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

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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:
Collaborator:
Open Philanthropy Project
Information provided by (Responsible Party):
Michael Donnino, Beth Israel Deaconess Medical Center

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.

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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


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




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



Information from the National Library of Medicine

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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03389555


Locations
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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
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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

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

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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:
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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