ORIGINAL ARTICLES Vitamin C, Hydrocortisone and Thiamine in Patients with Septic Shock (VITAMINS) trial: study protocol and statistical analysis plan Tomoko Fujii, Andrew A Udy, Adam M Deane, Nora Luethi, Michael Bailey, Glenn M Eastwood, Daniel Frei, Craig French, Neil Orford, Yahya Shehabi, Paul J Young and Rinaldo Bellomo, on behalf of the VITAMINS trial investigators Sepsis is a dysregulated host response to infection. ABSTRACT Adjunctive therapies targeting the inflammatory cascade are being increasingly explored, although, to date, they Background: Septic shock is associated with poor outcomes. have failed to demonstrate consistent benefit, and sepsis Vitamin C (ascorbic acid) is a cellular antioxidant and has and septic shock continue to lead to poor outcomes. anti-inflammatory properties. Whether the combination Hospital mortality in patients with septic shock remains as therapy of vitamin C, thiamine and hydrocortisone reduces high as 22% in Australia and New Zealand.1 From a global vasopressor dependency in septic shock is unclear. perspective, perhaps 50 million patients with sepsis are Objectives: To describe the protocol and statistical analysis treated in hospitals every year.2 plan of a multicentre, open-label, prospective, phase 2 Moreover, the mortality from sepsis and septic shock in randomised clinical trial evaluating the effects of vitamin middle and low income countries is reported to be as high C, thiamine and hydrocortisone when compared with as 60%.3-5 In addition, patients with sepsis have numerous hydrocortisone monotherapy on the duration of vasopressor short and long term complications and are at increased risk administration in critically ill patients with septic shock. of death for up to several years following the acute event.6-9 Methods: VITAMINS is a multicentre cardiovascular efficacy Thus, effective, low cost and safe treatment strategies are trial in adult patients with septic shock. Randomisation urgently needed. occurs via a secure website with stratification by site, and In animal models, exogenous vitamin C (ascorbic acid) allocation concealment is maintained throughout the trial. has been reported to attenuate the inflammatory cascade, The primary outcome is the duration of time alive and reduce the endothelial injury characteristic of sepsis, free of vasopressor administration at Day 7. Secondary enhance the release of endogenous catecholamines, and outcomes include feasibility endpoints and some patient- improve vasopressor responsiveness.10-15 These effects have centred outcomes. All analyses will be conducted on an resulted in reduced organ injury and increased survival in intention-to-treat basis. some models. However, their effects in critically ill humans Conclusion: The VITAMINS trial will determine whether are unclear due to insufficient clinical data.16 combination therapy of vitamin C, thiamine and Relative thiamine deficiency frequently occurs in critically ill hydrocortisone when compared with hydrocortisone patients with sepsis.17 Thiamine increases the conversion of increases vasopressor-free hours in critically ill patients glyoxylate, a by-product of vitamin C metabolism, to oxalate. with septic shock. The conduct of this study will provide Oxalate is excreted by the kidney, and serum concentrations important information on the feasibility of studying this will increase with renal impairment.18 In patients with renal intervention in a phase 3 trial. impairment receiving high dose vitamin C, supersaturation Trial registration: ClinicalTrials.gov, identification No. of serum with oxalate may result in tissue deposition as well NCT03333278. as crystallisation in the kidney. Also, thiamine can reverse oxidative stress that is not related to thiamine deficiency, Crit Care Resusc 2019; 21 (2): 119-125 suggesting that thiamine may act as a site-directed antioxidant.19 Exogenous thiamine may, therefore, limit oxidative injury and restore energy production.20 be useful. The combination therapy was reported to reduce A single-centre retrospective before-and-after study of the time of vasopressor administration and mortality in 94 patients supported the concept that administration of patients with severe sepsis and septic shock.21 In this study, high dose intravenous vitamin C (1.5 g four times per day), hydrocortisone was administered to ≈ 60% of patients together with high dose intravenous thiamine (200 mg twice in the control group. Since this study was published, the a day) and hydrocortisone (50 mg four times per day) may ADRENAL (Adjunctive Corticosteroid Treatment in Critically Critical Care and Resuscitation • Volume 21 Number 2 • June 2019 119 ORIGINAL ARTICLES Ill Patients with Septic Shock) trial established that the Randomisation duration of vasopressor