Lessening Organ Dysfunction with VITamin C (LOVIT)

The LOVIT and LOVIT-COVID Trials are coordinated by the Unité de Recherche Clinique et Épidémiologique (URCE) of the CIUSSS de l'Estrie-CHUS.

Access the LOVIT and LOVIT-COVID Resource Centre (restricted access)

The LOVIT Trial is a multicentre concealed-allocation parallel-group blinded randomized controlled trial to ascertain the effect of high-dose intravenous vitamin C compared to plac

ebo on mortality or persistent organ dysfunction at 28 days in septic intensive care unit patients.

The principal investigators of the LOVIT Trial are Dr. François Lamontagne and Dr. Neill Adhikari.

This study is centrally coordinated by the Unité de Recherche Clinique et Épidémiologique (URCE) at the Research Center of the Centre Hospitalier Universitaire de Sherbrooke (CRCHUS), Sherbrooke, QC, Canada.

This trial was conducted in 35 sites in Canada, New Zealand and France and enrolled 872 patients. The first LOVIT patient was enrolled on November 14, 2018 and the last patient was enrolled on July 19, 2021. We completed the final 6-month follow-up on January 24, 2022.

We would like to thank the investigators, health care professionals, research and laboratory personnel, study and data coordinators, and the patients and their caregivers who participated in this trial.

The results of the LOVIT trial were presented at the Critical Care Reviews meeting in Belfast on June 15, 2022, and the manuscript was simultaneously published in the New England Journal of Medicine. An updated systematic review was also published in NEJM Evidence (see Relevant Publications).

The study showed that participants in the vitamin C group had a higher risk of death or persistent organ dysfunction at 28 days, compared to participants who received placebo. At day 28, 191 of 429 participants (44.5%) in the vitamin C group had died or had persistent organ dysfunction, as compared with 167 of 434 participants (38.5%) in the placebo group.

Two other studies on the effects of vitamin C in patients with sepsis are in progress: LOVIT India: The Indian Lessening Organ dysfunction with VITamin C in sepsis (PI: Bharath Kumar Tirupakuzhi Vijayaraghavan, India) and LOVIT ARDS: Lessening Organ Dysfunction with VITamin C in septic ARDS (PI: Djillali Annane, France). These are independent trials.

An Individual Patient Data Meta-Analysis (IPDMA) is coming soon.

Lessening Organ Dysfunction with VITamin C - COVID-19 (LOVIT-COVID)

The LOVIT-COVID Trial 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 patients with COVID-19, in the hospital either on a medical ward or in the intensive care unit.

The principal investigators of the LOVIT-COVID Trial are Dr. François Lamontagne and Dr. Neill Adhikari.

This trial is conducted in 15 sites in Canada. Recruitment is currently on pause.

Background
Treatment options for sepsis are limited to antimicrobials and supportive care (intravenous fluids, vasopressors, mechanical ventilation and renal replacement therapy). Recent preliminary evidence suggests that intravenous vitamin C may be the first therapy to mitigate the dysregulated cascade of events transforming an infection into sepsis. However, definitive practice changing evidence requires a large trial powered to detect a plausible, modest, and clinically important difference in mortality.

Primary Outcome
Death or persistent organ dysfunction (defined as continued dependency on mechanical ventilation, renal replacement therapy, or vasopressors) at 28 days.

Secondary Outcomes
- Mortality and health-related quality of life at 6 months.
- Daily organ function (SOFA score days 1, 2, 3, 4, 7, 10, 14, and 28).
- Global tissue dysoxia, biomarkers for inflammation, infection, and endothelial injury on days 1, 3, 7.
- Occurrence of stage 3 acute kidney injury as defined by KDIGO criteria;
- Acute hemolysis as defined by:
- 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;
▪ 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.
- Hypoglycemia as defined by core lab-validated glucose levels of less than < 3.8 mmol/L.

Study design
Parallel blinded randomized controlled trial.

