Lessening Organ Dysfunction With VITamin C

COVID-19 Clinical Trial

— LOVIT  

Official title:

Lessening Organ Dysfunction With VITamin C (LOVIT)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03680274
• Other study ID #: MP-31-2019-2945
• Status: Completed
• Phase: Phase 3
• Start date: November 8, 2018
• Est. completion date: January 24, 2022

Study information

• Verified date: March 2022
• Source: Université de Sherbrooke
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

LOVIT 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 septic intensive care unit patients. Patients with COVID-19 are considered eligible for this study.

Description:

Background. The burden of sepsis is increasing worldwide. It is the cause of 8 million global deaths each year. Currently, treatment options are limited to antimicrobials and supportive care such as intravenous fluids, vasopressors, mechanical ventilation, and renal replacement therapy. In the absence of effective therapies specifically targeting the dysregulated immune response, prolonged use of these life-sustaining therapies can be debilitating. A growing body of evidence suggesting that vitamin C, an inexpensive and readily available intervention, is potentially lifesaving in sepsis. Intravenous vitamin C may be the first therapy to mitigate the dysregulated cascade of events that leads to sepsis. If proven effective, vitamin C could be used worldwide and drastically change outcomes in high- and low-income settings alike. Objectives. To determine whether intravenous vitamin C, compared to placebo, reduces mortality and morbidity in sepsis (induced by bacterial and viral pathogens (as COVID-19)), and compare clinical and biochemical measures of organ dysfunction, and health-related quality of life (HRQoL) at 6 months. 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 Trial will be conducted in adult general Canadian and international intensive care units. 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 3 of the 25 participating centers. Relevance. In the context of increasing off-label use of vitamin C for sepsis and ongoing trials of vitamin C bundled with other pharmacological interventions, the LOVIT Trial will constitute a rigorous assessment of the effect of vitamin C monotherapy on patient-important outcomes.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 872
• Est. completion date: January 24, 2022
• Est. primary completion date: August 15, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Admitted to the intensive care unit with proven or suspected infection as the main diagnosis;

2. Currently treated with a continuous IV infusion of vasopressors (norepinephrine, epinephrine, vasopressin, dopamine, phenylephrine).

Exclusion Criteria:

1. > 24 hours of intensive care unit admission;

2. Known Glucose-6-phosphate dehydrogenase (G6PD) deficiency;

3. Pregnancy;

4. Known allergy to vitamin C;

5. Known kidney stones within the past 1 year;

6. Received any intravenous vitamin C during this hospitalization unless incorporated in parenteral nutrition;

7. Expected death or withdrawal of life-sustaining treatments within 48 hours;

8. Previously enrolled in this study;

9. Previously enrolled in a trial with which co-enrolment is not allowed. The LOVIT trial has broad eligibility criteria and includes patients with a primary diagnosis of sepsis of any cause (including sepsis caused by viral pathogens as COVID-19).

Related Conditions & MeSH terms

• Coronavirus
• Coronavirus Infections
• COVID-19
• Intensive Care Unit
• Pandemic
• Sepsis
• Vitamin C

Intervention

Drug:
• Vitamin C
Intravenous vitamin C administered in bolus doses of 50 mg/kg mixed in a 50-mL solution of either dextrose 5% in water (D5W) or normal saline (0.9% NaCl), during 30 to 60 minutes, every 6 hours for 96 hours (i.e. 200 mg/kg/day and 16 doses in total).

Other:
• Control
Dextrose 5% in water (D5W) or normal saline (0.9% NaCl) in a volume to match the vitamin C.

Locations

Country	Name	City	State
Canada	Research Center of the CHUS	Sherbrooke	Quebec

Sponsors (2)

Lead Sponsor	Collaborator
Université de Sherbrooke	Lotte & John Hecht Memorial Foundation

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of deceased participants or with persistent organ dysfunction	Defined as death or dependency on mechanical ventilation, renal replacement, or vasopressors	Both assessed at 28 days
Secondary	Number of participants with persistent organ dysfunction-free days in intensive care unit	Persistent organ dysfunction-free days in intensive care unit	Up to day 28
Secondary	Number of participants deceased at 6 months	Mortality at 6 months	6 months
Secondary	Score of health related quality of life in 6-month survivors	Assessed by the questionnaire EuroQol-5D (EQ-5D-5L). The EQ-5D-5L essentially consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS).; The descriptive system comprises five 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 his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five 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 analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'.	6 months
Secondary	Global tissue dysoxia	Assessed by serum lactate concentration	Days 1, 3, 7
Secondary	Organ function (including renal 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 6 different sub-scores, one each for the respiratory (PaO2/FiO2 mmHg), cardiovascular (mean arterial pressure OR administration of vasopressors required), hepatic (liver bilirubin (mg/dl) [µmol/L]), coagulation (platelets×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
Secondary	Rate of inflammation	Assessed by interleukin-1 beta (IL-1ß), tumor necrosis factor-alpha (TNF-a), C-reactive protein (CRP).	Days 1, 3, 7
Secondary	Rate of infection	Assessed by procalcitonin (PCT)	Days 1, 3, 7
Secondary	Rate of endothelial injury	Assessed by thrombomodulin (TM) and angiopoietin-2 (ANG-2)	Days 1, 3, 7
Secondary	Occurrence of stage 3 acute kidney injury	Assessed by KDIGO (Kidney Disease: Improving Global Outcomes) criteria	Up to day 28
Secondary	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: - 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
Secondary	Hypoglycemia	Core lab-validated glucose level of less than 3.8 mmol/L	During the time participants receive the 16 doses of the investigational product and the 7 days following the last dose
Secondary	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)
Secondary	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)
Secondary	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)