Purpose of trial:

Primary purpose is to test the feasibility of the study ( proportion of patients that adhere to study protocol, ability to enroll patients , monthly recruitment etc.). The secondary purpose is to test the effectiveness of vitamin C for patients with sepsis. 

Background:

Sepsis is characterized by a dysregulated immune and microvascular response to infection; current therapy emphasizes antibiotics and supportive care for organ dysfunction. In septic humans, vitamin C levels are low and are associated with multiple defects in cellular, immunological, and endothelial function, along with increased mortality. Intravenous vitamin C restores immunological and microvascular function in animal models of sepsis. A 2017 single-centre before-after study suggested that high-dose intravenous Vitamin C is associated with a very large reduction in mortality. Recently, a phase 2 trial of Vitamin C in Sepsis with Acute Lung Injury, showed no difference in the co-primary outcoof change in organ dysfunction score or inflammatory markers. In secondary outcomes, the authors showed a large reduction in mortality; however, this was one of 46 other secondary outcomes and there was no adjustment for multiplicity, thus strongly rendering this result susceptible to an inflated type 1 error. A systematic review of trials of all vitamin C therapies in critical illness shows no treatment effect, but confidence intervals are wide, and the quality of evidence is low.

Objective:

We propose a pilot feasibility randomized controlled trial (RCT) in India as a closely related study to the multi-centre International RCT of Vitamin C in sepsis (the LOVIT multi-centre study). The larger international trial will aim to ascertain the effect of high-dose intravenous vitamin C, compared to placebo, on mortality or persistent organ dysfunction at 28 days in septic ICU patients. Our trial, limited to a single centre in India, will primarily focus on feasibility outcomes such as the number of patients enrolled per month and the proportion of patients that adhere to study protocol. Mortality and persistent organ dysfunction at 28 days will be recorded as secondary outcomes. We hypothesize that this trial will meet feasibility targets in India (1 patient enrolled per month and >90% of all study drug doses administered as prescribed).

Methods:

Main eligibility criteria:

1) patients ≥ 18 years old;

2) admitted to the ICU with proven or suspected infection as the main diagnosis;

3) currently treated with a continuous intravenous infusion of vasopressors; and

Interventions:
After informed consent (from patient or substitute decision-maker), patients will be randomly assigned to vitamin C (intravenous, 50 mg/kg every 6h) vs. placebo for 96 hours.

Outcomes:

The primary outcome will be the proportion of patients that adhere to study protocol (i.e. proportion of patients who received all doses of study drug as prescribed).

Secondary outcomes will include number of patients enrolled per month, extent of contamination (i.e. proportion of patients that receive open label Vitamin C in either group during the ICU stay) and a validated composite of death or persistent organ dysfunction – defined as continued dependency on mechanical ventilation, renal replacement therapy, or vasopressors – assessed at 28 days. Secondary outcomes will also include the 6-month mortality and health-related quality of life

Publication details: Study will be published in peer reviewed journals and presented at national and international scientific meetings. 

Sample size:

The International LOVIT trial aims to enrol 800 patients in 25 ICUs in Canada, Europe and India which will provide 80% power to detect a 10% absolute difference in the primary outcome, assuming a control group event rate of 50%. In India, we will aim to enrol up to 100 patients over a 36-month period from Apollo Main Hospital, Greams Road, Chennai.

Mitigating risk of bias:

Risk of bias will be minimized by allocation concealment; blinding of patients, caregivers, and outcomes assessors; complete follow-up; and strict adherence to the intention-to-treat principle.

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, this trial will constitute a trustworthy assessment of the effect of vitamin C alone on patient-important outcomes.Specific to India, the burden of sepsis is large and mortality rates are as high as 60%. Some of the key drivers of the high mortality in this region are the high prevalence of infections caused by multi-drug resistant pathogens, tropical infections and challenges around health care access, awareness and affordability. LOVIT-India will be the only RCT of intravenous vitamin C in sepsis in India and the only RCT of intravenous vitamin C alone in any low- or middle-income country (LMIC). This trial would also pave the way for future collaborations in testing interventions in the field of critical care in India and other LMICs in the region.