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

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

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.

Study Overview

• Status: Completed
• Conditions: Sepsis; Septic Shock; Metabolic Disturbance
• Intervention / Treatment: Drug: vitamin C, vitamin B1, hydrocortisone; Drug: Normal saline

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.

• Study Type: Interventional
• Enrollment (Actual): 205
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic - Arizona
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Cambridge, Massachusetts, United States, 02138
      • Mount Auburn Hospital
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
    • Detroit, Michigan, United States, 48201
      • Harper University Hospital
    • Detroit, Michigan, United States, 48201
      • Detroit Receiving Hospital
    • Detroit, Michigan, United States, 48235
      • Sinai Grace Hospital
    • Royal Oak, Michigan, United States, 48073
      • Beaumont Hospital
  • New York
    • Manhasset, New York, United States, 11030
      • North Shore University Hospital
    • New York, New York, United States, 11040
      • Long Island Jewish Hospital
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas Health Science Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adult patient (age ≥ 18 years)
2. Suspected (cultures drawn and antibiotic given) or confirmed (via culture results) infection
3. Receiving vasopressor (norepinephrine, phenylephrine, epinephrine, dopamine, angiotensin II or vasopressin)

Exclusion Criteria:

1. Member of a protected population (pregnant, prisoner)
2. Known kidney stones within the past 1 year (except for asymptomatic, incidentally noted stones on imaging)
3. End stage renal disease (ESRD) requiring dialysis
4. Known Glucose-6-Phosphate Dehydrogenase deficiency
5. Known Hemachromatosis
6. Comfort Measures Only status
7. Anticipated death within 24-hours despite maximal therapy (as determined by the enrolling physician)
8. Receiving supplemental thiamine in a dose greater than that contained in a multivitamin
9. Clinical indication for steroids (e.g. chronic use) as determined by the clinical team providing this drug
10. Clinical indication for thiamine as determined by the clinical team providing this drug
11. Clinical indication for ascorbic acid as determined by the clinical team providing this drug
12. Known allergy to vitamin C, hydrocortisone, or thiamine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Vitamin C, Vitamin B1, Corticosteroids; 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; 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.; Other Names: Ascorbic Acid; Thiamine
PLACEBO_COMPARATOR: Placebo; Normal Saline Solution (0.9%NaCl) in a volume to match all experimental arm components	Drug: Normal saline; Normal saline (0.9% NaCl solution) volume to match all components

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ventilator Free Days	Days not receiving invasive mechanical ventilation	Ventilator free days over the first 7-days after enrollment
Shock Free Days	Days not receiving vasopressor	Vasopressor free days over the first 7-days after enrollment
ICU Free Days	Number of days that the patient was not in the ICU. Timeframe listed below.	From enrollment until 28 days after enrollment
Hospital Mortality	Hospital mortality rate	Enrollment until hospital discharge, death, or 30-days. Whichever comes first.
Intensive Care Unit (ICU) Mortality	ICU mortality rate	Enrollment until ICU discharge, death, or 30-days. Whichever comes first.
Number of Participants With Delirium	Describes if patient has delirium as defined by the Confusion Assessment Method (CAM)-ICU. The CAM-ICU method requires that the patient have 3 features to qualify for delirium: Acute Onset of Changes or Fluctuations in the Course of Mental Status (AND ); Inattention (AND); Disorganized thinking (OR) Altered Level of Consciousness	On day 3 (at approximately 72 hours) after the first study drug dose
Hospital Disposition: Survivors Discharged Home	Home hospital disposition in patients who survive to discharge	Enrollment until hospital discharge, death, or 30-days, whichever comes first.

Collaborators and Investigators

• Sponsor: Beth Israel Deaconess Medical Center
• Collaborators: Open Philanthropy

Publications and helpful links

General Publications

• Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest. 2017 Jun;151(6):1229-1238. doi: 10.1016/j.chest.2016.11.036. Epub 2016 Dec 6.
• Moskowitz A, Andersen LW, Cocchi MN, Karlsson M, Patel PV, Donnino MW. Thiamine as a Renal Protective Agent in Septic Shock. A Secondary Analysis of a Randomized, Double-Blind, Placebo-controlled Trial. Ann Am Thorac Soc. 2017 May;14(5):737-741. doi: 10.1513/AnnalsATS.201608-656BC.
• Donnino MW, Andersen LW, Chase M, Berg KM, Tidswell M, Giberson T, Wolfe R, Moskowitz A, Smithline H, Ngo L, Cocchi MN; Center for Resuscitation Science Research Group. Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study. Crit Care Med. 2016 Feb;44(2):360-7. doi: 10.1097/CCM.0000000000001572.
• Grossestreuer AV, Moskowitz A, Andersen LW, Holmberg MJ, Konacki V, Berg KM, Chase M, Cocchi MN, Donnino MW. Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Health-Related Quality of Life in Sepsis. Crit Care Explor. 2020 Nov 23;2(12):e0270. doi: 10.1097/CCE.0000000000000270. eCollection 2020 Dec.
• Moskowitz A, Huang DT, Hou PC, Gong J, Doshi PB, Grossestreuer AV, Andersen LW, Ngo L, Sherwin RL, Berg KM, Chase M, Cocchi MN, McCannon JB, Hershey M, Hilewitz A, Korotun M, Becker LB, Otero RM, Uduman J, Sen A, Donnino MW; ACTS Clinical Trial Investigators. Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock: The ACTS Randomized Clinical Trial. JAMA. 2020 Aug 18;324(7):642-650. doi: 10.1001/jama.2020.11946.
• Moskowitz A, Yankama T, Andersen LW, Huang DT, Donnino MW, Grossestreuer AV; ACTS Clinical Trial Investigators. Ascorbic Acid, Corticosteroids and Thiamine in Sepsis (ACTS) protocol and statistical analysis plan: a prospective, multicentre, double-blind, randomised, placebo-controlled clinical trial. BMJ Open. 2019 Dec 17;9(12):e034406. doi: 10.1136/bmjopen-2019-034406.

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 9, 2018
• Primary Completion (ACTUAL): November 26, 2019
• Study Completion (ACTUAL): February 28, 2020

Study Registration Dates

• First Submitted: December 27, 2017
• First Submitted That Met QC Criteria: January 2, 2018
• First Posted (ACTUAL): January 3, 2018

Study Record Updates

• Last Update Posted (ACTUAL): February 16, 2021
• Last Update Submitted That Met QC Criteria: January 29, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Sepsis; Metabolic Resuscitation
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Sepsis; Toxemia; Shock, Septic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Protective Agents; Micronutrients; Antioxidants; Vitamin B Complex; Vitamins; Hydrocortisone; Ascorbic Acid; Thiamine
• Other Study ID Numbers: 2017P000436

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No