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The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) Protocol: a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial.

ABSTRACT: BACKGROUND:Sepsis accounts for 30% to 50% of all in-hospital deaths in the United States. Other than antibiotics and source control, management strategies are largely supportive with fluid resuscitation and respiratory, renal, and circulatory support. Intravenous vitamin C in conjunction with thiamine and hydrocortisone has recently been suggested to improve outcomes in patients with sepsis in a single-center before-and-after study. However, before this therapeutic strategy is adopted, a rigorous assessment of its efficacy is needed. METHODS:The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled trial. It will enroll patients with sepsis causing respiratory or circulatory compromise or both. Patients will be randomly assigned (1:1) to receive intravenous vitamin C (1.5?g), thiamine (100?mg), and hydrocortisone (50?mg) every 6 h or matching placebos until a total of 16 administrations have been completed or intensive care unit discharge occurs (whichever is first). Patients randomly assigned to the comparator group are permitted to receive open-label stress-dose steroids at the discretion of the treating clinical team. The primary outcome is consecutive days free of ventilator and vasopressor support (VVFDs) in the 30?days following randomization. The key secondary outcome is mortality at 30?days. Sample size will be determined adaptively by using interim analyses with pre-stated stopping rules to allow the early recognition of a large mortality benefit if one exists and to refocus on the more sensitive outcome of VVFDs if an early large mortality benefit is not observed. DISCUSSION:VICTAS is a large, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled trial that will test the efficacy of vitamin C, thiamine, and hydrocortisone as a combined therapy in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. Because the components of this therapy are inexpensive and readily available and have very favorable risk profiles, demonstrated efficacy would have immediate implications for the management of sepsis worldwide. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT03509350 . First registered on April 26, 2018, and last verified on December 20, 2018. Protocol version: 1.4, January 9, 2019.

SUBMITTER: Hager DN

PROVIDER: S-EPMC6451231 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) Protocol: a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial.

Hager David N DN Hooper Michael H MH Bernard Gordon R GR Busse Laurence W LW Ely E Wesley EW Fowler Alpha A AA Gaieski David F DF Hall Alex A Hinson Jeremiah S JS Jackson James C JC Kelen Gabor D GD Levine Mark M Lindsell Christopher J CJ Malone Richard E RE McGlothlin Anna A Rothman Richard E RE Viele Kert K Wright David W DW Sevransky Jonathan E JE Martin Greg S GS

Trials 20190405 1

<h4>Background</h4>Sepsis accounts for 30% to 50% of all in-hospital deaths in the United States. Other than antibiotics and source control, management strategies are largely supportive with fluid resuscitation and respiratory, renal, and circulatory support. Intravenous vitamin C in conjunction with thiamine and hydrocortisone has recently been suggested to improve outcomes in patients with sepsis in a single-center before-and-after study. However, before this therapeutic strategy is adopted, a ...[more]

PMID: 30953543

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Project description:ImportanceSepsis is associated with long-term cognitive impairment and worse psychological and functional outcomes. Potential mechanisms include intracerebral oxidative stress and inflammation, yet little is known about the effects of early antioxidant and anti-inflammatory therapy on cognitive, psychological, and functional outcomes in sepsis survivors.ObjectiveTo describe observed differences in long-term cognitive, psychological, and functional outcomes of vitamin C, thiamine, and hydrocortisone between the intervention and control groups in the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) randomized clinical trial.Design, setting, and participantsThis prespecified secondary analysis reports the 6-month outcomes of the multicenter, double-blind, placebo-controlled VICTAS randomized clinical trial, which was conducted between August 2018 and July 2019. Adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction who survived to discharge or day 30 were recruited from 43 intensive care units in the US. Participants were randomized 1:1 to either the intervention or control group. Cognitive, psychological, and functional outcomes at 6 months after randomization were assessed via telephone through January 2020. Data analyses were conducted between February 2021 and December 2022.InterventionsThe intervention group received intravenous vitamin C (1.5 g), thiamine hydrochloride (100 mg), and hydrocortisone sodium succinate (50 mg) every 6 hours for 96 hours or until death or intensive care unit discharge. The control group received matching placebo.Main outcomes and measuresCognitive performance, risk of posttraumatic stress disorder and depression, and functional status were assessed using a battery of standardized instruments that were administered during a 1-hour telephone call 6 months after randomization.ResultsAfter exclusions, withdrawals, and deaths, the final sample included 213 participants (median [IQR] age, 57 [47-67] years; 112 males [52.6%]) who underwent long-term outcomes assessment and had been randomized to either the intervention group (n = 108) or control group (n = 105). The intervention group had lower immediate memory scores (adjusted OR [aOR], 0.49; 95% CI, 0.26-0.89), higher odds of posttraumatic stress disorder (aOR, 3.51; 95% CI, 1.18-10.40), and lower odds of receiving mental health care (aOR, 0.38; 95% CI, 0.16-0.89). No other statistically significant differences in cognitive, psychological, and functional outcomes were found between the 2 groups.Conclusions and relevanceIn survivors of sepsis, treatment with vitamin C, thiamine, and hydrocortisone did not improve or had worse cognitive, psychological, and functional outcomes at 6 months compared with patients who received placebo. These findings challenge the hypothesis that antioxidant and anti-inflammatory therapy during critical illness mitigates the development of long-term cognitive, psychological, and functional impairment in sepsis survivors.Trial registrationClinicalTrials.gov Identifier: NCT03509350.

Project description:BackgroundMany randomized controlled trials (RCTs) employ mortality at a given time as a primary outcome. There are at least three common ways to measure 90-day mortality: first, all-location mortality, that is, all-cause mortality within 90 days of randomization at any location. Second, ARDSnet mortality is death in a healthcare facility of greater intensity than the patient was in prior to the hospitalization during which they were randomized. Finally, in-hospital mortality is death prior to discharge from the primary hospitalization of randomization. Data comparing the impact of these different measurements on sample size are lacking. We evaluated the extent to which event rates vary by mortality definition.MethodsThis was a retrospective cohort study of 30,691 patients hospitalized at Veterans Affairs (VA) hospitals for sepsis during 2009. 12,727 (41.5%) received care in an ICU setting. For each patient, we measured event rates for three different 90-day mortality outcomes: all-location mortality, ARDSnet mortality, and in-hospital mortality. We also calculated sample sizes necessary to power an example RCT given those event rates.ResultsAt 90 days, all-location mortality was 26.4% (95% CI 25.9-26.9%), ARDSnet mortality was 19.2% (95% CI 18.8-19.7%), and in-hospital mortality was 13.4% (95% CI 13.0-13.8%) (p < 0.01 all comparisons). These respective event rates result in different required sample sizes to achieve a 20% relative reduction in mortality with 80% power and a 5% false positive rate. Such a trial of VA sepsis patients would require 2080 patients for all-location mortality, 3080 for ARDSnet mortality, and 4796 for in-hospital mortality. Among sepsis patients mechanically ventilated in an ICU, 2438 experienced all-location mortality (46.2% [95% CI 44.8-47.5%]), 2181 experienced ARDSnet mortality (41.3% [95% CI 40.0-42.6%]), and 1894 experienced in-hospital mortality (36.0% [95% CI 34.7-37.3%]).ConclusionsEvent rates vary substantially in sepsis patients based on the chosen 90-day mortality definition. This could have important implications for RCT design trade-offs.

Dataset Information

The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) Protocol: a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial.

Publications

The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) Protocol: a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial.

Similar Datasets

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