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.
Project description: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.
Project description:Importance:It is unclear whether vitamin C, hydrocortisone, and thiamine are more effective than hydrocortisone alone in expediting resolution of septic shock. Objective:To determine whether the combination of vitamin C, hydrocortisone, and thiamine, compared with hydrocortisone alone, improves the duration of time alive and free of vasopressor administration in patients with septic shock. Design, Setting, and Participants:Multicenter, open-label, randomized clinical trial conducted in 10 intensive care units in Australia, New Zealand, and Brazil that recruited 216 patients fulfilling the Sepsis-3 definition of septic shock. The first patient was enrolled on May 8, 2018, and the last on July 9, 2019. The final date of follow-up was October 6, 2019. Interventions:Patients were randomized to the intervention group (n?=?109), consisting of intravenous vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), and thiamine (200 mg every 12 hours), or to the control group (n?=?107), consisting of intravenous hydrocortisone (50 mg every 6 hours) alone until shock resolution or up to 10 days. Main Outcomes and Measures:The primary trial outcome was duration of time alive and free of vasopressor administration up to day 7. Ten secondary outcomes were prespecified, including 90-day mortality. Results:Among 216 patients who were randomized, 211 provided consent and completed the primary outcome measurement (mean age, 61.7 years [SD, 15.0]; 133 men [63%]). Time alive and vasopressor free up to day 7 was 122.1 hours (interquartile range [IQR], 76.3-145.4 hours) in the intervention group and 124.6 hours (IQR, 82.1-147.0 hours) in the control group; the median of all paired differences was -0.6 hours (95% CI, -8.3 to 7.2 hours; P?=?.83). Of 10 prespecified secondary outcomes, 9 showed no statistically significant difference. Ninety-day mortality was 30/105 (28.6%) in the intervention group and 25/102 (24.5%) in the control group (hazard ratio, 1.18; 95% CI, 0.69-2.00). No serious adverse events were reported. Conclusions and Relevance:In patients with septic shock, treatment with intravenous vitamin C, hydrocortisone, and thiamine, compared with intravenous hydrocortisone alone, did not significantly improve the duration of time alive and free of vasopressor administration over 7 days. The finding suggests that treatment with intravenous vitamin C, hydrocortisone, and thiamine does not lead to a more rapid resolution of septic shock compared with intravenous hydrocortisone alone. Trial Registration:ClinicalTrials.gov Identifier: NCT03333278.
Project description:The combination of thiamine, ascorbic acid, and hydrocortisone has recently emerged as a potential adjunctive therapy to antibiotics, infectious source control, and supportive care for patients with sepsis and septic shock. In the present manuscript, we provide a comprehensive review of the pathophysiologic basis and supporting research for each element of the thiamine, ascorbic acid, and hydrocortisone drug combination in sepsis. In addition, we describe potential areas of synergy between these therapies and discuss the strengths/weaknesses of the two studies to date which have evaluated the drug combination in patients with severe infection. Finally, we describe the current state of current clinical practice as it relates to the thiamine, ascorbic acid, and hydrocortisone combination and present an overview of the randomized, placebo-controlled, multi-center Ascorbic acid, Corticosteroids, and Thiamine in Sepsis (ACTS) trial and other planned/ongoing randomized clinical trials.
Project description:INTRODUCTION:Septic shock is a common and highly morbid condition. To date, there is no specific therapy proven to attenuate organ injury in septic shock. Recent studies have suggested a role for the combination of ascorbic acid, corticosteroids and thiamine, although randomised data are lacking. METHODS AND ANALYSIS:The Ascorbic Acid, Corticosteroids, and Thiamine in Sepsis trial is a multi-centre, double-blind, randomised, placebo-controlled clinical trial that aims to determine the impact of ascorbic acid, corticosteroids and thiamine versus placebo on organ injury and mortality in patients with septic shock. Patients are randomised to receive 1500 mg of ascorbic acid, 100 mg of thiamine and 50 mg of hydrocortisone parenterally versus matching placebo every 6 hours for 4 days. Clinical and laboratory data are collected at the time of study enrolment, at 24, 72 and 120 hours. The primary end-point for the trial is change in the Sequential Organ Failure Assessment score between enrolment and 72 hours. Additional key secondary outcomes include the incidence of renal failure and 30-day mortality. ETHICS AND DISSEMINATION:The study was approved by the international review board of each participating study site. Study findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER:The trial is registered on clinicaltrials.gov (NCT03389555). It was posted on 3 January 2018.
Project description:Sepsis is a common cause of delirium in the intensive care unit (ICU). Recently, vitamin C and thiamine administration has been gaining interest as a potential adjunct therapy for sepsis. We investigated the impact of early vitamin C and thiamine administration on ICU delirium-free days among critically ill patients in septic shock. We performed a single-center, retrospective study of patients who visited the emergency department (ED) from January 2017 to July 2018. We categorized patients into a treatment (received vitamin C and thiamine) and control group. We compared delirium-free days within 14 days after ICU admission using propensity score matching. Of 435 patients with septic shock, we assigned 89 propensity score-matched pairs to the treatment and control groups. The median delirium-free days did not differ between treatment (11, interquartile range [IQR] 5-14 days) and control (12, IQR 6-14 days) groups (p = 0.894). Secondary outcomes were not different between the two groups, including delirium incidence and 28-day mortality. These findings were consistent after subgroup analysis for patients who met the sepsis-3 definition of septic shock. Vitamin C and thiamine administration showed no association with ICU delirium-free days among patients in septic shock.
Project description:BACKGROUND:Sepsis is a health problem of global importance; treatments focus on controlling infection and supporting failing organs. Recent clinical research suggests that intravenous vitamin C may decrease mortality in sepsis. We have designed a randomized controlled trial (RCT) to ascertain the effect of vitamin C on the composite endpoint of death or persistent organ dysfunction at 28?days in patients with sepsis. METHODS:LOVIT (Lessening Organ dysfunction with VITamin C) is a multicenter, parallel-group, blinded (participants, clinicians, study personnel, Steering Committee members, data analysts), superiority RCT (minimum n =?800). Eligible patients have sepsis as the diagnosis for admission to the intensive care unit (ICU) and are receiving vasopressors. Those admitted to the ICU for more than 24?h are excluded. Eligible patients are randomized to high-dose intravenous vitamin C (50?mg/kg every 6?h for 96?h) or placebo. The primary outcome is a composite of death or persistent organ dysfunction (need for vasopressors, invasive mechanical ventilation, or new and persisting renal replacement therapy) at day 28. Secondary outcomes include persistent organ dysfunction-free days to day 28, mortality and health-related quality of life at 6?months, biomarkers of dysoxia, inflammation, infection, endothelial function, and adverse effects (hemolysis, acute kidney injury, and hypoglycemia). Six subgroup analyses are planned. DISCUSSION:This RCT will provide evidence of the effect of high-dose intravenous vitamin C on patient-important outcomes in patients with sepsis. TRIAL REGISTRATION:clinicaltrials.gov, NCT03680274, first posted 21 September 2018.
Project description:BACKGROUND:Thiamine, an essential vitamin for aerobic metabolism and glutathione cycling, may decrease the effects of critical illnesses. The objective of this study was to determine whether intravenous thiamine administration can reduce vasopressor requirements in patients with septic shock. METHODS:This study was a prospective randomized double-blind placebo-controlled trial. We included adult patients with septic shock who required a vasopressor within 1-24?h after admission between March 2018 and January 2019 at a tertiary hospital in Thailand. Patients were divided into two groups: those who received 200?mg thiamine or those receiving a placebo every 12?h for 7?days or until hospital discharge. The primary outcome was the number of vasopressor-free days over 7?days. The pre-defined sample size was 31 patients per group, and the study was terminated early due to difficult recruitment. RESULTS:Sixty-two patients were screened and 50 patients were finally enrolled in the study, 25 in each group. There was no difference in the primary outcome of vasopressor-free days within the 7-day period between the thiamine and placebo groups (mean: 4.9?days (1.9) vs. 4.0?days (2.7), p =?0.197, mean difference?-?0.9, 95% CI (-?2.9 to 0.5)). However, the reductions in lactate (p =?0.024) and in the vasopressor dependency index (p =?0.02) at 24?h were greater among subjects who received thiamine repletion vs. the placebo. No statistically significant difference was observed in SOFA scores within 7?days, vasopressor dependency index within 4?days and 7?days, or 28-day mortality. CONCLUSIONS:Thiamine was not associated to a significant reduction in vasopressor-free days over 7-days in comparison to placebo in patients with septic shock. Administration of thiamine could be associated with a reduction in vasopressor dependency index and lactate level within 24?h. The study is limited by early stopping and low sample size. TRIAL REGISTRATION:TCTR, TCTR20180310001. Registered 8 March 2018, http://www.clinicaltrials.in.th/index.php?tp=regtrials&menu=trialsearch&smenu=fulltext&task=search&task2=view1&id=3330 .
