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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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:
Collaborator:
The Marcus Foundation
Information provided by (Responsible Party):
Jonathan Sevransky, Emory University

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

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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


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




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.



Information from the National Library of Medicine

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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03509350


Locations
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Sponsors and Collaborators
Emory University
The Marcus Foundation
Investigators
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Principal Investigator: Jonathan Sevransky, MD, MHS Emory University
  Study Documents (Full-Text)

Documents provided by Jonathan Sevransky, Emory University:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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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    Key Record Dates
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

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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:
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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