Inclusion Criteria
· Patients ≥18 years old
· Admitted to ICU with proven or suspected infection as the main diagnosis
· Currently treated with a continuous intravenous infusion of vasopressors (norepinephrine, epinephrine, vasopressin, dopamine, phenylephrine).

Exclusion Criteria
·   > 24 hours of intensive care unit (ICU) admission
·   Known Glucose-6-phosphate dehydrogenase (G6PD) deficiency
·   Pregnancy
·   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).

Study Intervention
Experimental arm: vitamin C 50 mg/kg every 6 hours for 96 hours.
Control arm: placebo (0.9% NaCl or dextrose 5% in water).

Randomization
Web-based randomization system available 24/7. Eligible patients will be randomized in a 1:1 ratio to vitamin C or matching placebo. We will use permuted blocks of undisclosed and variable size and stratify randomization by site.

Sample Size
We will enroll a total of at least 800 patients. Sites are expected to enroll at least 1 patient per month.

Follow-up
Daily during ICU stay and telephone follow-up at 6 months.

Background
The COVID-19 pandemic began on 11 March 2020. There is no specific treatment. Vitamin C may mitigate the inflammatory response associated with COVID-19.

Objective
To compare the effect of high-dose intravenous vitamin C vs. placebo on a composite of death or persistent organ dysfunction – defined as dependency on mechanical ventilation, new renal replacement therapy, or vasopressors – assessed at 28 days.

Primary Outcome
Death or persistent organ dysfunction (defined as continued
dependency on mechanical ventilation, new renal replacement
therapy, or vasopressors) at 28 days

Secondary Outcomes

Number of whole and part study days for which the patient is alive and not admitted to an ICU up until the end of study day 21;
Persistent organ dysfunction-free days in ICU, up to day 28;
Mortality and health-related quality of life at 6 months;
Daily organ function (SOFA score days 1, 2, 3, 4, 7, 10, 14, and 28);
Global tissue dysoxia, biomarkers for inflammation, infection, and endothelial injury on days 1, 3, 7;
Occurrence of stage 3 acute kidney injury as defined by KDIGO criteria;
Acute hemolysis;
Hypoglycemia, as defined by core lab-validated glucose level <3.8 mmol/L.

Study Design
Parallel-group allocation-concealed blinded randomized controlled trial.

Inclusion Criteria

Patients ≥18 years old;
Confirmed diagnosis of COVID-19;
Admitted to a hospital (e.g. ward or intensive care unit (ICU)).

Exclusion Criteria

Receiving or have received vasopressors during current hospital admission;
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).

Randomization
Web-based randomization system available 24/7. Eligible patients will be randomized in a 1:1 ratio to vitamin C or matching placebo. We will use permuted blocks of undisclosed and variable size and stratify randomization by site.

Study Intervention
Experimental arm: vitamin C 50 mg/kg every 6 hours for 96 hours. Control arm: placebo.

Follow-up
Daily during hospital stay and telephone follow-up at 6 months. Sample Size Up to 800 patients.

Vitamin C Population Pharmacokinetic Substudy

The objective of this substudy is 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.

Three centers will participate in this substudy.At these centers, 100 consecutive consenting patients (i.e. distinct consent form) enrolled and randomized to either arm will participate by contributing serial blood samples for plasma vitamin C measurement. Plasma concentrations will be modeled over time using a population PK approach.

Each patient (in either arm) will provide serial blood samples that will be obtained by the bedside nurse or research coordinator at prespecified times for quantification of vitamin C in whole blood. Blood samples will be drawn around the 6th dose (second dose on day 2) at time 0 (immediately prior to the dose) and then after administration at times 1h, 2h, 4h and 6h (the 6h level will be immediately prior to the next dose). Therefore, each patient will provide 5 blood samples in addition to those required by the LOVIT protocol.

Sterring Committee Members

The SC is co-chaired by Dr. François Lamontagne (Co-Principal Investigator, Université de Sherbrooke) and by Dr. Neill Adhikari (Co-Principal Investigator, University of Toronto).

