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

• ClinicalTrials.gov Identifier: NCT03509350
• Recruitment Status: Completed
• First Posted: April 26, 2018
• Results First Posted: September 18, 2020
• Last Update Posted: September 18, 2020
• Sponsor: Emory University
• Collaborator: The Marcus Foundation
• Information provided by (Responsible Party): Jonathan Sevransky, Emory University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Sepsis	Drug: Vitamin C; Drug: Thiamine; Drug: Hydrocortisone; Drug: Vitamin C Placebo; Drug: Thiamine Placebo; Drug: Hydrocortisone Placebo	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 501 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Supportive Care
• Official Title: A Multi-center, Randomized, Placebo-controlled, Double-blind, Adaptive Clinical Trial of Vitamin C, Thiamine and Steroids as Combination Therapy in Patients With Sepsis.
• Actual Study Start Date: August 22, 2018
• Actual Primary Completion Date: August 22, 2019
• Actual Study Completion Date: January 29, 2020

Arms and Interventions

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 Name: Ascorbic acid; Drug: Thiamine; Intravenous thiamine (100 mg every 6 hours) will be administered for 4 days or until ICU discharge.; Other Name: Thiamine hydrochloride; Drug: Hydrocortisone; Intravenous hydrocortisone (50 mg every 6 hours) will be administered for 4 days or until ICU discharge.; Other Name: 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 Name: 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 Name: 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 Name: Placebo

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Mortality at 30 Days [ Time Frame: Day 30 ]
   The number of participants who did not survive until Day 30 will be compared between study arms.
2. Intensive Care Unit (ICU) Mortality [ Time Frame: Day 30 ]
   The number of participants who die while in the ICU will be compared between study arms.
3. Mortality at 180 Days [ Time Frame: Day 180 ]
   The number of participants who did not survive until Day 180 will be compared between study arms.
4. Length of ICU Stay [ Time Frame: Day 30 ]
   The number of days in the ICU will be compared between study arms.
5. Length of Hospital Stay [ Time Frame: Day 30 ]
   The number of days in the hospital will be compared between study arms.
6. Digit Span Test Score [ Time Frame: Day 180 ]
   The digit span test will be used to assesses attention. 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 amount of numbers the participant was able to remember in each test. Higher scores indicate greater ability to pay attention and to remember sequences.
7. Delirium Telephone Confusion Assessment Method (CAM) [ Time Frame: 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.
8. Hayling Test Score [ Time Frame: Day 180 ]
   Executive function will be 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.
9. Controlled Oral Word Association Test (COWAT) Score [ Time Frame: Day 180 ]
   Language will be 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.
10. Wechsler Memory Scale IV - Paragraph Recall Score [ Time Frame: Day 180 ]
    Memory will be assessed with the Paragraph Recall from the Wechsler Memory Scale IV. Participants listen to two short paragraphs and are asked to recall details from each story immediately and after 30 minutes. Scores represent the number of correctly remembered details. Total scores for each recall time period (immediate and after 30 minutes) range from 0 to 25 with higher scores reflecting better memory.
11. Telephone Interview for Cognitive Status (TICS) [ Time Frame: 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.
12. Wechsler Adult Intelligence Scale (WAIS)-IV Similarities Score [ Time Frame: Day 180 ]
    Reasoning will be assessed with the WAIS-IV Similarities instrument. Participants are 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.
13. Katz Index of Independence in Activities of Daily Living (ADL) Score [ Time Frame: Day 180 ]
    Activities of daily living will be 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.
14. Employment Questionnaire [ Time Frame: Day 180 ]
    The Employment Questionnaire is a brief measure of the participant's employment history and ability or capacity to work. There is not a summary score for this qualitative questionnaire.
15. Functional Activities Questionnaire (FAQ) Score [ Time Frame: Day 180 ]
    Instrumental activities of daily living will be 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.
16. Patient-Reported Outcomes Measurement Information System (PROMIS) Depression 6 [ Time Frame: Day 180 ]
    Depression will be 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.
17. Posttraumatic Stress Disorder - 8 (PTSD-8) [ Time Frame: Day 180 ]
    Posttraumatic Stress Disorder (PTSD) will be assessed with the Posttraumatic Stress Disorder - 8 instrument. The PTSD-8 includes 8 items which are answered on a 4 point scale where 1 = not at all and 4 = all of the time. Total scores range from 8 to 32 where higher scores indicate greater symptoms of PTSD.
18. EuroQol, 5 Dimension (EQ5D) [ Time Frame: Day 180 ]
    Quality of life will be assessed with the EuroQol, 5 dimension (EQ5D) questionnaire. The EQ5D asks about 5 dimensions of health (mobility, self-care, usual activities, pain, and depression). These 5 items are assessed on a scale from 1 to 5 where 1 =no problems and 5 = extremely problematic. Total raw scores range from 5 to 25 where higher scores indicate lower quality of life. The questionnaire also includes a visual analog scale where respondents rate their current health; 0 = worst health imaginable and 100 = best health imaginable.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Arizona

