Ascorbic Acid, Corticosteroids, and Thiamine in Sepsis (ACTS) Trial

Study Overview
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Brief Summary
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In this study, we aim to determine whether the combination of Ascorbic Acid (Vitamin C), Thiamine (Vitamin B1), and Corticosteroids improves the trajectory of organ failure and reduces mortality in patients with sepsis and septic shock as compared to placebo.

Detailed Description
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Sepsis and Septic Shock are common and highly morbid clinical conditions without any specific therapy aside from antibiotics. A recent quasi-experimental study (Marik et. al., PMID 27940189) demonstrated a remarkable benefit when the combination of Ascorbic Acid (Vitamin C), Corticosteroids, and Thiamine (Vitamin B1) were given to patients with sepsis. In particular, patients who received this combination of medications required a shorter amount of time on vasopressors, suffered less organ failure, and had improved mortality. Vitamin C has long been suggested for treatment of patients with severe infection as it exerts significant anti-oxidant effects and reduces endothelial permeability. Corticosteroids, a mainstay of therapy for refractory shock in sepsis, have also been shown to enhance the beneficial cellular effects of vitamin C. Finally, thiamine has been shown to be an effective mitochondrial resuscitator in sepsis, especially for the  30% of septic shock patients who present with thiamine deficiency (Donnino et. al, PMID 26771781). In this study, we aim to reproduce the findings of Marik et. al. using a more rigorous study design (i.e. a blinded, randomized clinical trial) and focus on the important clinical outcomes of organ failure and death.

Official Title
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Ascorbic Ccid, Hydrocortisone, and Thiamine in Sepsis and Septic Shock - A Randomized, Double-Blind, Placebo-Controlled Trial

Conditions
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Sepsis, Septic Shock, Metabolic Disturbance

Intervention / Treatment
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* Drug: vitamin C, vitamin B1, hydrocortisone
* Drug: Normal saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patient (age ≥ 18 years) Suspected (cultures drawn and antibiotic given) or confirmed (via culture results) infection Receiving vasopressor (norepinephrine, phenylephrine, epinephrine, dopamine, angiotensin II or vasopressin) Exclusion Criteria: Member of a protected population (pregnant, prisoner) Known kidney stones within the past 1 year (except for asymptomatic, incidentally noted stones on imaging) End stage renal disease (ESRD) requiring dialysis Known Glucose-6-Phosphate Dehydrogenase deficiency Known Hemachromatosis Comfort Measures Only status Anticipated death within 24-hours despite maximal therapy (as determined by the enrolling physician) Receiving supplemental thiamine in a dose greater than that contained in a multivitamin Clinical indication for steroids (e.g. chronic use) as determined by the clinical team providing this drug Clinical indication for thiamine as determined by the clinical team providing this drug Clinical indication for ascorbic acid as determined by the clinical team providing this drug Known allergy to vitamin C, hydrocortisone, or thiamine

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vitamin C, Vitamin B1, Corticosteroids<br>The combination of vitamin C, vitamin B1, hydrocortisone : Vitamin C (ascorbic acid) 1.5g every 6 hours x 4-days Vitamin B1 (thiamine) 100mg every 6 hours x 4-days Hydrocortisone 50mg every 6 hours x 4-days | Drug: vitamin C, vitamin B1, hydrocortisone<br>* Vitamin C (1.5g) plus vitamin B1 (100mg) will be diluted in 100ml 0.9% NACL(normal saline) and administered IV every 6 hours for 4 days or until participant is discharged from the ICU. Hydrocortisone 50mg/ml will be administered via IV push over 1-2 minutes every 6hours for 4 days or until the patient is discharged from the ICU.<br>* Other names: Thiamine;|
| Placebo Comparator: Placebo<br>Normal Saline Solution (0.9%NaCl) in a volume to match all experimental arm components | Drug: Normal saline<br>* Normal saline (0.9% NaCl solution) volume to match all components<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sequential Organ Failure Assessment (SOFA) Score at Baseline and 72 Hours | Sequential Organ Failure Assessment (SOFA) Score at Baseline and 72 Hours. The SOFA score ranges from a minimum of 0 to a maximum of 24, with higher scores meaning worse outcomes. | Enrollment to 72-hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal Failure | Development of renal failure as defined by a Kidney Disease Improving Global Outcomes [KDIGO] stage 3 or higher. There are 3 stages in the KDIGO scale with stage 3 being the worst (corresponds to renal failure). Stage 1- serum creatinine 1.5 to 1.9 times baseline OR an increase in serum creatinine ≥ 0.3 mg/dL OR urine output < 0.5ml/kg/hour for 6-12 hours. Stage 2- serum creatinine 2.0-2.9 times baseline OR urine output <0.5mg/kg/hour for ≥ 12 hours Stage 3- serum creatinine 3.0 times baseline (or serum creatinine of more than or equal to 4.0 mg/dl with an acute increase of at least 0.5 mg/dl) (OR) Urine output less than 0.3 ml/kg/hour for 24 hours or anuria for 12 hours or new renal replacement therapy | Enrollment until 7-days or discharge from the ICU | 
| 30-day Mortality | Mortality rate | Enrollment until 30-days after enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sepsis, Metabolic Resuscitation