VICTAS: Vitamin C, Thiamine, and Steroids in Sepsis

• Sponsor: Emory University (Other)
• Overall Status: Completed
• CT.gov ID: NCT03509350
• Collaborator: The Marcus Foundation (Other)
• Enrollment: 501
• Locations: 43
• Arms: 2
• Actual Duration (Months): 17.2
• Patients Per Site: 11.7
• Patients Per Site Per Month: 0.7

Study Details

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
• 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: Aug 22, 2018
• Actual Primary Completion Date: Aug 22, 2019
• Actual Study Completion Date: Jan 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 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

Outcome Measures

Primary Outcome Measures

1. Vasopressor and Ventilator-free Days (VVFD) [Up to Day 30]

   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.

Secondary Outcome Measures

1. Mortality at 30 Days [Day 30]

   The number of participants who did not survive until Day 30 is compared between study arms.

2. Intensive Care Unit (ICU) Mortality [Day 30]

   The number of participants who died while in the ICU is compared between study arms.

3. Mortality at 180 Days [Day 180]

   The number of participants who did not survive until Day 180 is compared between study arms.

4. Length of ICU Stay [Day 30]

   The number of days that participants were in the ICU is compared between study arms.

5. Length of Hospital Stay [Day 30]

   The number of days that participants were in the hospital is compared between study arms.

6. Digit Span Test Score [Day 180]

   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.

7. Number of Participants With Delirium Assessed With the DeliriumTelephone Confusion Assessment Method (CAM) [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 [Day 180]

   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.

9. Controlled Oral Word Association Test (COWAT) Score [Day 180]

   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.

10. Wechsler Memory Scale III - Delayed Recall Logical Memory Score [Day 180]

    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.

11. Telephone Interview for Cognitive Status (TICS) [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 [Day 180]

    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.

13. Katz Index of Independence in Activities of Daily Living (ADL) Score [Day 180]

    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.

14. Number of Participants Employed [Day 180]

    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.

15. Functional Activities Questionnaire (FAQ) Score [Day 180]

    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.

16. Patient-Reported Outcomes Measurement Information System (PROMIS) Depression 6 [Day 180]

    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.

17. Posttraumatic Stress Disorder-8 (PTSD-8) Score [Day 180]

    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.

18. EuroQol, 5 Dimension (EQ-5D) Visual Analog Scale Score [Day 180]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	Maricopa Integrated Health System	Phoenix	Arizona	United States	80045
2	University of Arizona	Tucson	Arizona	United States	85724
3	David Geffen School of Medicine at UCLA	Los Angeles	California	United States	30322
4	Stanford University	Stanford	California	United States	21201
5	University of Colorado Denver	Denver	Colorado	United States	19140
6	Denver Health	Denver	Colorado	United States	80204
7	Yale New Haven Hospital	New Haven	Connecticut	United States	94304
8	Christiana Care	Newark	Delaware	United States	19718
9	Medstar Washington Hospital Center	Washington	District of Columbia	United States	20010
10	University of Florida Jacksonville	Jacksonville	Florida	United States	32209
11	Piedmont Healthcare	Atlanta	Georgia	United States	30078
12	Grady Memorial Hospital	Atlanta	Georgia	United States	30303
13	Emory University Hospital	Atlanta	Georgia	United States	30322
14	Emory Saint Joseph's Hospital	Atlanta	Georgia	United States	30342
15	Lousiana State University	New Orleans	Louisiana	United States	70112
16	Johns Hopkins Bayview	Baltimore	Maryland	United States	21224
17	Johns Hopkins Hospital	Baltimore	Maryland	United States	21287
18	University of Maryland School of Medicine	Baltimore	Maryland	United States	55415
19	Baystate Health	Springfield	Massachusetts	United States	01199
20	University of Michigan	Ann Arbor	Michigan	United States	48109
21	Henry Ford Health System	Detroit	Michigan	United States	27710
22	Hennepin County Medical Center	Minneapolis	Minnesota	United States	48202
23	Mayo Clinic	Rochester	Minnesota	United States	55902
24	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
25	Montefiore Medical Center Weiler	Bronx	New York	United States	10461
26	Montefiore Medical Center Moses	Bronx	New York	United States	10467
27	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
28	Duke University	Durham	North Carolina	United States	90024
29	Wake Forest University	Winston-Salem	North Carolina	United States	43210
30	University of Cincinnati Physicians Company	Cincinnati	Ohio	United States	23114
31	Cleveland Clinic	Cleveland	Ohio	United States	44195
32	Ohio State University Wexner Medical Center	Columbus	Ohio	United States	45241
33	Oregon Health Sciences University	Portland	Oregon	United States	27157
34	University of Pennsylvania Health System Hospital	Philadelphia	Pennsylvania	United States	19104
35	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	21224
36	Temple University	Philadelphia	Pennsylvania	United States	29425
37	Medical University of South Carolina	Charleston	South Carolina	United States	19107
38	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
39	Intermountain Medical Center	Murray	Utah	United States	84157
40	University of Utah	Salt Lake City	Utah	United States	37235
41	Sentara Healthcare	Norfolk	Virginia	United States	23507
42	Virginia Commonwealth University	Richmond	Virginia	United States	23284
43	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)

• Study Protocol and Statistical Analysis Plan - Apr 22, 2019

More Information

Publications

None provided.

• Responsible Party: Jonathan Sevransky, Professor, Emory University
• ClinicalTrials.gov Identifier: NCT03509350
• Other Study ID Numbers: IRB00102528; IRB00164053
• First Posted: Apr 26, 2018
• Last Update Posted: Apr 13, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• 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, Professor, Emory University: Vitamin C; Thiamine; Corticosteroid
• Additional relevant MeSH terms: Sepsis; Toxemia; Vitamins; Ascorbic Acid; Thiamine; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate

Study Results

Participant Flow

Recruitment Details	Participant enrollment began on August 22, 2018. Follow-up for the primary outcome measure was completed on August 22, 2019 and follow up for the secondary outcome measures was completed on January 29, 2020. Participants were recruited from multiple sites in the United States of America.

Arm/Group Title	Treatment Protocol	Control Protocol
Arm/Group Description	Participants randomized to the treatment protocol received the VICTAS Intervention, consisting of intravenous vitamin C, thiamine, and hydrocortisone for four days or until ICU discharge.	Participants in the control group received a placebo to match the VICTAS intervention, which was administered for four days or until ICU discharge.
Period Title: Overall Study
STARTED	252	249
COMPLETED	252	247
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	Treatment Protocol	Control Protocol	Total
Arm/Group Description	Participants randomized to the treatment protocol received the VICTAS Intervention, consisting of intravenous vitamin C, thiamine, and hydrocortisone for four days or until ICU discharge.	Participants in the control group received a placebo to match the VICTAS intervention, which was administered for four days or until ICU discharge.	Total of all reporting groups
Overall Participants	252	249	501
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	148 58.7%	143 57.4%	291 58.1%
>=65 years	104 41.3%	106 42.6%	210 41.9%
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	62	61	62
Sex: Female, Male (Count of Participants)
Female	113 44.8%	115 46.2%	228 45.5%
Male	139 55.2%	134 53.8%	273 54.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	32 12.7%	24 9.6%	56 11.2%
Not Hispanic or Latino	211 83.7%	215 86.3%	426 85%
Unknown or Not Reported	9 3.6%	10 4%	19 3.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	70 27.8%	80 32.1%	150 29.9%
White	149 59.1%	135 54.2%	284 56.7%
More than one race	33 13.1%	34 13.7%	67 13.4%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	252 100%	249 100%	501 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

This analysis uses an intent-to-treat (ITT) analysis set, which includes all participants who enrolled in the study.

Arm/Group Title	Treatment Protocol	Control Protocol
Arm/Group Description	Participants randomized to the treatment protocol received the VICTAS Intervention, consisting of intravenous vitamin C, thiamine, and hydrocortisone for four days or until ICU discharge.	Participants in the control group received a placebo to match the VICTAS intervention, which was administered for four days or until ICU discharge.
Measure Participants	252	249
Median (Inter-Quartile Range) [days]	25	26

2. Secondary Outcome

Title	Mortality at 30 Days
Description	The number of participants who did not survive until Day 30 is compared between study arms.
Time Frame	Day 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Protocol	Control Protocol
Arm/Group Description	Participants randomized to the treatment protocol received the VICTAS Intervention, consisting of intravenous vitamin C, thiamine, and hydrocortisone for four days or until ICU discharge.	Participants in the control group received a placebo to match the VICTAS intervention, which was administered for four days or until ICU discharge.
Measure Participants	252	249
Count of Participants [Participants]	56 22.2%	60 24.1%

3. Secondary Outcome

Title	Intensive Care Unit (ICU) Mortality
Description	The number of participants who died while in the ICU is compared between study arms.
Time Frame	Day 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Protocol	Control Protocol
Arm/Group Description	Participants randomized to the treatment protocol received the VICTAS Intervention, consisting of intravenous vitamin C, thiamine, and hydrocortisone for four days or until ICU discharge.	Participants in the control group received a placebo to match the VICTAS intervention, which was administered for four days or until ICU discharge.
Measure Participants	252	249
Count of Participants [Participants]	52 20.6%	49 19.7%

4. Secondary Outcome

Title	Mortality at 180 Days
Description	The number of participants who did not survive until Day 180 is compared between study arms.
Time Frame	Day 180

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Protocol	Control Protocol
Arm/Group Description	Participants randomized to the treatment protocol received the VICTAS Intervention, consisting of intravenous vitamin C, thiamine, and hydrocortisone for four days or until ICU discharge.	Participants in the control group received a placebo to match the VICTAS intervention, which was administered for four days or until ICU discharge.
Measure Participants	252	249
Count of Participants [Participants]	102 40.5%	94 37.8%

5. Secondary Outcome

Title	Length of ICU Stay
Description	The number of days that participants were in the ICU is compared between study arms.
Time Frame	Day 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Protocol	Control Protocol
Arm/Group Description	Participants randomized to the treatment protocol received the VICTAS Intervention, consisting of intravenous vitamin C, thiamine, and hydrocortisone for four days or until ICU discharge.	Participants in the control group received a placebo to match the VICTAS intervention, which was administered for four days or until ICU discharge.
Measure Participants	252	249
Mean (Standard Deviation) [days]	6.7 (7.3)	6.4 (6.9)

6. Secondary Outcome

Title	Length of Hospital Stay
Description	The number of days that participants were in the hospital is compared between study arms.
Time Frame	Day 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Protocol	Control Protocol
Arm/Group Description	Participants randomized to the treatment protocol received the VICTAS Intervention, consisting of intravenous vitamin C, thiamine, and hydrocortisone for four days or until ICU discharge.	Participants in the control group received a placebo to match the VICTAS intervention, which was administered for four days or until ICU discharge.
Measure Participants	252	249
Mean (Standard Deviation) [days]	12.6 (10)	13.5 (25.7)

7. Secondary Outcome

Title	Digit Span Test Score
Description	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.
Time Frame	Day 180

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Protocol	Control Protocol
Arm/Group Description	Participants randomized to the treatment protocol received the VICTAS Intervention, consisting of intravenous vitamin C, thiamine, and hydrocortisone for four days or until ICU discharge.	Participants in the control group received a placebo to match the VICTAS intervention, which was administered for four days or until ICU discharge.
Measure Participants	252	249
Mean (Standard Deviation) [numbers recalled]	8.3 (3.1)	9.5 (3.8)

8. Secondary Outcome

Title	Number of Participants With Delirium Assessed With the DeliriumTelephone Confusion Assessment Method (CAM)
Description	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.
Time Frame	Day 180

Outcome Measure Data

Analysis Population Description

Telephone data are available only on 168 participants

Arm/Group Title	Treatment Protocol	Control Protocol
Arm/Group Description	Participants randomized to the treatment protocol received the VICTAS Intervention, consisting of intravenous vitamin C, thiamine, and hydrocortisone for four days or until ICU discharge.	Participants in the control group received a placebo to match the VICTAS intervention, which was administered for four days or until ICU discharge.
Measure Participants	86	82
Count of Participants [Participants]	0 0%	0 0%

9. Secondary Outcome

Title	Hayling Test Score
Description	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.
Time Frame	Day 180

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Protocol	Control Protocol
Arm/Group Description	Participants randomized to the treatment protocol received the VICTAS Intervention, consisting of intravenous vitamin C, thiamine, and hydrocortisone for four days or until ICU discharge.	Participants in the control group received a placebo to match the VICTAS intervention, which was administered for four days or until ICU discharge.
Measure Participants	252	249
Mean (Standard Deviation) [units on a scale]	4.2 (1.9)	4.2 (1.8)

10. Secondary Outcome

Title	Controlled Oral Word Association Test (COWAT) Score
Description	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.
Time Frame	Day 180

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Protocol	Control Protocol
Arm/Group Description	Participants randomized to the treatment protocol received the VICTAS Intervention, consisting of intravenous vitamin C, thiamine, and hydrocortisone for four days or until ICU discharge.	Participants in the control group received a placebo to match the VICTAS intervention, which was administered for four days or until ICU discharge.
Measure Participants	252	249
Mean (Standard Deviation) [words]	40 (11)	40 (11)

11. Secondary Outcome

Title	Wechsler Memory Scale III - Delayed Recall Logical Memory Score
Description	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.
Time Frame	Day 180

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Protocol	Control Protocol
Arm/Group Description	Participants randomized to the treatment protocol received the VICTAS Intervention, consisting of intravenous vitamin C, thiamine, and hydrocortisone for four days or until ICU discharge.	Participants in the control group received a placebo to match the VICTAS intervention, which was administered for four days or until ICU discharge.
Measure Participants	252	249
Mean (Standard Deviation) [correct story details]	6.9 (2.8)	8.1 (3.2)

12. Secondary Outcome

Title	Telephone Interview for Cognitive Status (TICS)
Description	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.
Time Frame	Day 180

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Protocol	Control Protocol
Arm/Group Description	Participants randomized to the treatment protocol received the VICTAS Intervention, consisting of intravenous vitamin C, thiamine, and hydrocortisone for four days or until ICU discharge.	Participants in the control group received a placebo to match the VICTAS intervention, which was administered for four days or until ICU discharge.
Measure Participants	252	249
Mean (Standard Deviation) [score on a scale]	30.6 (4.9)	31.2 (5.2)

13. Secondary Outcome

Title	Wechsler Adult Intelligence Scale (WAIS)-IV Similarities Score
Description	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.
Time Frame	Day 180

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Protocol	Control Protocol
Arm/Group Description	Participants randomized to the treatment protocol received the VICTAS Intervention, consisting of intravenous vitamin C, thiamine, and hydrocortisone for four days or until ICU discharge.	Participants in the control group received a placebo to match the VICTAS intervention, which was administered for four days or until ICU discharge.
Measure Participants	252	249
Mean (Standard Deviation) [score on a scale]	7.7 (3.3)	8.2 (3.2)

14. Secondary Outcome

Title	Katz Index of Independence in Activities of Daily Living (ADL) Score
Description	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.
Time Frame	Day 180

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Protocol	Control Protocol
Arm/Group Description	Participants randomized to the treatment protocol received the VICTAS Intervention, consisting of intravenous vitamin C, thiamine, and hydrocortisone for four days or until ICU discharge.	Participants in the control group received a placebo to match the VICTAS intervention, which was administered for four days or until ICU discharge.
Measure Participants	252	249
Mean (Standard Deviation) [score on a scale]	2.8 (3.9)	2.4 (3.6)

15. Secondary Outcome

Title	Number of Participants Employed
Description	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.
Time Frame	Day 180

Outcome Measure Data

Analysis Population Description

This analysis includes participants who completed the Employment Questionnaire.