In addition to the two Chairs, the SC will include the following members:

Marie-Claude Battista (Director of the Unité de recherche clinique et épidémiologique, Research Center of the Centre hospitalier universitaire de Sherbooke, Sherbrooke, QC, Canada)

Dian Cohen (Patient representative, Hatley, QC, Canada)

Dr. Deborah Cook (McMaster University, Hamilton, ON, Canada)

Andrew Day (Biostatistician, Queen’s University, Kingston, ON, Canada)

Dr. Gordon Guyatt (McMaster University, Hamilton, ON, Canada)

Dr. Daren Heyland (Queen’s University, Kingston, ON Canada)

Salmaan Kanji (Clinical Pharmacy Specialist-Critical Care, University of Ottawa, ON, Canada)

Ruxandra Pinto (Biotatistician, Sunnybrook Health Sciences Centre, Toronto, ON, Canada)

Marie-Hélène Masse (Project Leader, Unité de recherche clinique et épidémiologique, Research Center of the Centre hospitalier universitaire de Sherbooke, Sherbrooke, QC, Canada)

Julie Ménard (Co-project Leader, Unité de recherche clinique et épidémiologique, Research Center of the Centre hospitalier universitaire de Sherbooke, Sherbrooke, QC, Canada)

Sheila Sprague (Senior Project Leader, McMaster University, Hamilton, ON, Canada)

Data Safety Monitoring Board Members

Dr. Andreas Laupacis (Li Ka Shing Knowledge Institute, Toronto, ON, Canada)

Dr. Lauren Griffith (McMaster University, Hamilton, ON, Canada)

Dr. Scott Halpern (University of Pennsylvania, PA, USA)

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 and LOVIT-COVID Trials will constitute a trustworthy assessment of the effect of vitamin C alone on patient-important outcomes.

The eligibility criteria are simple and pragmatic: all patients admitted to the ICU with proven or suspected infection as the main who are receiving vasopressor therapy.

The randomization system is accessible 24/7 on Internet and bags can be prepared in advance to allow off-business hours randomization.

The intervention is easy to implement: participants receive vitamin C or placebo every 6 hours for 96 hours.

The safety profile for vitamin C is remarkably favourable.

All co-interventions are at the discretion of the treating team.

Blood and urine samples are collected only on days 1, 3, and 7 and will coincide with routine urine and blood testing.

Study participants will be involved by being asked about their quality of life at 6 months.

If vitamin C is proven to be effective, it is likely to be used worldwide and improve outcomes globally, given low cost and ease of administration.
The LOVIT and LOVIT-COVID Coordinating Centre team is highly supportive and responsive to your needs and suggestions!

LOVIT

INSTITUTION	# of rand.
CIUSSS de l'Estrie CHUS	204
Kingston General Hospital	46
Institut Universitaire de Cardiologie et Pneumologie de Québec	7
CIUSSS de Chaudière-Appalaches (Hôtel-Dieu de Lévis)	15
Centre Hospitalier de l'Université de Montréal	25
Juravinski Hospital	100
Hamilton General Hospital	41
Hôpital Maisonneuve-Rosemont	2
CIUSSS Mauricie-Centre-du-Québec	5
Centre Universitaire de Santé McGill - Hôpital Royal Victoria	6
Centre Universitaire de Santé McGill - Hôpital Général de Montréal	1
Ottawa Hospital Research Institute - Ottawa General Hospital	89
Ottawa Hospital Research Institute - Ottawa Civic Hospital	39
University of Alberta	9
St. Joseph's Healthcare, Hamilton	30
Hôpital du Sacré-Coeur de Montréal	5
Sunnybrook Health Sciences Centre	81
Vancouver Island Health Authority	10
Mount Sinai Hospital	15
Royal Alexandra Hospital	12
CHU de Québec - Université Laval	15
London Health Sciences Centre	7
Oakville Trafalgar Memorial Hospital	4
Vitalite Health Network - New Brunswick	7
University Health Network, Toronto	2
Niagara Health	-
Aukland City Hospital - General ICU (NZ)	19
Rotorua Hospital (NZ)	22
Christchurch Hospital (NZ)	11
Wellington Hospital (NZ)	12
Auckland City Hospital (CVICU) Team (NZ)	7
Tauranga Hospital (NZ)	6
Waikato Hospital (NZ)	2
Dunedin Hospital (NZ)	7
Hôpital Raymond-Poicarré (FR)	8
l'Hôpital Lariboisière (FR)	-
l'Hôpital Henri-Mondor (FR)	1
Apollo Hospital (Chennai, India)	11

LOVIT-COVID
Sites actively recruiting

INSTITUTION	# of rand.
CIUSSS de l'Estrie CHUS	115
Royal Alexandra Hospital	5
Sunnybrook Health Sciences Centre	133
Centre Hospitalier de l'Université de Montréal	5
St. Joseph's Healthcare, Hamilton	46
CHU de Québec - Université Laval	16
Hamilton General Hospital	14
Niagara Health	28
Royal Victoria Regional Health Centre	9
Ottawa Hospital Research Institute - Ottawa General Hospital	14
Ottawa Hospital Research Institute - Ottawa Civic Hospital	4
Oakville Trafalgar Memorial Hospital	-
Juravinski Hospital	3

Relevant Publications

Below you will find relevant publications for the LOVIT Trial:

V itamin C for the critically ill: Is the evidence strong enough?

Vitamin C Supplementation in the Critically Ill: A Systematic Review and Meta-Analysis

Aministration of Intravenous Ascorbic Acid-Practical Considerations for Clinicians

Lessening Organ dysfunction with VITamin C (LOVIT): protocol for a randomized controlled trial

Lessening Organ Dysfunction With Vitamin C (LOVIT) Trial: Statistical Analysis Plan

Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit

High-dose vitamin-C induced prolonged factitious hyperglycemia in a peritoneal dialysis patient: a case report

Parenteral Vitamin C in Patients with Severe Infection: A Systematic Review

IV Vitamin C in Adults With Sepsis: A Bayesian Reanalysis of a Randomized Controlled Trial

A Pilot Feasibility Randomized Controlled Trial of Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit: The Lessening Organ Dysfunction with Vitamin C-India (LOVIT-India) Trial (in press)

Intravenous Vitamin C for Patients Hospitalized With COVID-19: Two Harmonized Randomized Clinical Trials

LOVIT_Newsletter_Vol 3- Issue 4 - 18-MAY-2021

LOVIT Newsletter_Vol 3-Issue 5 - 21-JUN-2021

LOVIT Newsletter Vol 3-Issue 6 - JULY 22-2021

LOVIT Newsletter Vol 3 - Issue 7 - 08-SEP-2021

LOVIT Newsletter Vol 3 - Special Issue - 09-SEP-2021

LOVIT-COVID Newsletter Vol 4 - Issue 1 - 14-APR-2022

LOVIT Newsletter Vol 4 - Special Edition - 14-APR-2022

LOVIT Newsletter Vol 4 - Issue 2 - 15-JUN-2022

Question: Can we randomize a patient admitted to ICU (who received or not vasopressors initially) and who was discharged and then readmitted?
Answer: He cannot be randomized. It must be his 1st ICU admission during this hospital stay.

Question: Are patients with COVID-19 (suspected of or confirmed) eligible to participate in LOVIT?
Answer: Yes, patient with sepsis from bacterial or viral (influenza, COVID-19) source are eligible.

Question: Is the dose of vitamin C received by participants in the LOVIT Trial bigger than in cancer trials?
Answer: The dose of vitamin C received by participants in the LOVIT Trial is less than the one received by participants in cancer trials.

Question: Can patients with acute kidney injury participate in LOVIT?
Answer: Patients can participate as acute kidney injury is not an exclusion criteria.

