Clinical trial NCT04401150: Lessening Organ Dysfunction With VITamin C - COVID-19
Official title: Lessening Organ Dysfunction With VITamin C - COVID
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Vitamin C
COVID-19
Hospitalized Patients
Keywords: Vitamin C
COVID-19
Hospitalized patients
Pandemic
Coronavirus
Lead sponsor: Université de Sherbrooke
Sponsor class: OTHER
Collaborators: name: Lotte & John Hecht Memorial Foundation
First posted: 2020-05-26
Enrollment: 392
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized controlled trial
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Death or persistent organ dysfunction
timeFrame: Both assessed at 28 days
Secondary outcomes:
measure: Number of intensive care unit-free days
timeFrame: Assessed at 21 days
measure: Persistent organ dysfunction-free days in ICU
timeFrame: Assessed at 28 days
measure: Number of patients deceased at 6 months
timeFrame: 6 months
measure: Health related quality of life in 6-month survivors
timeFrame: 6 months
measure: Organ function
timeFrame: Days 1, 2, 3, 4, 7, 10, 14, 28
measure: Global tissue dysoxia
timeFrame: Days 1, 3, 7
measure: Rate of inflammation
timeFrame: Days 1, 3, 7
measure: Rate of infection
timeFrame: Days 1, 3, 7
measure: Rate of endothelial injury
timeFrame: Days 1, 3, 7
measure: Occurrence of stage 3 acute kidney injury
timeFrame: Up to day 28
measure: Acute hemolysis
timeFrame: Up to day 28
measure: Hypoglycemia
timeFrame: During the time participants receive the 16 doses of the investigational product and the 7 days following the last dose.
measure: Vitamin C volume of distribution
timeFrame: 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).
measure: Vitamin C clearance
timeFrame: 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).
measure: Vitamin C plasma concentration
timeFrame: 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).
Other outcomes:
Locations:
city: Sherbrooke
country: Canada
facility: Research Center of the CHUS
state: Quebec
city: Sherbrooke
country: Canada
facility: Research Centre of the CHUS
state: Quebec
Study officials:
affiliation: Université de Sherbrooke and CIUSSS de l'Estrie - CHUS
name: François Lamontagne, MD, FRCPC, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: Sunnybrook Health Sciences Centre, University of Toronto
name: Neill K Adhikari, MDCM, FRCPC, MSc
role: PRINCIPAL_INVESTIGATOR
References: