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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

Tracking Information
First Submitted Date  ICMJE December 27, 2017
First Posted Date  ICMJE January 3, 2018
Results First Submitted Date  ICMJE November 24, 2020
Results First Posted Date  ICMJE January 29, 2021
Last Update Posted Date February 16, 2021
Actual Study Start Date  ICMJE February 9, 2018
Actual Primary Completion Date November 26, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 11, 2021)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: January 2, 2018)
Sequential Organ Failure Assessment (SOFA) Score Change [ Time Frame: Enrollment to 72-hours ]
Change in degree of organ dysfunction as defined by the Sequential Organ Failure Assessment (SOFA) Score
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 11, 2021)
  • 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
  • 30-day Mortality [ Time Frame: Enrollment until 30-days after enrollment ]
    Mortality rate
Original Secondary Outcome Measures  ICMJE
 (submitted: January 2, 2018)
  • Renal Failure [ Time Frame: Enrollment until 72-hours after enrollment ]
    Development of renal failure as defined by a Kidney Disease Improving Global Outcomes [KDIGO] grade 3 or higher
  • 30-day Mortality [ Time Frame: Enrollment until 30-days after enrollment ]
    Mortality rate
Current Other Pre-specified Outcome Measures
 (submitted: January 29, 2021)
  • Ventilator Free Days [ Time Frame: Ventilator free days over the first 7-days after enrollment ]
    Days not receiving invasive mechanical ventilation
  • Shock Free Days [ Time Frame: Vasopressor free days over the first 7-days after enrollment ]
    Days not receiving vasopressor
  • 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.
  • Hospital Mortality [ Time Frame: Enrollment until hospital discharge, death, or 30-days. Whichever comes first. ]
    Hospital mortality rate
  • Intensive Care Unit (ICU) Mortality [ Time Frame: Enrollment until ICU discharge, death, or 30-days. Whichever comes first. ]
    ICU mortality rate
  • 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
  • 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
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ascorbic Acid, Corticosteroids, and Thiamine in Sepsis (ACTS) Trial
Official Title  ICMJE Ascorbic Ccid, Hydrocortisone, and Thiamine in Sepsis and Septic Shock - A Randomized, Double-Blind, Placebo-Controlled Trial
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Sepsis
  • Septic Shock
  • Metabolic Disturbance
Intervention  ICMJE
  • 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
  • Drug: Normal saline
    Normal saline (0.9% NaCl solution) volume to match all components
Study Arms  ICMJE
  • 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
    Intervention: Drug: vitamin C, vitamin B1, hydrocortisone
  • Placebo Comparator: Placebo
    Normal Saline Solution (0.9%NaCl) in a volume to match all experimental arm components
    Intervention: Drug: Normal saline
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 24, 2020)
205
Original Estimated Enrollment  ICMJE
 (submitted: January 2, 2018)
200
Actual Study Completion Date  ICMJE February 28, 2020
Actual Primary Completion Date November 26, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03389555
Other Study ID Numbers  ICMJE 2017P000436
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Michael Donnino, Beth Israel Deaconess Medical Center
Study Sponsor  ICMJE Beth Israel Deaconess Medical Center
Collaborators  ICMJE Open Philanthropy Project
Investigators  ICMJE
Principal Investigator: Michael W Donnino, MD Beth Israel Deaconess Medical Center
PRS Account Beth Israel Deaconess Medical Center
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP