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

Sepsis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03389555
• Other study ID #: 2017P000436
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: February 9, 2018
• Est. completion date: February 28, 2020

Study information

• Verified date: January 2021
• Source: Beth Israel Deaconess Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 205
• Est. completion date: February 28, 2020
• Est. primary completion date: November 26, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Metabolic Disturbance
• Sepsis
• Septic Shock
• Shock, Septic
• Toxemia

Intervention

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.
• Normal saline
Normal saline (0.9% NaCl solution) volume to match all components

Locations

Country	Name	City	State
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Brigham and Women's Hospital	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	The University of Texas Health Science Center	Houston	Texas
United States	North Shore University Hospital	Manhasset	New York
United States	Long Island Jewish Hospital	New York	New York
United States	Mayo Clinic - Arizona	Phoenix	Arizona
United States	University Of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Beaumont Hospital	Royal Oak	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
Beth Israel Deaconess Medical Center	Open Philanthropy Project

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Ventilator Free Days	Days not receiving invasive mechanical ventilation	Ventilator free days over the first 7-days after enrollment
Other	Shock Free Days	Days not receiving vasopressor	Vasopressor free days over the first 7-days after enrollment
Other	ICU Free Days	Number of days that the patient was not in the ICU. Timeframe listed below.	From enrollment until 28 days after enrollment
Other	Hospital Mortality	Hospital mortality rate	Enrollment until hospital discharge, death, or 30-days. Whichever comes first.
Other	Intensive Care Unit (ICU) Mortality	ICU mortality rate	Enrollment until ICU discharge, death, or 30-days. Whichever comes first.
Other	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
Other	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.
Primary	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	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
Secondary	30-day Mortality	Mortality rate	Enrollment until 30-days after enrollment