Vitamin C, Thiamine, and Steroids in Sepsis

Sepsis is an inflammatory syndrome with life threatening organ dysfunction resulting from a
dysregulated host response to infection. The global burden is estimated to exceed 15 million
cases annually. In the United States, the incidence is increasing and currently there are
more 1,750,000 cases each year, with more than half requiring intensive care unit (ICU)
admission. Further, sepsis cases account for 30%- 50% of all hospital deaths, making it the
3rd leading cause of death in the United States, and is the most expensive reason for
hospitalization with annual expenditures exceeding $20 billion. Notably, even among those
that do survive, many endure significant reductions in physical, emotional and cognitive
quality of life. New therapeutic approaches to reduce the high morbidity and mortality of
sepsis are needed.

Current management strategies focus on early aggressive fluid resuscitation, blood pressure
support with vasopressors, early appropriate antibiotics, and the identification and control
of infected sites. Though outcomes have improved with the bundled deployment of these
strategies, mortality remains high at 20 - 30%. Despite over a hundred phase 2 and phase 3
clinical trials of pharmacological agents with the potential to improve sepsis outcomes, only
antibiotics have demonstrated reproducible benefits.

The purpose of the current study is therefore to determine (or confirm) the efficacy of the
combination therapy consisting of vitamin C, thiamine, and corticosteroids in the management
of patients with circulatory and/or respiratory dysfunction resulting from sepsis. This
subset of sepsis patients has been chosen because they are easily identified, have a high
mortality, and consume significant critical care resources. As such, any improvements in
outcomes attributed to effective therapies would be of great value to patients, as well as
their care providers and healthcare systems. Further, because the promulgated therapies are
composed of three inexpensive and readily available drugs, its efficacy would have important
implications the management of sepsis in both well and poorly resourced settings worldwide.

The VItamin C, Thiamine And Steroids in Sepsis (VICTAS) Study is a double-blind,
placebo-controlled, adaptive randomized clinical trial designed to investigate the efficacy
of the combined use of vitamin C, thiamine and corticosteroids (the Treatment Protocol)
versus indistinguishable placebos (the Control Protocol) for patients with sepsis. The trial
will enroll up to 2000 participant and employs a novel endpoint that approximates a patient's
risk of death based on the time spent on vasopressors or receiving respiratory support. Time
spent on vasopressors or receiving respiratory support captures a patient's speed of
recovery. Mortality rate is a key secondary endpoint for the trial.

Specific Aims

1. To demonstrate the efficacy of combination therapy using vitamin C, thiamine and
corticosteroids to reduce the duration of cardiovascular and respiratory organ
dysfunction in critically ill patients with sepsis.

2. To demonstrate the efficacy of combination therapy using vitamin C, thiamine and
corticosteroids to reduce 30-day mortality in critically ill patients with sepsis.

Explicit subject consent for participation in long term telephone follow-up will be sought
for all patients at all sites. Participation in long term outcome assessments is not required
for participation in other aspects of the VICTAS study, i.e., patients may individually opt
out of this portion of the study. In these participants a diverse array of neurocognitive
outcomes will be assessed approximately 6 months after patient discharge. Evaluations will be
done using a specially-designed battery of tests that evaluates key aspects of functioning
and behavior and will be administered via phone by the Vanderbilt Long-Term Outcomes team,
which will serve as the coordinating center for these follow-up assessments. The battery,
which takes about 40 minutes to complete, will assess cognition, mental health, quality of
life, and employment - all of which have been shown to be adversely affected in between one
third and two thirds of survivors of sepsis.

Inclusion Criteria:

- Suspected or confirmed infection as evidenced by ordering of blood cultures and
administration of at least one antimicrobial agent

- Acute respiratory or cardiovascular organ dysfunction attributed to sepsis as
evidenced by at least one of the following requirements:

1. Vasopressor Requirement - Continuous infusion of norepinephrine, epinephrine,
vasopressin, dopamine, phenylephrine or other vasopressor agents at any dose for
greater than 1 hour and required to maintain a mean arterial pressure ≥ 65 mm Hg
despite intravenous crystalloid infusion of at least 1000cc

2. Respiratory Support Requirement - Acute hypoxemic respiratory failure defined as
persistent hypoxemia ( partial pressure of arterial oxygen (PaO2)/fraction of
inspired oxygen (FiO2) ≤ 300 or blood oxygen saturation (SpO2)/FiO2 ≤ 315)
requiring (1) intubation and mechanical ventilation, or (2) positive pressure
ventilation via tight-fitting face mask (i.e. continuous positive airway pressure
(CPAP) or bilevel positive airway pressure (BiPAP) or (3) high flow nasal cannula
≥ 45 liter per minute (LPM) flow and FiO2 ≥ 0.40

- Anticipated or confirmed intensive care unit (ICU) admission

Exclusion Criteria:

- Organ dysfunction present > 24 hours at time of enrollment

- Limitations of care (defined as refusal of cardiovascular and respiratory support
modes described in inclusion criteria 7.1.b) including "do not intubate" (DNI) status

- Current hospitalization > 30 days at time of randomization

- Chronic hypoxemia requiring supplemental non-invasive oxygen (nasal cannula or NIPPV)
or home mechanical ventilation

- Chronic cardiovascular failure requiring home mechanical hemodynamic support (e.g.,
LVAD) or home chemical hemodynamic support (e.g., milrinone)

- Known allergy or contraindication to vitamin C, thiamine, and/or corticosteroids
(including previously or currently diagnosed primary hyperoxaluria and/or oxalate
nephropathy, or nown/suspected ethylene glycol ingestion, or known glucose-6-phosphate
dehydrogenase (G6PD) deficiency)

- Currently receiving intravenous vitamin C as a treatment for sepsis OR any dose of
vitamin C exceeding 1 gram daily

- Chronic disease/illness that, in the opinion of the site investigator, have an
expected lifespan of < 30 days unrelated to current sepsis diagnosis (e.g., stage IV
malignancy, neurodegenerative disease, etc.)

- Pregnancy or known active breastfeeding

- Prisoner or Incarceration

- Current participation in another interventional pharmaceutical research study for
sepsis

- Inability or unwillingness of subject or legal surrogate/representative to give
written informed consent