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.

• Vitamin C (Drug), also known as Ascorbic acid: Intravenous vitamin C (1.5 grams every 6 hours) will be administered for 4 days or until ICU discharge.
• Thiamine (Drug), also known as Thiamine hydrochloride: Intravenous thiamine (100 mg every 6 hours) will be administered for 4 days or until ICU discharge.
• Hydrocortisone (Drug), also known as Hydrocortisone sodium succinate: Intravenous hydrocortisone (50 mg every 6 hours) will be administered for 4 days or until ICU discharge.
• Vitamin C Placebo (Drug), also known as Placebo: A placebo to match intravenous vitamin C (1.5 grams every 6 hours) will be administered for 4 days or until ICU discharge.
• Thiamine Placebo (Drug), also known as Placebo: A placebo to match intravenous thiamine (100 mg every 6 hours) will be administered for 4 days or until ICU discharge.
• Hydrocortisone Placebo (Drug), also known as Placebo: A placebo to match intravenous hydrocortisone (50 mg every 6 hours) will be administered for 4 days or until ICU discharge. Steroids will be used when clinically indicated.

Primary outcomes

• Vasopressor and Ventilator-free Days (VVFD) [Up to Day 30]: The primary outcome measure is VVFD in the first 30 days after the start of treatment. The endpoint was recorded to the nearest day. Participants who died are scored zero days, even if there was a period during which the participant was alive and free of vasopressors and mechanical ventilation. Participants who must return to ventilation and/or vasopressors had their counters reset at zero days.

Secondary outcomes

• Mortality at 30 Days [Day 30]: The number of participants who did not survive until Day 30 is compared between study arms.
• Intensive Care Unit (ICU) Mortality [Day 30]: The number of participants who died while in the ICU is compared between study arms.
• Mortality at 180 Days [Day 180]: The number of participants who did not survive until Day 180 is compared between study arms.
• Length of ICU Stay [Day 30]: The number of days that participants were in the ICU is compared between study arms.
• Length of Hospital Stay [Day 30]: The number of days that participants were in the hospital is compared between study arms.
• Digit Span Test Score [Day 180]: The Digit Span Test is used to assesses attention. In the Digit Span Test, participants are read a series of numbers and are asked to repeat them back in the same order. The Digit Span test is scored by the number of digits the participant is able to remember in each test. Higher scores indicate greater ability to pay attention and to remember sequences. The average adult can remember about 7 numbers, plus or minus two, without making an error.
• Number of Participants With Delirium Assessed With the DeliriumTelephone Confusion Assessment Method (CAM) [Day 180]: The Telephone CAM evaluates dementia with 9-items, where additional questions are asked if symptoms are present. Rather than providing a summary score, if participants exhibit signs of a change in mental status which fluctuates and they experience inattention, along with disorganized thinking or altered level of consciousness, delirium is suggested.
• Hayling Test Score [Day 180]: Executive function is assessed with the Hayling Test. The Hayling Test includes two parts of 15 items each where participants complete sentences by providing the missing word. The test is scored as the amount of time it takes, in seconds, to recite a correct response and the appropriateness of the response (in Part 2). Scaled scores range from 1 to 10 where 1 = impaired, 6 = average, and 10 = very superior.
• Controlled Oral Word Association Test (COWAT) Score [Day 180]: Language is assessed with the Controlled Oral Word Association Test (COWAT). Participants generate words beginning with selected letters within 60 seconds. Generating a higher number of words indicates greater language skills.
• Wechsler Memory Scale III - Delayed Recall Logical Memory Score [Day 180]: Memory is assessed with the Logical Memory subtest from the Wechsler Memory Scale III. Participants listened to two short paragraphs and were asked to recall details from each story after 30 minutes. Scores represent the number of correctly remembered details. Total scores range from 0 to 25 with higher scores reflecting better memory.
• Telephone Interview for Cognitive Status (TICS) [Day 180]: The Telephone Interview for Cognitive Status (TICS) is an 11-item instrument assessing orientation. Correct responses to the items are scored in a variety of ways, depending on how much of the response is correct. Total scores range from 0 to 41 with higher scores indicating increased cognitive orientation.
• Wechsler Adult Intelligence Scale (WAIS)-IV Similarities Score [Day 180]: Reasoning is assessed with the WAIS-IV Similarities instrument. Participants were asked to explain how two words are alike. Responses are scored according to how correct they are, with a score of 0 for incorrect answers. After 3 consecutive scores of 0 the survey is stopped. Total raw scores vary depending on the number of word pairs presented. Higher scores indicate better performance. Scores will be compared between study arms.
• Katz Index of Independence in Activities of Daily Living (ADL) Score [Day 180]: Activities of daily living is assessed with the Katz ADL instrument. The Katz ADL has 6 items asking if participants can perform daily tasks independently. Responses are scored as 1 = yes and 0 = no. Total scores range from 0 to 6 with higher scores indicating greater independence.
• Number of Participants Employed [Day 180]: The Employment Questionnaire is a brief measure of the participant's employment history and ability or capacity to work. The number of participants who indicated being employed are presented here.
• Functional Activities Questionnaire (FAQ) Score [Day 180]: Instrumental activities of daily living is assessed with the Functional Activities Questionnaire (FAQ). The FAQ includes 10 items which are scored on a scale from 0 to 3 where 0 = normal and 3 = dependent. Total scores range from 0 to 30 and lower scores indicate that the respondent is able to perform daily activities. A score of 9 (where the person is dependent in 3 activities) is used as a cut-point indicating impairments with functioning.
• Patient-Reported Outcomes Measurement Information System (PROMIS) Depression 6 [Day 180]: Depression is assessed with the PROMIS Depression 6 instrument. This tool includes 6 items with response options on a scale of 1 to 5. Total raw scores range from 6 to 30 with higher scores indicating greater symptoms of depression.
• Posttraumatic Stress Disorder-8 (PTSD-8) Score [Day 180]: Posttraumatic Stress Disorder (PTSD) is assessed with the Posttraumatic Stress Disorder - 8 instrument. The PTSD-8 includes 8 items which are answered on a 4 point scale where 01 = not at all and 3 = all of the time. Total scores range from 0 to 24 where higher scores indicate greater symptoms of PTSD.
• EuroQol, 5 Dimension (EQ-5D) Visual Analog Scale Score [Day 180]: Quality of life is assessed with the Visual Analog Scale of the EuroQol, 5 dimension (EQ-5D) questionnaire. The EQ-5D asks about 5 dimensions of health (mobility, self-care, usual activities, pain, and depression). The questionnaire includes a visual analog scale where respondents rate their current health where 0 = worst health imaginable and 100 = best health imaginable.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Suspected or confirmed infection as evidenced by ordering of blood cultures and administration of at least one antimicrobial agent
* Anticipated or confirmed intensive care unit (ICU) admission
* 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 ≥ 40 liter per minute (LPM) flow and FiO2 ≥ 0.40