Arm/Group Title	Treatment Protocol	Control Protocol
Arm/Group Description	Participants randomized to the treatment protocol received the VICTAS Intervention, consisting of intravenous vitamin C, thiamine, and hydrocortisone for four days or until ICU discharge.	Participants in the control group received a placebo to match the VICTAS intervention, which was administered for four days or until ICU discharge.
Measure Participants	99	96
Count of Participants [Participants]	17 6.7%	25 10%

16. Secondary Outcome

Title	Functional Activities Questionnaire (FAQ) Score
Description	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.
Time Frame	Day 180

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Protocol	Control Protocol
Arm/Group Description	Participants randomized to the treatment protocol received the VICTAS Intervention, consisting of intravenous vitamin C, thiamine, and hydrocortisone for four days or until ICU discharge.	Participants in the control group received a placebo to match the VICTAS intervention, which was administered for four days or until ICU discharge.
Measure Participants	252	249
Mean (Standard Deviation) [score on a scale]	9.5 (10.8)	7.7 (9.2)

17. Secondary Outcome

Title	Patient-Reported Outcomes Measurement Information System (PROMIS) Depression 6
Description	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.
Time Frame	Day 180

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Protocol	Control Protocol
Arm/Group Description	Participants randomized to the treatment protocol received the VICTAS Intervention, consisting of intravenous vitamin C, thiamine, and hydrocortisone for four days or until ICU discharge.	Participants in the control group received a placebo to match the VICTAS intervention, which was administered for four days or until ICU discharge.
Measure Participants	252	249
Mean (Standard Deviation) [score on a scale]	11.9 (6.3)	11.9 (5.9)

18. Secondary Outcome

Title	Posttraumatic Stress Disorder-8 (PTSD-8) Score
Description	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.
Time Frame	Day 180

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Protocol	Control Protocol
Arm/Group Description	Participants randomized to the treatment protocol received the VICTAS Intervention, consisting of intravenous vitamin C, thiamine, and hydrocortisone for four days or until ICU discharge.	Participants in the control group received a placebo to match the VICTAS intervention, which was administered for four days or until ICU discharge.
Measure Participants	252	249
Mean (Standard Deviation) [score on a scale]	5.7 (5.8)	5.2 (5.1)

19. Secondary Outcome

Title	EuroQol, 5 Dimension (EQ-5D) Visual Analog Scale Score
Description	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.
Time Frame	Day 180

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Protocol	Control Protocol
Arm/Group Description	Participants randomized to the treatment protocol received the VICTAS Intervention, consisting of intravenous vitamin C, thiamine, and hydrocortisone for four days or until ICU discharge.	Participants in the control group received a placebo to match the VICTAS intervention, which was administered for four days or until ICU discharge.
Measure Participants	252	249
Mean (Standard Deviation) [units on a scale]	66 (22)	67 (22)

Adverse Events

Time Frame	Adverse events potentially associated with the study treatment and serious adverse events were monitored from the time of randomization up to Day 30. Mortality was recorded from the time of randomization up to Day 180.
Adverse Event Reporting Description	Adverse events that were not considered serious or potentially associated with the treatment were not recorded.
Arm/Group Title	Treatment Protocol		Control Protocol
Arm/Group Description	Participants randomized to the treatment protocol received the VICTAS Intervention, consisting of intravenous vitamin C, thiamine, and hydrocortisone for four days or until ICU discharge.		Participants in the control group received a placebo to match the VICTAS intervention, which was administered for four days or until ICU discharge.
All Cause Mortality
	Treatment Protocol		Control Protocol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	102/252 (40.5%)		94/249 (37.8%)
Serious Adverse Events
	Treatment Protocol		Control Protocol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/252 (0%)		0/249 (0%)
Other (Not Including Serious) Adverse Events
	Treatment Protocol		Control Protocol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/252 (0.8%)		0/249 (0%)
Blood and lymphatic system disorders
Hemorrhagic shock due to hemolysis	1/252 (0.4%)	1	0/249 (0%)	0
Renal and urinary disorders
Worsening of renal function	1/252 (0.4%)	1	0/249 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.