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

• Authors: Christopher J. Lindsell, Vanderbilt University Medical Center; Anna McGlothlin, Berry Consultants; Samuel Nwosu, Vanderbilt University Medical Center; Todd W. Rice, Vanderbilt University Medical Center; Alex Hall, Emory University; Gordon R. Bernard, Vanderbilt University Medical Center; Laurence Busse, Emory University; E. Wesley Ely, Vanderbilt University Medical Center; Alpha A. Fowler, Virginia Commonwealth University; David F. Gaieski, Thomas Jefferson University; Jeremiah S. Hinson, Johns Hopkins University; Michael H. Hooper, Eastern Virginia Medical School; James C. Jackson, Vanderbilt University Medical Center; Gabor D. Kelen, Johns Hopkins University; Mark Levine, National Institute of Diabetes and Digestive and Kidney Diseases; Gregory Martin, Emory University; Richard E. Rothman, Johns Hopkins University; Jonathan Sevransky, Emory University; Kert Viele, Berry Consultants; David Wright, Emory University; David N. Hager, Johns Hopkins University
• Journal Title: Trials
• Volume: Volume 20, Number 1
• Publisher: BMC (part of Springer Nature) | 2019-12-04, Pages 670-670
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1186/s13063-019-3775-8
• Subjects: Health Sciences, Nutrition; Health Sciences, Medicine and Surgery
• Keywords: Adaptive sample size; Sepsis; Septic shock; Statistical analysis plan; Steroids; Thiamine; Vitamin C

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.