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

David N Hager, Michael H Hooper, Gordon R Bernard, Laurence W Busse, E Wesley Ely, Alpha A Fowler, David F Gaieski, Alex Hall, Jeremiah S Hinson, James C Jackson, Gabor D Kelen, Mark Levine, Christopher J Lindsell, Richard E Malone, Anna McGlothlin, Richard E Rothman, Kert Viele, David W Wright, Jonathan E Sevransky, Greg S Martin, David N Hager, Michael H Hooper, Gordon R Bernard, Laurence W Busse, E Wesley Ely, Alpha A Fowler, David F Gaieski, Alex Hall, Jeremiah S Hinson, James C Jackson, Gabor D Kelen, Mark Levine, Christopher J Lindsell, Richard E Malone, Anna McGlothlin, Richard E Rothman, Kert Viele, David W Wright, Jonathan E Sevransky, Greg S Martin

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.

Keywords: Hydrocortisone; Mortality; Randomized controlled trial; Sepsis; Septic shock; Thiamine; Vitamin C.

Conflict of interest statement

Ethics approval and consent to participate

The study protocol and consent form have been approved by a cIRB at Johns Hopkins University (IRB protocol number: IRB00164053). Prior to the activation of any participating site, the protocol approved by the cIRB will be reviewed by each site’s local IRB to ensure compliance with local standards and regulations. Similarly, the cIRB approved consent form will be reviewed locally by the IRB of each participating site and amended so that it is compliant with local standards and regulations. Potential participants or legally authorized representatives (if applicable) at each site will be approached by credentialed study personnel at each site to inform them of the study. Participants or legally authorized representatives (if applicable) will provide consent.

Consent for publication

Not applicable.

Competing interests

EWE reports funding for the VICTAS trial to his institution from the Marcus Foundation and has received honoraria from Pfizer, Orion, and Masimo for continuing medical education activities (no speakers’ bureaus or stocks and so on). DNH, GRB, AH, JSH, JCJ, REM, and RER report funding for the VICTAS trial to his institution from the Marcus Foundation. CJL was named as co-inventor on patents related to risk stratification in septic shock. AM and KV are salaried employees of Berry Consulting, which is under contract with Emory University to support the design work and execution of the VICTAS trial. DWW reports the grant for the VICTAS trial to his institution from the Marcus Foundation as well as grants from the National Institutes of Health (NIH), the National Highway Transportation Safety Administration, the Department of Defense, NICO Corporation, and the Centers for Disease Control and Prevention. JES reports grants for the VICTAS trial to his institution from the Marcus Foundation, funding from the Biomedical Advanced Research and Development Authority, and a stipend from the Society of Critical Care Medicine to support his editorial position for the journal Critical Care Medicine. GSM reports grants for the VICTAS trial to his institution from the Marcus Foundation as well as grants from the NIH and Bristol-Myers Squibb to his institution. MHH, LWB, ABF, DFG, GDK and ML declare that they have no competing interests.

Access to data: A de-identified dataset from participants in the VICTAS trial will be made publicly available about one year after publication of the primary manuscript.

Dissemination and authorship policy: The VICTAS trial publications protocol (Additional file 1) will ensure the rapid and accurate translation of study results to the scientific, medical, and global community and maximize the scholarly productivity of the trial. The protocol will outline the steps needed for publishing data related to the VICTAS trial, including concept generation and submission, writing and analysis responsibilities, and authorship.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Administrative organization of study. Abbreviations: CCC Clinical Coordinating Center, DCC Data Coordinating Center, DSMB data safety monitoring board, IRB institutional review board, JHU Johns Hopkins University, PI principal investigator.
Fig. 2
Fig. 2
Overview of study progression. Abbreviations: CAM-ICU Confusion Assessment Method for the Intensive Care Unit, DC discharge, ICU intensive care unit, SOFA Sequential Organ Failure Assessment.

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