Exclusion Criteria:

* Weight < 40 kilograms (kg)
* Prior enrollment in this study
* Qualifying organ dysfunction no longer present at the time subject would be randomized
* Cardiovascular or respiratory organ failure caused by an illness other than sepsis
* First episode of qualifying organ dysfunction during the current emergency department (ED) or ICU admission occurred > 24 hours before the subject could be randomized
* Limitations of care (defined as refusal of cardiovascular and respiratory support modes) 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 known/suspected ethylene glycol ingestion, or known glucose-6-phosphate dehydrogenase (G6PD) deficiency)
* Use of vitamin C at a dose of > 1 gram daily within the 24 hours preceding first episode of qualifying organ dysfunction during a given ED or ICU admission
* 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 research study
* Inability or unwillingness of subject or legal surrogate/representative to give written informed consent

Participant flow

Outcome results

• Vasopressor and Ventilator-free Days (VVFD) (Primary), Median, days: Treatment Protocol 25 (0 to 29); Control Protocol 26 (0 to 28)
• Mortality at 30 Days (Secondary), Count of participants, Participants: Treatment Protocol 56; Control Protocol 60
• Intensive Care Unit (ICU) Mortality (Secondary), Count of participants, Participants: Treatment Protocol 52; Control Protocol 49
• Mortality at 180 Days (Secondary), Count of participants, Participants: Treatment Protocol 102; Control Protocol 94
• Length of ICU Stay (Secondary), Mean, days: Treatment Protocol 6.7 +/- 7.3; Control Protocol 6.4 +/- 6.9
• Length of Hospital Stay (Secondary), Mean, days: Treatment Protocol 12.6 +/- 10; Control Protocol 13.5 +/- 25.7
• Digit Span Test Score (Secondary), Mean, numbers recalled: Treatment Protocol 8.3 +/- 3.1; Control Protocol 9.5 +/- 3.8
• Number of Participants With Delirium Assessed With the DeliriumTelephone Confusion Assessment Method (CAM) (Secondary), Count of participants, Participants: Treatment Protocol 0; Control Protocol 0
• Hayling Test Score (Secondary), Mean, units on a scale: Treatment Protocol 4.2 +/- 1.9; Control Protocol 4.2 +/- 1.8
• Controlled Oral Word Association Test (COWAT) Score (Secondary), Mean, words: Treatment Protocol 40 +/- 11; Control Protocol 40 +/- 11
• Wechsler Memory Scale III - Delayed Recall Logical Memory Score (Secondary), Mean, correct story details: Treatment Protocol 6.9 +/- 2.8; Control Protocol 8.1 +/- 3.2
• Telephone Interview for Cognitive Status (TICS) (Secondary), Mean, score on a scale: Treatment Protocol 30.6 +/- 4.9; Control Protocol 31.2 +/- 5.2
• Wechsler Adult Intelligence Scale (WAIS)-IV Similarities Score (Secondary), Mean, score on a scale: Treatment Protocol 7.7 +/- 3.3; Control Protocol 8.2 +/- 3.2
• Katz Index of Independence in Activities of Daily Living (ADL) Score (Secondary), Mean, score on a scale: Treatment Protocol 2.8 +/- 3.9; Control Protocol 2.4 +/- 3.6
• Number of Participants Employed (Secondary), Count of participants, Participants: Treatment Protocol 17; Control Protocol 25
• Functional Activities Questionnaire (FAQ) Score (Secondary), Mean, score on a scale: Treatment Protocol 9.5 +/- 10.8; Control Protocol 7.7 +/- 9.2
• Patient-Reported Outcomes Measurement Information System (PROMIS) Depression 6 (Secondary), Mean, score on a scale: Treatment Protocol 11.9 +/- 6.3; Control Protocol 11.9 +/- 5.9
• Posttraumatic Stress Disorder-8 (PTSD-8) Score (Secondary), Mean, score on a scale: Treatment Protocol 5.7 +/- 5.8; Control Protocol 5.2 +/- 5.1
• EuroQol, 5 Dimension (EQ-5D) Visual Analog Scale Score (Secondary), Mean, units on a scale: Treatment Protocol 66 +/- 22; Control Protocol 67 +/- 22

