number of study days in ICU without persistant organ dysfunction | Assessed at 28 days | 
| Number of patients deceased at 6 months | Mortality at 6 months | 6 months | 
| Health related quality of life in 6-month survivors | Assessed by the EQ-5D-5L EuroQol questionnaire (EQ-5D-5L). The EQ-5D-5L essentially consists of 2 pages: the EQ-5D descriptive system and the EQ-5D visual analog scale (EQ VAS). The descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The patient is asked to indicate her/his health state by ticking the box next to the most appropriate statement in each of the 5 dimension. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the 5 dimensions can be combined into a 5-digit number that describes the patient's health state. The EQ-VAS records the patient's self-rated health on a vertical visual analog scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. | 6 months | 
| Organ function | Assessed by the Sequential Organ Failure Assessment (SOFA) score. Used to track a person's status during the stay in an intensive care unit to determine the extent of a person's organ function or rate of failure. The score is based on six different sub-scores, one each for the respiratory (PaO2/fraction of inspired oxygen FiO2) mmHg), cardiovascular (mean arterial pressure OR administration of vasopressors required), hepatic (liver bilirubin mg/dl [µmol/L]), coagulation (platelets x 103/µl), renal (kidneys creatinine (mg/dl) [µmol/L] (or urine output)), and neurological (Glasgow coma scale). The sub-score of each system ranges from 0 (best) to +4 (worst). | Days 1, 2, 3, 4, 7, 10, 14, 28 | 
| Global tissue dysoxia | Assessed by serum lactate concentration | Days 1, 3, 7 | 
| Rate of inflammation | Assessed by interleukin-1 beta (IL-1ß), tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP). | Days 1, 3, 7 | 
| Rate of infection | Assessed by procalcitonin (PCT). | Days 1, 3, 7 | 
| Rate of endothelial injury | Assessed by thrombomodulin (TM) and angiopoietin-2 (ANG-2). | Days 1, 3, 7 | 
| Occurrence of stage 3 acute kidney injury | Assessed by Kidney Disease: Improving Global Outcomes (KDIGO) criteria | Up to day 28 | 
| Acute hemolysis | clinician judgment of hemolysis, as recorded in the chart, OR hemoglobin drop of at least 25 g/L within 24 hours of a dose of investigational product plus 2 of the following: reticulocyte count >2 times upper limit of normal at clinical site lab; haptoglobin <lower limit of normal at clinical site lab; indirect (unconjugated) bilirubin >2 times upper limit of normal at clinical site lab; lactate dehydrogenase (LDH) >2 times upper limit of normal at clinical site lab. Severe hemolysis: o hemoglobin <75 g/L AND at least 2 of the above criteria AND requires 2 units of packed red blood cells. | Up to day 28 | 
| Hypoglycemia | Core lab-validated glucose level <3.8 mmol/L | During the time participants receive the 16 doses of the investigational product and the 7 days following the last dose. | 
| Vitamin C volume of distribution | Assessed by chromatography-tandem mass spectrometry | 8th dose of vitamin C at time 0 (immediately prior to the dose) and then after administration at times 1 hour, 2 hours, 4 hours and 6 hours (Pharmacokynetic substudy). | 
| Vitamin C clearance | Assessed by chromatography-tandem mass spectrometry | 8th dose of vitamin C at time 0 (immediately prior to the dose) and then after administration at times 1 hour, 2 hours, 4 hours and 6 hours (Pharmacokynetic substudy). | 
| Vitamin C plasma concentration | Assessed by chromatography-tandem mass spectrometry | 8th dose of vitamin C at time 0 (immediately prior to the dose) and then after administration at times 1 hour, 2 hours, 4 hours and 6 hours (Pharmacokynetic substudy). | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Vitamin C, COVID-19, Hospitalized patients, Pandemic, Coronavirus