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

• ClinicalTrials.gov Identifier: NCT03389555
• Recruitment Status: Completed
• First Posted: January 3, 2018
• Results First Posted: January 29, 2021
• Last Update Posted: February 16, 2021
• Sponsor: Beth Israel Deaconess Medical Center
• Collaborator: Open Philanthropy Project
• Information provided by (Responsible Party): Michael Donnino, Beth Israel Deaconess Medical Center

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Sepsis; Septic Shock; Metabolic Disturbance	Drug: vitamin C, vitamin B1, hydrocortisone; Drug: Normal saline	Phase 2; Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 205 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Ascorbic Ccid, Hydrocortisone, and Thiamine in Sepsis and Septic Shock - A Randomized, Double-Blind, Placebo-Controlled Trial
• Actual Study Start Date: February 9, 2018
• Actual Primary Completion Date: November 26, 2019
• Actual Study Completion Date: February 28, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Sequential Organ Failure Assessment (SOFA) Score at Baseline and 72 Hours [ Time Frame: 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 :

1. Renal Failure [ Time Frame: 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

2. 30-day Mortality [ Time Frame: Enrollment until 30-days after enrollment ]
   Mortality rate

Other Outcome Measures:

1. Ventilator Free Days [ Time Frame: Ventilator free days over the first 7-days after enrollment ]
   Days not receiving invasive mechanical ventilation
2. Shock Free Days [ Time Frame: Vasopressor free days over the first 7-days after enrollment ]
   Days not receiving vasopressor
3. ICU Free Days [ Time Frame: From enrollment until 28 days after enrollment ]
   Number of days that the patient was not in the ICU. Timeframe listed below.
4. Hospital Mortality [ Time Frame: Enrollment until hospital discharge, death, or 30-days. Whichever comes first. ]
   Hospital mortality rate
5. Intensive Care Unit (ICU) Mortality [ Time Frame: Enrollment until ICU discharge, death, or 30-days. Whichever comes first. ]
   ICU mortality rate
6. Number of Participants With Delirium [ Time Frame: On day 3 (at approximately 72 hours) after the first study drug dose ]

   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:

   1. Acute Onset of Changes or Fluctuations in the Course of Mental Status (AND )
   2. Inattention (AND)
   3. Disorganized thinking (OR) Altered Level of Consciousness
7. Hospital Disposition: Survivors Discharged Home [ Time Frame: Enrollment until hospital discharge, death, or 30-days, whichever comes first. ]
   Home hospital disposition in patients who survive to discharge

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Arizona

Mayo Clinic - Arizona

Phoenix, Arizona, United States, 85054

United States, Massachusetts

Brigham and Women's Hospital

Boston, Massachusetts, United States, 02115

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02215

Mount Auburn Hospital

Cambridge, Massachusetts, United States, 02138

United States, Michigan

Detroit Receiving Hospital

Detroit, Michigan, United States, 48201

Harper University Hospital

Detroit, Michigan, United States, 48201

Henry Ford Hospital

Detroit, Michigan, United States, 48202

Sinai Grace Hospital

Detroit, Michigan, United States, 48235

Beaumont Hospital

Royal Oak, Michigan, United States, 48073

United States, New York

North Shore University Hospital

Manhasset, New York, United States, 11030

Long Island Jewish Hospital

New York, New York, United States, 11040

United States, Pennsylvania

University Of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States, 15213

United States, Texas

The University of Texas Health Science Center

Houston, Texas, United States, 77030

Sponsors and Collaborators

Beth Israel Deaconess Medical Center

Open Philanthropy Project

Investigators

• Principal Investigator: Michael W Donnino, MD; Beth Israel Deaconess Medical Center

  Study Documents (Full-Text)

Documents provided by Michael Donnino, Beth Israel Deaconess Medical Center:

Study Protocol  [PDF] December 13, 2018

Statistical Analysis Plan  [PDF] December 13, 2018

More Information

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Michael Donnino, Associate Professor of Emergency Medicine, Beth Israel Deaconess Medical Center
• ClinicalTrials.gov Identifier: NCT03389555
• Other Study ID Numbers: 2017P000436
• First Posted: January 3, 2018
• Results First Posted: January 29, 2021
• Last Update Posted: February 16, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Michael Donnino, Beth Israel Deaconess Medical Center:

Sepsis; Metabolic Resuscitation

Additional relevant MeSH terms:

Sepsis; Toxemia; Shock, Septic; Infection; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Shock; Vitamins; Ascorbic Acid; Thiamine; Hydrocortisone; Micronutrients; Nutrients; Growth Substances; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents; Vitamin B Complex