Vitamin C, Thiamine, and Steroids in Sepsis

NCT ID: NCT03509350

Last Updated: 2021-04-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 501 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-08-22
• Study Completion Date: 2020-01-29

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.

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.

Conditions

Sepsis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: SUPPORTIVE_CARE
• Blinding Strategy: DOUBLE

Study Groups

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.

Group Type: EXPERIMENTAL

Vitamin C

Intervention Type: DRUG

Intravenous vitamin C (1.5 grams every 6 hours) will be administered for 4 days or until ICU discharge.

Thiamine

Intervention Type: DRUG

Intravenous thiamine (100 mg every 6 hours) will be administered for 4 days or until ICU discharge.

Hydrocortisone

Intervention Type: DRUG

Intravenous hydrocortisone (50 mg every 6 hours) will be administered for 4 days or until ICU discharge.

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.

Group Type: PLACEBO_COMPARATOR

Vitamin C Placebo

Intervention Type: DRUG

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

Intervention Type: DRUG

A placebo to match intravenous thiamine (100 mg every 6 hours) will be administered for 4 days or until ICU discharge.

Hydrocortisone Placebo

Intervention Type: DRUG

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.

Interventions

Vitamin C

Intravenous vitamin C (1.5 grams every 6 hours) will be administered for 4 days or until ICU discharge.

Intervention Type: DRUG

Thiamine

Intravenous thiamine (100 mg every 6 hours) will be administered for 4 days or until ICU discharge.

Intervention Type: DRUG

Hydrocortisone

Intravenous hydrocortisone (50 mg every 6 hours) will be administered for 4 days or until ICU discharge.

Intervention Type: 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.

Intervention Type: DRUG

Thiamine Placebo

A placebo to match intravenous thiamine (100 mg every 6 hours) will be administered for 4 days or until ICU discharge.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Ascorbic acid; Thiamine hydrochloride; Hydrocortisone sodium succinate; Placebo; Placebo; Placebo

Eligibility 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The Marcus Foundation

OTHER

Sponsor Role: collaborator

Emory University

OTHER

Sponsor Role: lead

Responsible Party

Jonathan Sevransky

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jonathan Sevransky, MD, MHS

Role: PRINCIPAL_INVESTIGATOR

Emory University

Locations

Maricopa Integrated Health System

Phoenix, Arizona, United States

University of Arizona

Tucson, Arizona, United States

David Geffen School of Medicine at UCLA

Los Angeles, California, United States

Stanford University

Stanford, California, United States

University of Colorado Denver

Denver, Colorado, United States

Denver Health

Denver, Colorado, United States

Yale New Haven Hospital

New Haven, Connecticut, United States

Christiana Care

Newark, Delaware, United States

Medstar Washington Hospital Center

Washington D.C., District of Columbia, United States

University of Florida Jacksonville

Jacksonville, Florida, United States

Piedmont Healthcare

Atlanta, Georgia, United States

Grady Memorial Hospital

Atlanta, Georgia, United States

Emory University Hospital

Atlanta, Georgia, United States

Emory Saint Joseph's Hospital

Atlanta, Georgia, United States

Lousiana State University

New Orleans, Louisiana, United States

Johns Hopkins Bayview

Baltimore, Maryland, United States

Johns Hopkins Hospital

Baltimore, Maryland, United States

University of Maryland School of Medicine

Baltimore, Maryland, United States

Baystate Health

Springfield, Massachusetts, United States

University of Michigan

Ann Arbor, Michigan, United States

Henry Ford Health System

Detroit, Michigan, United States

Hennepin County Medical Center

Minneapolis, Minnesota, United States

Mayo Clinic

Rochester, Minnesota, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Montefiore Medical Center Weiler

The Bronx, New York, United States

Montefiore Medical Center Moses

The Bronx, New York, United States

Duke University

Durham, North Carolina, United States

Wake Forest University

Winston-Salem, North Carolina, United States

University of Cincinnati Physicians Company

Cincinnati, Ohio, United States

Cleveland Clinic

Cleveland, Ohio, United States

Ohio State University Wexner Medical Center

Columbus, Ohio, United States

Oregon Health Sciences University

Portland, Oregon, United States

University of Pennsylvania Health System Hospital

Philadelphia, Pennsylvania, United States

Thomas Jefferson University

Philadelphia, Pennsylvania, United States

Temple University

Philadelphia, Pennsylvania, United States

Medical University of South Carolina

Charleston, South Carolina, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Intermountain Medical Center

Murray, Utah, United States

University of Utah

Salt Lake City, Utah, United States

Sentara Healthcare

Norfolk, Virginia, United States

Virginia Commonwealth University

Richmond, Virginia, United States

Bon Secours

Richmond, Virginia, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 36853612 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33620405 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32317004 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32007132 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31801567 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30953543 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

IRB00164053

Identifier Type: OTHER

Identifier Source: secondary_id

IRB00102528

Identifier Type: -

Identifier Source: org_study_id