Clinical trial NCT03509350: Vitamin C, Thiamine, and Steroids in Sepsis
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Sepsis
Keywords: Vitamin C
Thiamine
Corticosteroid
Lead sponsor: Emory University
Sponsor class: OTHER
Collaborators: name: The Marcus Foundation
First posted: 2018-04-26
Enrollment: 501
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

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.

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

Primary outcomes:
measure: Vasopressor and Ventilator-free Days (VVFD)
timeFrame: Up to Day 30
Secondary outcomes:
measure: Mortality at 30 Days
timeFrame: Day 30
measure: Intensive Care Unit (ICU) Mortality
timeFrame: Day 30
measure: Mortality at 180 Days
timeFrame: Day 180
measure: Length of ICU Stay
timeFrame: Day 30
measure: Length of Hospital Stay
timeFrame: Day 30
measure: Digit Span Test Score
timeFrame: Day 180
measure: Number of Participants With Delirium Assessed With the DeliriumTelephone Confusion Assessment Method (CAM)
timeFrame: Day 180
measure: Hayling Test Score
timeFrame: Day 180
measure: Controlled Oral Word Association Test (COWAT) Score
timeFrame: Day 180
measure: Wechsler Memory Scale III - Delayed Recall Logical Memory Score
timeFrame: Day 180
measure: Telephone Interview for Cognitive Status (TICS)
timeFrame: Day 180
measure: Wechsler Adult Intelligence Scale (WAIS)-IV Similarities Score
timeFrame: Day 180
measure: Katz Index of Independence in Activities of Daily Living (ADL) Score
timeFrame: Day 180
measure: Number of Participants Employed
timeFrame: Day 180
measure: Functional Activities Questionnaire (FAQ) Score
timeFrame: Day 180
measure: Patient-Reported Outcomes Measurement Information System (PROMIS) Depression 6
timeFrame: Day 180
measure: Posttraumatic Stress Disorder-8 (PTSD-8) Score
timeFrame: Day 180
measure: EuroQol, 5 Dimension (EQ-5D) Visual Analog Scale Score
timeFrame: Day 180
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Maricopa Integrated Health System
state: Arizona
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Los Angeles
country: United States
facility: David Geffen School of Medicine at UCLA
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Denver
country: United States
facility: University of Colorado Denver
state: Colorado
city: Denver
country: United States
facility: Denver Health
state: Colorado
city: New Haven
country: United States
facility: Yale New Haven Hospital
state: Connecticut
city: Newark
country: United States
facility: Christiana Care
state: Delaware
city: Washington
country: United States
facility: Medstar Washington Hospital Center
state: District of Columbia
city: Jacksonville
country: United States
facility: University of Florida Jacksonville
state: Florida
city: Atlanta
country: United States
facility: Piedmont Healthcare
state: Georgia
city: Atlanta
country: United States
facility: Grady Memorial Hospital
state: Georgia
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
city: Atlanta
country: United States
facility: Emory Saint Joseph's Hospital
state: Georgia
city: New Orleans
country: United States
facility: Lousiana State University
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins Bayview
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Baltimore
country: United States
facility: University of Maryland School of Medicine
state: Maryland
city: Springfield
country: United States
facility: Baystate Health
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Bronx
country: United States
facility: Montefiore Medical Center Weiler
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center Moses
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Physicians Company
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Wexner Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health Sciences University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania Health System Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Norfolk
country: United States
facility: Sentara Healthcare
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Richmond
country: United States
facility: Bon Secours
state: Virginia
Study officials:
affiliation: Emory University
name: Jonathan Sevransky, MD, MHS
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.