Maricopa Integrated Health System

Phoenix, Arizona, United States, 80045

University of Arizona

Tucson, Arizona, United States, 85724

United States, California

David Geffen School of Medicine at UCLA

Los Angeles, California, United States, 30322

Stanford University

Stanford, California, United States, 21201

United States, Colorado

University of Colorado Denver

Denver, Colorado, United States, 19140

Denver Health

Denver, Colorado, United States, 80204

United States, Connecticut

Yale New Haven Hospital

New Haven, Connecticut, United States, 94304

United States, Delaware

Christiana Care

Newark, Delaware, United States, 19718

United States, District of Columbia

Medstar Washington Hospital Center

Washington, District of Columbia, United States, 20010

United States, Florida

University of Florida Jacksonville

Jacksonville, Florida, United States, 32209

United States, Georgia

Piedmont Healthcare

Atlanta, Georgia, United States, 30078

Grady Memorial Hospital

Atlanta, Georgia, United States, 30303

Emory University Hospital

Atlanta, Georgia, United States, 30322

Emory Saint Joseph's Hospital

Atlanta, Georgia, United States, 30342

United States, Louisiana

Lousiana State University

New Orleans, Louisiana, United States, 70112

United States, Maryland

Johns Hopkins Bayview

Baltimore, Maryland, United States, 21224

Johns Hopkins Hospital

Baltimore, Maryland, United States, 21287

University of Maryland School of Medicine

Baltimore, Maryland, United States, 55415

United States, Massachusetts

Baystate Health

Springfield, Massachusetts, United States, 01199

United States, Michigan

University of Michigan

Ann Arbor, Michigan, United States, 48109

Henry Ford Health System

Detroit, Michigan, United States, 27710

United States, Minnesota

Hennepin County Medical Center

Minneapolis, Minnesota, United States, 48202

Mayo Clinic

Rochester, Minnesota, United States, 55902

United States, Nebraska

University of Nebraska Medical Center

Omaha, Nebraska, United States, 68198

United States, New York

Montefiore Medical Center Weiler

Bronx, New York, United States, 10461

Montefiore Medical Center Moses

Bronx, New York, United States, 10467

Memorial Sloan Kettering Cancer Center

New York, New York, United States, 10065

United States, North Carolina

Duke University

Durham, North Carolina, United States, 90024

Wake Forest University

Winston-Salem, North Carolina, United States, 43210

United States, Ohio

University of Cincinnati Physicians Company

Cincinnati, Ohio, United States, 23114

Cleveland Clinic

Cleveland, Ohio, United States, 44195

Ohio State University Wexner Medical Center

Columbus, Ohio, United States, 45241

United States, Oregon

Oregon Health Sciences University

Portland, Oregon, United States, 27157

United States, Pennsylvania

University of Pennsylvania Health System Hospital

Philadelphia, Pennsylvania, United States, 19104

Thomas Jefferson University

Philadelphia, Pennsylvania, United States, 21224

Temple University

Philadelphia, Pennsylvania, United States, 29425

United States, South Carolina

Medical University of South Carolina

Charleston, South Carolina, United States, 19107

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37232

United States, Utah

Intermountain Medical Center

Murray, Utah, United States, 84157

University of Utah

Salt Lake City, Utah, United States, 37235

United States, Virginia

Sentara Healthcare

Norfolk, Virginia, United States, 23507

Virginia Commonwealth University

Richmond, Virginia, United States, 23284

Bon Secours

Richmond, Virginia, United States, 85008

Sponsors and Collaborators

Emory University

The Marcus Foundation

Investigators

• Principal Investigator: Jonathan Sevransky, MD, MHS; Emory University

  Study Documents (Full-Text)

Documents provided by Jonathan Sevransky, Emory University:

Study Protocol and Statistical Analysis Plan  [PDF] April 22, 2019

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

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.

• Responsible Party: Jonathan Sevransky, Professor, Emory University
• ClinicalTrials.gov Identifier: NCT03509350
• Other Study ID Numbers: IRB00102528; IRB00164053 ( Other Identifier: Johns Hopkins IRB )
• First Posted: April 26, 2018
• Results First Posted: September 18, 2020
• Last Update Posted: September 18, 2020
• Last Verified: August 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

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

Keywords provided by Jonathan Sevransky, Emory University:

Vitamin C; Thiamine; Corticosteroid

Additional relevant MeSH terms:

Sepsis; Toxemia; Infection; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Vitamins; Ascorbic Acid; Thiamine; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Micronutrients; Nutrients; Growth Substances; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents; Vitamin B Complex