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

Phase 2

Completed

Interventions: Drug: vitamin C, vitamin B1, hydrocortisone
Drug: Normal saline

Brief Summary: 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: 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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
Vitamin C, Vitamin B1, Corticosteroids	vitamin C, vitamin B1, hydrocortisone	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
Placebo	Normal saline	Normal Saline Solution (0.9%NaCl) in a volume to match all experimental arm components

Primary Outcome Measures

Name	Time	Method
Sequential Organ Failure Assessment (SOFA) Score at Baseline and 72 Hours	Enrollment to 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.

Secondary Outcome Measures

Name	Time	Method
30-day Mortality	Enrollment until 30-days after enrollment	Mortality rate
Renal Failure	Enrollment until 7-days or discharge from the ICU	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

Locations (13): Brigham and Women's Hospital
🇺🇸
Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
🇺🇸
Boston, Massachusetts, United States
Mount Auburn Hospital
🇺🇸
Cambridge, Massachusetts, United States
Detroit Receiving Hospital
🇺🇸
Detroit, Michigan, United States
Harper University Hospital
🇺🇸
Detroit, Michigan, United States
Henry Ford Hospital
🇺🇸
Detroit, Michigan, United States
Sinai Grace Hospital
🇺🇸
Detroit, Michigan, United States
North Shore University Hospital
🇺🇸
Manhasset, New York, United States
Long Island Jewish Hospital
🇺🇸
New York, New York, United States
University Of Pittsburgh Medical Center
🇺🇸
Pittsburgh, Pennsylvania, United States
Beaumont Hospital
🇺🇸
Royal Oak, Michigan, United States
The University of Texas Health Science Center
🇺🇸
Houston, Texas, United States
Mayo Clinic - Arizona
🇺🇸
Phoenix, Arizona, United States