Question: How can we be sure that the participant receives all the dose of the Investigation Product including what is in the tubing?
Answer: Do what you usually do to flush the line as long as it is always done the same way (ex: IP bag can be installed higher than the bag containing solute).

Question: How many vials of vitamin C will be reimbursed?
Answer: Only vials of vitamin C used for each participant assigned to vitamin C group will be reimbursed.

Question: What are the recommendations to handle and process the samples of a patient with COVID-19 suspected or confirmed?
Answer: Institutional instructions must me followed first but the World Health Organization recommends to manipulate the samples in a confinement room of level 2.

Question: Patient is admitted for sepsis but no vasoppressors are required. Few hours later, patient needs to be sedated and then requires vasopressor infusion. Is this patient eligible if he didn't reach the 24 hours of admission?
Answer: Yes, this patient is eligible even if the vasopressors weren't started before sedation. This patient must still be on vasopressors at time of randomization.

Statstrip Glucometers and error #9:

Two sites experienced a problem with the Statstrip Xpress glucometer having an error #9. This error means that there is something in the blood sample that does not allow the device to measure the glucose value. We invite you to report this kind or error on Form 7— Adverse Event. All problems will be reported to the company which provided us the glucometers.

Clinical Trials (NCT03680274)

www.clinicaltrials.gov

Unité de Recherche Clinique et Épidémiologique

LOVIT and LOVIT-COVID Team

Sort by: Last Name Position

Dr. François Lamontagne Department of Internal Medicine, Université de Sherbrooke Contact Info CIUSSS de l'Estrie-CHUS3001 12e avenue N.Sherbrooke, QC J1H 5N4 francois.lamontagne@usherbrooke.ca

Dr. Neill KJ Adhikari Department of Critical Care Medicine, Sunnybrook Health Sciences Centre Contact Info University of Toronto 2075 Bayview Ave Toronto, ON M4N 3N5 neill.adhikari@sunnybrook.ca

Marie-Hélène Masse Project Leader, Centre de recherche CIUSSS de l'Estrie - CHUS Contact Info Université de Sherbrooke 3001, 12e Avenue N Sherbrooke, QC J1H 5N4 marie-helene.masse.ciussse-chus@ssss.gouv.qc.ca

Julie Ménard PhD Co-Project Leader, Centre de recherche CIUSSS de l'Estrie - CHUS Contact Info Université de Sherbrooke 3001, 12e Avenue N Sherbrooke, QC J1H 5N4

Sheila Sprague PhD Senior Project Leader, Associate Professor Department of Clinical Epidemiology and Biostatistics Contact Info McMaster University 1280, Main Street West Hamilton, Ontario, L8S 4K1 sprags@mcmaster.ca

Marie-Claude Battista PhD Operational Manager, Unité de Recherche Clinique et Épidémiologique (URCE) Centre de recherche CIUSSS de l'Estrie - CHUS Contact Info Université de Sherbrooke 3001, 12 Avenue N Sherbrooke, QC, J1H 5N4 marie-claude.battista@usherbrooke.ca

Contact

If you have any ideas or suggestions about information that you would find helpful to see on this website, please contact one of our Project Leaders:

Marie-Hélène Masse
Julie Ménard
Sheila Sprague

Principal Investigators
Dr. François Lamontagne
Dr. Neill Adhikari

Thanks to all Participating Centres and collaborators for engaging in this research program!

Thanks to the CCCTG for endorsing this research project.

Lessening Organ Dysfunction with VITamin C (LOVIT)

Lessening Organ Dysfunction with VITamin C - COVID-19 (LOVIT-COVID)

Study overview LOVIT

Study overview LOVIT-COVID

Substudies

Vitamin C Population Pharmacokinetic Substudy

Steering Committee and Data Safety Monitoring Board

Sterring Committee Members

Data Safety Monitoring Board Members

Top 10 reasons to participate in LOVIT and LOVIT-COVID

Participating centre status

Relevant publications

Relevant Publications

Newsletters

Frequently asked questions

External links

LOVIT and LOVIT-COVID Team

Contact