Adverse events

Time frame: Adverse events potentially associated with the study treatment and serious adverse events were monitored from the time of randomization up to Day 30. Mortality was recorded from the time of randomization up to Day 180.

Other adverse events by term

• Results publication: Williams Roberson S, Nwosu S, Collar EM, Kiehl AL, Harrison FE, Bastarache J, Wilson JE, Mart MF, Sevransky JE, Ely EW, Lindsell CJ, Jackson JC; VICTAS Investigators. Association of Vitamin C, Thiamine, and Hydrocortisone Infusion With Long-term Cognitive, Psychological, and Functional Outcomes in Sepsis Survivors: A Secondary Analysis of the Vitamin C, Thiamine, and Steroids in Sepsis Randomized Clinical Trial. JAMA Netw Open. 2023 Feb 1;6(2):e230380. doi: 10.1001/jamanetworkopen.2023.0380. PMID 36853612
• Results publication: Sevransky JE, Rothman RE, Hager DN, Bernard GR, Brown SM, Buchman TG, Busse LW, Coopersmith CM, DeWilde C, Ely EW, Eyzaguirre LM, Fowler AA, Gaieski DF, Gong MN, Hall A, Hinson JS, Hooper MH, Kelen GD, Khan A, Levine MA, Lewis RJ, Lindsell CJ, Marlin JS, McGlothlin A, Moore BL, Nugent KL, Nwosu S, Polito CC, Rice TW, Ricketts EP, Rudolph CC, Sanfilippo F, Viele K, Martin GS, Wright DW; VICTAS Investigators. Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial. JAMA. 2021 Feb 23;325(8):742-750. doi: 10.1001/jama.2020.24505. PMID 33620405
• Results publication: Lindsell CJ, McGlothlin A, Nwosu S, Rice TW, Hall A, Bernard GR, Busse LW, Ely EW, Fowler AA, Gaieski DF, Hinson JS, Hooper MH, Jackson JC, Kelen GD, Levine M, Martin GS, Rothman RE, Sevransky JE, Viele K, Wright DW, Hager DN. In response: Letter on update to the Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) protocol. Trials. 2020 Apr 22;21(1):351. doi: 10.1186/s13063-020-04290-6. PMID 32317004
• Results publication: Morgan J. Surviving sepsis and intensive care unit delirium: a remarkable recovery. Lancet Respir Med. 2020 Mar;8(3):241-242. doi: 10.1016/S2213-2600(20)30043-6. Epub 2020 Jan 30. No abstract available. PMID 32007132
• Results publication: Lindsell CJ, McGlothlin A, Nwosu S, Rice TW, Hall A, Bernard GR, Busse LW, Ely EW, Fowler AA, Gaieski DF, Hinson JS, Hooper MH, Jackson JC, Kelen GD, Levine M, Martin GS, Rothman RE, Sevransky JE, Viele K, Wright DW, Hager DN. Update to the Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) protocol: statistical analysis plan for a prospective, multicenter, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial. Trials. 2019 Dec 4;20(1):670. doi: 10.1186/s13063-019-3775-8. PMID 31801567
• Results publication: Hager DN, Hooper MH, Bernard GR, Busse LW, Ely EW, Fowler AA, Gaieski DF, Hall A, Hinson JS, Jackson JC, Kelen GD, Levine M, Lindsell CJ, Malone RE, McGlothlin A, Rothman RE, Viele K, Wright DW, Sevransky JE, Martin GS. The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) Protocol: a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial. Trials. 2019 Apr 5;20(1):197. doi: 10.1186/s13063-019-3254-2. PMID 30953543

• Study Protocol and Statistical Analysis Plan (PDF, 2019-04-22)

• Jonathan Sevransky, MD, MHS, Principal investigator, Emory University