Project description:BACKGROUND:Septic shock is a life-threatening condition with underlying circulatory and cellular/metabolic abnormalities. Vitamin C and thiamine are potential candidates for adjunctive therapy; they are expected to improve outcomes based on recent experimental and clinical research. The aim of the Ascorbic Acid and Thiamine Effect in Septic Shock (ATESS) trial is to evaluate the effects of early combination therapy with intravenous vitamin C and thiamine on recovery from organ failure in patients with septic shock. METHODS:This study is a randomized, double-blind, placebo-controlled, multicentre trial in adult patients with septic shock recruited from six emergency departments in South Korea. Patients will be randomly allocated into the treatment or control group (1:1 ratio), and we will recruit 116 septic shock patients (58 per group). For the treatment group, vitamin C (50?mg/kg) and thiamine (200?mg) will be mixed in 50?ml of 0.9% saline and administered intravenously every 12?h for a total of 48?h. For the placebo group, an identical volume of 0.9% saline will be administered in the same manner. The primary outcome is the delta Sequential Organ Failure Assessment (SOFA) score (?SOFA?=?initial SOFA at enrolment - follow-up SOFA after 72?h). DISCUSSION:This trial will provide valuable evidence about the effectiveness of vitamin C and thiamine therapy for septic shock. If effective, this therapy might improve survival and become one of the main therapeutic adjuncts for patients with septic shock. TRIAL REGISTRATION:ClinicalTrials.gov, NCT03756220 . Registered on 5 December 2018.
Project description:PURPOSE:To evaluate the effects of early combination therapy with intravenous vitamin C and thiamine on recovery from organ failure in patients with septic shock. METHODS:The ascorbic acid and thiamine effect in septic shock (ATESS) trial was a multi-centre, double-blind, randomized, controlled trial conducted in four academic emergency departments, enrolling adult patients with septic shock from December 2018 through January 2020. Patients were randomly assigned in a 1:1 ratio to either the treatment group [intravenous vitamin C (50 mg/kg, maximum single dose 3 g) and thiamine (200 mg) administration every 12 h for a total of 48 h] or the placebo group (identical volume of 0.9% saline with the same protocol). The primary outcome was ? Sequential Organ Failure Assessment (SOFA) score (SOFA score at enrolment-SOFA score after 72 h). Eighteen secondary outcomes were predefined, including shock reversal and 28-day mortality. RESULTS:A total of 111 patients were enrolled, of which 53 were assigned to the treatment group and 58 were assigned to the placebo group. There was no significant difference in ?SOFA scores between the treatment group and the placebo group [3, interquartile range (IQR) - 1 to 5 vs. 3, IQR 0-4, respectively, p?=?0.96]. Predefined secondary outcomes were also not significantly different between the groups. CONCLUSION:In this study, vitamin C and thiamine administration in the early phase of septic shock did not improve organ function compared with placebo, despite improvements in vitamin C and thiamine levels.
Project description:This study aimed to identify septic phenotypes in patients receiving vitamin C, hydrocortisone, and thiamine using temperature and white blood cell count. Data were obtained from septic shock patients who were also treated using a vitamin C protocol in a medical intensive care unit. Patients were divided into groups according to the temperature measurements as well as white blood cell counts within 24 h before starting the vitamin C protocol. In the study, 127 patients included who met the inclusion criteria. In the cohort, four groups were identified: "Temperature ?37.1 °C, white blood cell count ?15.0 1000/mm3" (group A; n = 27), "?37.1 °C, <15.0 1000/mm3" (group B; n = 30), "<37.1 °C, ?15.0 1000/mm3" (group C; n = 35) and "<37.1 °C, <15.0 1000/mm3" (group D; n = 35). The intensive care unit mortality rates were 15% for group A, 33% for group B, 34% for group C, and 49% for group D (p = 0.051). The temporal improvement in organ dysfunction and vasopressor dose seemed more apparent in group A patients. Our results suggest that different subphenotypes exist among sepsis patients treated using a vitamin C protocol, and clinical outcomes might be better for patients with the hyperinflammatory subphenotype.