is reduced with hydrocortisone Allocation concealment administration.22 The Vitamin C, Hydrocortisone and Thiamine in Patients A permuted block randomisation method with variable block with Septic Shock (VITAMINS) trial is a multicentre pilot sizes of 2, 4 and 6 and stratified by site was developed. The feasibility randomised clinical trial to further evaluate random allocation sequence was generated centrally using the role of vitamin C and thiamine. The VITAMINS trial a computer software program at the coordinating centre, is managed by the Australian and New Zealand Intensive the ANZIC-RC. This was then embedded into the Research Care Research Centre (ANZIC-RC) at Monash University Electronic Data Capture (REDCap) system, which is a secure 24 and is supported by the Intensive Care Foundation (www. web application for managing online data collection. intensivecarefoundation.org.au). This report presents ICU patients are allocated to either group in a 1:1 ratio as the trial protocol and the statistical analysis plan. The soon as possible after fulfilling the eligibility criteria, and VITAMINS trial is registered with ClinicalTrials.gov randomisation is performed using the REDCap system at (identification No. NCT03333278) each study site. To limit selection bias, site investigators, site research coordinators, and statisticians cannot access the allocation sequence. Objectives The primary aim of the VITAMINS trial is to determine Blinding whether the intravenous administration of vitamin C, The VITAMINS trial is an open-label study; accordingly, all thiamine and hydrocortisone in patients with septic shock site personnel are aware of the study intervention assigned increases the duration of time alive and free of vasopressor to the participants. administration at Day 7 after randomisation compared with hydrocortisone alone. Study interventions Methods Intervention group Patients in the intervention group receive intravenous Study design and participants vitamin C (1.5 g, every 6 hours), thiamine (200 mg, every 12 This is a multicentre, open-label, prospective, phase 2 hours), and hydrocortisone (50 mg, every 6 hours). Vitamin randomised clinical trial. Patients admitted to a study C is diluted in a 100 mL solvent of either 0.9% saline or 5% intensive care unit (ICU) with a primary diagnosis of septic dextrose in water and infused over one hour. For patients shock will be screened for inclusion. in whom the treating clinician wishes to restrict fluid administration, vitamin C (1.5 g) can be diluted into 50 mL Study population of solvent. Thiamine (200 mg) is added to a 100 mL solvent of either 0.9% saline or 5% dextrose in water and infused Inclusion criteria over 30–60 minutes. For patients in whom the treating clinician wishes to restrict fluid administration, thiamine All diagnostic criteria for septic shock (based on the Sepsis-3 can be diluted into 50 mL of solvent. Hydrocortisone is 23 consensus ) have to be fulfilled simultaneously within a administered by slow intravenous injection over at least 24-hour period before enrolment. In addition, the patient 30 seconds. Hydrocortisone can be stopped or tapered must be receiving a vasopressor infusion continuously at the after the completion of study treatment as per the treating time of enrolment. clinician. We recommend a taper of 3 days. Thus, inclusion criteria include: suspected or documented infection; acute increase of ≥ 2 Sequential Organ Failure Assessment Control group (SOFA) points due to the infection; Patients in the control arm of the study receive need for vasopressor therapy to maintain the mean hydrocortisone 50 mg intravenous every 6 hours.22,25 arterial pressure (MAP) > 65 mm Hg for > 2 hours; and Hydrocortisone is administered by slow intravenous lactate > 2 mmol/L, despite adequate fluid resuscitation. injection over at least 30 seconds. Hydrocortisone can be stopped or tapered after the completion of study treatment Exclusion criteria as per the treating clinician. Patients also receive thiamine Patients will be excluded from the study if any of the criteria if clinically indicated at the discretion of the attending listed in Table 1 apply. ICU clinician. As the administration of intravenous vitamin 120 Critical Care and Resuscitation • Volume 21 Number 2 • June 2019 ORIGINAL ARTICLES Table 1. Exclusion criteria of the VITAMINS trial . Age < 18 years . Pregnancy . DNR (do not resuscitate)/DNI (do not intubate) orders . Death is deemed to be imminent or inevitable during this admission, and either the attending physician, patient or substitute decision maker is not committed to active treatment . Patients with known human immunodeficiency virus (HIV) infection . Patients with known glucose-6-phosphate dehydrogenase (G6PD) deficiency .