A Randomized, Double Blind, Placebo-Controlled Trial to Investigate the Effect of Vitamin C, Hydrocortisone and Thiamine on the Outcome of Patients with Septic Shock
Trial Snapshot
- Phase
- Phase 2
- Status
- Terminated
- Sponsor
- Enrollment
- 24
- Locations
- 2
- Primary Endpoint
- Hospital Mortality
Study Overview
Brief Summary
Prior data has shown that both corticosteroids and vitamin C reduce the activation of nuclear factor ƘB (NFƘB), thereby ultimately attenuating the systemic inflammatory response to sepsis/septic shock and augmenting the responsiveness to vasopressors. Therefore, the current investigators hypothesized that the combined use of vitamin C and stress-dose hydrocortisone may improve the outcomes of patients with septic shock. The investigators intend to perform a randomized, multicenter, parallel group, double-blind, placebo-controlled trial of vitamin C plus stress-dose hydrocortisone or placebo plus placebo for a total of four days after randomization of patients fulfilling the current consensus criteria for septic shock. The primary outcome will be hospital mortality, whereas the scondary outcomes will include 60-day, 28-day mortality, time to vasopressor cessation, procalcitonin clearance and change in the Sequential Organ Failure Assessment score over the first 4 days after randomization, neurologic failure-free days, and length of stay in the intensive care unit (ICU) and the hospital. Target enrollment will be 400 patients.
Detailed Description
Background and Significance:
The global burden of sepsis is substantial with an estimated 15 to 19 million cases per year; the vast majority of these cases occur in low income countries. With more timely diagnosis and improvement in supportive care the 28-day mortality from sepsis in high income countries has declined to about 25%, however, the mortality from septic shock remains as high as 45%. Moreover, the mortality from sepsis and septic shock in low income countries is reported to be as high as 60%. Over the last 3 decades over 100 phase II and phase III clinical trials have been performed testing various novel pharmacologic agents and therapeutic interventions in an attempt to improve the outcome of patients with sepsis and septic shock; all of these studies have failed to show an improvement in patient outcomes. A large body of experimental data has demonstrated that both corticosteroids and intravenous vitamin C reduce activation of nuclear factor ƘB (NFƘB) and attenuatethe release of pro-inflammatory mediators, reduce the endothelial injury characteristic of sepsis (thereby reducing endothelial permeability and improving macrocirculatory flow), augment the release of endogenous catecholamines, and enhance vasopressor responsiveness. In addition, recent evidence suggests that thiamine may be neuroprotective in severe shock states.
Specific Aims of the Study:
The aim of this study is to determine the effect of the combination of intravenous vitamin C, hydrocortisone and thiamine on the clinical course and outcome of patients with septic shock.
Study Design:
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description
Participants, Investigators performing the follow-up, and care providers will be blinded
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •i. Diagnosis of septic shock within 12 hours of admission to the ICU
Exclusion Criteria
- •i. Age < 18 years ii. Pregnant iii. Patients with an end-stage underlying disease who are unlikely to survive to hospital discharge iv. Patients with acquired immunodeficiency syndrome and a CD4 count of < 50 per microliter v. Patients with known glucose-6 phosphate dehydrogenase (G-6PD) deficiency. vi. Patients with septic shock transferred from another hospital vii. Patients with septic shock for more than 12 hours viii. Patients who require off-label treatment with corticosteroids for an indication other than sepsis ix. Lack of written, informed consent
Arms & Interventions
Control
"Placebo plus placebo:" Patients with septic shock treated with placebo (corresponding to Vitamin C) and placebo (corresponding to hydrocortisone) for 4 days after randomization.
Intervention: Placebo plus placebo (Drug)
Vitamin-Steroid
"Combined Vitamin C and Stress-Dose Hydrocortisone": Patients with septic shock treated with 1500 mg Vitamin C every 6 hours for 4 days after randomization, and stress-dose hydrocortisone for 4 days (250 mg on day 1; and 200 mg on days 2, 3, and 4) after randomization.
Intervention: Combined Vitamin C and Stress-Dose Hydrocortisone (Drug)
Outcomes
Primary Outcomes
Hospital Mortality
Time Frame: 90 days
Death before hospital discharge
Secondary Outcomes
- Delta Sequential Organ Failure Assessment (SOFA) score(4 days)
- 28-day mortality(28 days)
- Intensive Care Unit (ICU) mortality(90 days)
- Procalcitonin (PCT) clearance .(4 days)
- Neurologic failure-free days (defined as daily follow-up Glasgow Coma Score >9) within the first 28 days of follow-up(28 days)
- 60-day mortality(60 days)
- ICU length of stay(90 days)
- ICU free days to day 28.(28 days)
- Hospital length of stay(90 days)
Investigators
Spyros D. Mentzelopoulos
Associate Professor of Intensive Care Medicine
University of Athens