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

Abstract

Background: Observational research suggests that combined therapy with Vitamin C, thiamine and hydrocortisone may reduce mortality in patients with septic shock.

Methods and design: The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a multicenter, double-blind, adaptive sample size, randomized, placebo-controlled trial designed to test the efficacy of combination therapy with vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) given every 6 h for up to 16 doses in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. The primary outcome is ventilator- and vasopressor-free days with mortality as the key secondary outcome. Recruitment began in August 2018 and is ongoing; 501 participants have been enrolled to date, with a planned maximum sample size of 2000. The Data and Safety Monitoring Board reviewed interim results at N = 200, 300, 400 and 500, and has recommended continuing recruitment. The next interim analysis will occur when N = 1000. This update presents the statistical analysis plan. Specifically, we provide definitions for key treatment and outcome variables, and for intent-to-treat, per-protocol, and safety analysis datasets. We describe the planned descriptive analyses, the main analysis of the primary end point, our approach to secondary and exploratory analyses, and handling of missing data. Our goal is to provide enough detail that our approach could be replicated by an independent study group, thereby enhancing the transparency of the study.

Trial registration: ClinicalTrials.gov, NCT03509350. Registered on 26 April 2018.

Keywords: Adaptive sample size; Sepsis; Septic shock; Statistical analysis plan; Steroids; Thiamine; Vitamin C.

Conflict of interest statement

CJL reports funding for the VICTAS trial to his institution from the Marcus Foundation, and is named as co-inventor on patents related to risk stratification in septic shock. AM and KV are salaried employees of Berry Consultants, which is under contract with Emory University to support the design work and execution of the VICTAS trial. AH reports funding for the VICTAS trial to his institution from the Marcus Foundation as well as grants from the National Institutes of Health (NIH), Cerenovus, and the NICO Corporation. SN, GRB, DNH, JSH, TWR, and RER report funding for the VICTAS trial to their institutions from the Marcus Foundation. 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 (but no speakers’ bureaus or stocks etc.). ML is supported by the Intramural Research Program, NIDDK, NIH DK053212–12: Ascorbic acid as a pharmacologic agent in disease treatment. GSM reports grants for the VICTAS trial to his institution from the Marcus Foundation as well as grants from NIH, Biomedical Advanced Research and Development Authority (BARDA) and Bristol-Myers Squibb to his institution. JES reports grants for the VICTAS trial to his institution from the Marcus Foundation, funding from BARDA, and a stipend from the Society of Critical Care Medicine to support his editorial position for the journal Critical Care Medicine. DWW reports the grant for the VICTAS trial to his institution from the Marcus Foundation as well as grants from the NIH, the National Highway Transportation Safety Administration, the Department of Defense, NICO Corporation, and the Centers for Disease Control and Prevention. All remaining authors declare that they have no competing interests.

Figures

Fig. 1

Illustration of the calculation of ventilator- and vasopressor-free days (VVFDs) under various scenarios