Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS)

A Multi-center, Randomized, Placebo-controlled, Double-blind, Adaptive Clinical Trial of Vitamin C, Thiamine and Steroids as Combination Therapy in Patients With Sepsis.

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 versus indistinguishable placebos for patients with sepsis. The objective of this study is to demonstrate the efficacy of combination therapy using vitamin C, thiamine and corticosteroids in reducing mortality and improving organ function in critically ill patients with sepsis.

Study Overview

• Status: Completed
• Conditions: Sepsis
• Intervention / Treatment: Drug: Vitamin C; Drug: Thiamine; Drug: Hydrocortisone; Drug: Vitamin C Placebo; Drug: Thiamine Placebo; Drug: Hydrocortisone Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 501
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 80045
      • Maricopa Integrated Health System
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • California
    • Los Angeles, California, United States, 30322
      • David Geffen School of Medicine at UCLA
    • Stanford, California, United States, 21201
      • Stanford University
  • Colorado
    • Denver, Colorado, United States, 80204
      • Denver Health
    • Denver, Colorado, United States, 19140
      • University of Colorado Denver
  • Connecticut
    • New Haven, Connecticut, United States, 94304
      • Yale New Haven Hospital
  • Delaware
    • Newark, Delaware, United States, 19718
      • Christiana Care
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Medstar Washington Hospital Center
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida Jacksonville
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital
    • Atlanta, Georgia, United States, 30303
      • Grady Memorial Hospital
    • Atlanta, Georgia, United States, 30342
      • Emory Saint Joseph's Hospital
    • Atlanta, Georgia, United States, 30078
      • Piedmont Healthcare
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Lousiana State University
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins Bayview
    • Baltimore, Maryland, United States, 55415
      • University of Maryland School of Medicine
  • Massachusetts
    • Springfield, Massachusetts, United States, 01199
      • Baystate Health
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Detroit, Michigan, United States, 27710
      • Henry Ford Health System
  • Minnesota
    • Minneapolis, Minnesota, United States, 48202
      • Hennepin County Medical Center
    • Rochester, Minnesota, United States, 55902
      • Mayo Clinic
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center Weiler
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center Moses
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • North Carolina
    • Durham, North Carolina, United States, 90024
      • Duke University
    • Winston-Salem, North Carolina, United States, 43210
      • Wake Forest University
  • Ohio
    • Cincinnati, Ohio, United States, 23114
      • University of Cincinnati Physicians Company
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Columbus, Ohio, United States, 45241
      • Ohio State University Wexner Medical Center
  • Oregon
    • Portland, Oregon, United States, 27157
      • Oregon Health Sciences University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Health System Hospital
    • Philadelphia, Pennsylvania, United States, 21224
      • Thomas Jefferson University
    • Philadelphia, Pennsylvania, United States, 29425
      • Temple University
  • South Carolina
    • Charleston, South Carolina, United States, 19107
      • Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Utah
    • Murray, Utah, United States, 84157
      • Intermountain Medical Center
    • Salt Lake City, Utah, United States, 37235
      • University of Utah
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Sentara Healthcare
    • Richmond, Virginia, United States, 23284
      • Virginia Commonwealth University
    • Richmond, Virginia, United States, 85008
      • Bon Secours

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Protocol; Participants randomized to the treatment protocol will receive the VICTAS Intervention, consisting of intravenous vitamin C, thiamine, and hydrocortisone for four days or until ICU discharge.	Drug: Vitamin C; Intravenous vitamin C (1.5 grams every 6 hours) will be administered for 4 days or until ICU discharge.; Other Names: Ascorbic acid; Drug: Thiamine; Intravenous thiamine (100 mg every 6 hours) will be administered for 4 days or until ICU discharge.; Other Names: Thiamine hydrochloride; Drug: Hydrocortisone; Intravenous hydrocortisone (50 mg every 6 hours) will be administered for 4 days or until ICU discharge.; Other Names: Hydrocortisone sodium succinate
Placebo Comparator: Control Protocol; A placebo to match the VICTAS intervention will be administered for four days or until ICU discharge. During the treatment period, if an indication for steroids exist, the treating physicians are permitted to initiate open-label corticosteroid therapy based on local practice and international guidelines. If this occurs, the hydrocortisone/placebo will be withheld and subjects will be started on open-label corticosteroids.	Drug: Vitamin C Placebo; A placebo to match intravenous vitamin C (1.5 grams every 6 hours) will be administered for 4 days or until ICU discharge.; Other Names: Placebo; Drug: Thiamine Placebo; A placebo to match intravenous thiamine (100 mg every 6 hours) will be administered for 4 days or until ICU discharge.; Other Names: Placebo; Drug: Hydrocortisone 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.; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vasopressor and Ventilator-free Days (VVFD)	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.	Up to Day 30

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality at 30 Days	The number of participants who did not survive until Day 30 is compared between study arms.	Day 30
Intensive Care Unit (ICU) Mortality	The number of participants who died while in the ICU is compared between study arms.	Day 30
Mortality at 180 Days	The number of participants who did not survive until Day 180 is compared between study arms.	Day 180
Length of ICU Stay	The number of days that participants were in the ICU is compared between study arms.	Day 30
Length of Hospital Stay	The number of days that participants were in the hospital is compared between study arms.	Day 30
Digit Span Test Score	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.	Day 180
Number of Participants With Delirium Assessed With the DeliriumTelephone Confusion Assessment Method (CAM)	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.	Day 180
Hayling Test Score	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.	Day 180
Controlled Oral Word Association Test (COWAT) Score	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.	Day 180
Wechsler Memory Scale III - Delayed Recall Logical Memory Score	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.	Day 180
Telephone Interview for Cognitive Status (TICS)	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.	Day 180
Wechsler Adult Intelligence Scale (WAIS)-IV Similarities Score	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.	Day 180
Katz Index of Independence in Activities of Daily Living (ADL) Score	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.	Day 180
Number of Participants Employed	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.	Day 180
Functional Activities Questionnaire (FAQ) Score	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.	Day 180
Patient-Reported Outcomes Measurement Information System (PROMIS) Depression 6	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.	Day 180
Posttraumatic Stress Disorder-8 (PTSD-8) Score	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.	Day 180
EuroQol, 5 Dimension (EQ-5D) Visual Analog Scale Score	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.	Day 180

Collaborators and Investigators

• Sponsor: Emory University
• Collaborators: The Marcus Foundation
• Investigators: Principal Investigator: Jonathan Sevransky, MD, MHS, Emory University

Publications and helpful links

General Publications

• 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. Erratum In: JAMA. 2021 Sep 21;326(11):1072.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): August 22, 2018
• Primary Completion (Actual): August 22, 2019
• Study Completion (Actual): January 29, 2020

Study Registration Dates

• First Submitted: April 10, 2018
• First Submitted That Met QC Criteria: April 17, 2018
• First Posted (Actual): April 26, 2018

Study Record Updates

• Last Update Posted (Actual): April 13, 2021
• Last Update Submitted That Met QC Criteria: March 22, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Corticosteroid; Vitamin C; Thiamine
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Protective Agents; Micronutrients; Antioxidants; Vitamin B Complex; Vitamins; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Ascorbic Acid; Thiamine
• Other Study ID Numbers: IRB00102528; IRB00164053 (Other Identifier: Johns Hopkins IRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No