Lessening Organ Dysfunction With VITamin C (LOVIT)

• ClinicalTrials.gov Identifier: NCT03680274
• Recruitment Status: Recruiting
• First Posted: September 21, 2018
• Last Update Posted: December 31, 2020
• Sponsor: Université de Sherbrooke
• Collaborator: Lotte & John Hecht Memorial Foundation
• Information provided by (Responsible Party): François Lamontagne, Université de Sherbrooke

Tracking Information

• First Submitted Date: September 19, 2018
• First Posted Date: September 21, 2018
• Last Update Posted Date: December 31, 2020
• Actual Study Start Date: November 8, 2018
• Estimated Primary Completion Date: December 31, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 24, 2018)

Number of deceased participants or with persistent organ dysfunction [ Time Frame: Both assessed at 28 days ]

Defined as death or dependency on mechanical ventilation, renal replacement, or vasopressors

Original Primary Outcome Measures (submitted: September 20, 2018)

Death or persistent organ dysfunction [ Time Frame: Both assessed at 28 days ]

Defined as dependency on mechanical ventilation, renal replacement, or vasopressors

Current Secondary Outcome Measures (submitted: November 7, 2019)

• Number of participants with persistent organ dysfunction-free days in intensive care unit [ Time Frame: Up to day 28 ]
  Persistent organ dysfunction-free days in intensive care unit
• Number of participants deceased at 6 months [ Time Frame: 6 months ]
  Mortality at 6 months
• Score of health related quality of life in 6-month survivors [ Time Frame: 6 months ]
  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'.
• Global tissue dysoxia [ Time Frame: Days 1, 3, 7 ]
  Assessed by serum lactate concentration
• Organ function (including renal function) [ Time Frame: Days 1, 2, 3, 4, 7, 10, 14, 28 ]
  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 eah system ranges from 0 (best) to +4 (worst).
• Rate of inflammation [ Time Frame: Days 1, 3, 7 ]
  Assessed by interleukin-1 beta (IL-1ß), tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP)
• Rate of infection [ Time Frame: Days 1, 3, 7 ]
  Assessed by procalcitonin (PCT)
• Rate of endothelial injury [ Time Frame: Days 1, 3, 7 ]
  Assessed by thrombomodulin (TM) and angiopoietin-2 (ANG-2)
• Occurrence of stage 3 acute kidney injury [ Time Frame: Up to day 28 ]
  Assessed by KDIGO (Kidney Disease: Improving Global Outcomes) criteria
• Acute hemolysis [ Time Frame: Up to day 28 ]
  • 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
• Hypoglycemia [ Time Frame: During the time participants receive the 16 doses of the investigational product and the 7 days following the last dose ]
  Core lab-validated glucose level of less than 3.8 mmol/L
• Vitamin C volume of distribution [ Time Frame: 6th dose of vitamin C (second dose on day 2) 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) ]
  Assessed by chromatography-tandem mass spectrometry
• Vitamin C clearance [ Time Frame: 6th dose of vitamin C (second dose on day 2) 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) ]
  Assessed by chromatography-tandem mass spectrometry
• Vitamin C plasma concentration [ Time Frame: 6th dose of vitamin C (second dose on day 2) 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) ]
  Assessed by chromatography-tandem mass spectrometry

Original Secondary Outcome Measures (submitted: September 20, 2018)

• Persistent organ dysfunction-free days in intensive care unit [ Time Frame: Up to day 28 ]
  Persistent organ dysfunction-free days in intensive care unit
• Mortality at 6 months [ Time Frame: 6 months ]
  Mortality at 6 months
• Health related quality of life in 6-month survivors: EQ-5D [ Time Frame: 6 months ]
  Assessed by the questionnaire EuroQol-5D (EQ-5D)
• Global tissue dysoxia [ Time Frame: Days 1, 3, 7 ]
  Assessed by serum lactate concentration
• Organ function (including renal function) [ Time Frame: Days 1, 2, 3, 4, 7, 10, 14, 28 ]
  Assessed by the SOFA score
• Inflammation [ Time Frame: Days 1, 3, 7 ]
  Assessed by interleukin-1 beta (IL-1ß), tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP)
• Infection [ Time Frame: Days 1, 3, 7 ]
  Assessed by procalcitonin (PCT)
• Endothelial injury [ Time Frame: Days 1, 3, 7 ]
  Assessed by thrombomodulin (TM) and angiopoietin-2 (ANG-2)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Lessening Organ Dysfunction With VITamin C
• Official Title: Lessening Organ Dysfunction With VITamin C (LOVIT)
• Brief 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.

Detailed 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 6th dose (second dose on day 2) 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

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

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

Study Arms

• Experimental: Vitamin C
  Vitamin C: 50 mg/kg every 6 hours for 96 hours.
  Intervention: Drug: Vitamin C
• Placebo Comparator: Control
  Dextrose 5% in water (D5W) or normal saline (0.9% NaCl) in a volume to match the vitamin C.
  Intervention: Other: Control

• Publications *: Masse MH, Ménard J, Sprague S, Battista MC, Cook DJ, Guyatt GH, Heyland DK, Kanji S, Pinto R, Day AG, Cohen D, Annane D, McGuinness S, Parke R, Carr A, Arabi Y, Vijayaraghavan BKT, D'Aragon F, Carbonneau É, Maslove D, Hunt M, Rochwerg B, Millen T, Chassé M, Lebrasseur M, Archambault P, Deblois E, Drouin C, Lellouche F, Lizotte P, Watpool I, Porteous R, Clarke F, Marinoff N, Belley-Côté É, Bolduc B, Walker S, Iazzetta J, Adhikari NKJ, Lamontagne F; Canadian Critical Care Trials Group. Lessening Organ dysfunction with VITamin C (LOVIT): protocol for a randomized controlled trial. Trials. 2020 Jan 8;21(1):42. doi: 10.1186/s13063-019-3834-1.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 20, 2018): 800
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2022
• Estimated Primary Completion Date: December 31, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Marie-Helene Masse; 819-346-1110 ext 14173; marie-helene.masse3@usherbrooke.ca

Contact: Marie-Claude Battista, PhD; 819-346-1110 ext 12480; marie-claude.battista@usherbrooke.ca

• Listed Location Countries: Canada

Administrative Information

• NCT Number: NCT03680274
• Other Study ID Numbers: MP-31-2019-2945
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Responsible Party: François Lamontagne, Université de Sherbrooke
• Study Sponsor: Université de Sherbrooke
• Collaborators: Lotte & John Hecht Memorial Foundation

Investigators

• Principal Investigator: François Lamontagne, MD FRCPC MSc; Université de Sherbrooke and CIUSSS de l'Estrie - CHUS
• Principal Investigator: Neill Adhikari, MDCM FRCPC MSc; Sunnybrook Health Sciences Centre, University of Toronto

• PRS Account: Université de Sherbrooke
• Verification Date: December 2020