Clinical trial NCT03389555: Ascorbic Acid, Corticosteroids, and Thiamine in Sepsis (ACTS) Trial
Official title: Ascorbic Ccid, Hydrocortisone, and Thiamine in Sepsis and Septic Shock - A Randomized, Double-Blind, Placebo-Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Sepsis
Septic Shock
Metabolic Disturbance
Keywords: Sepsis
Metabolic Resuscitation
Lead sponsor: Beth Israel Deaconess Medical Center
Sponsor class: OTHER
Collaborators: name: Open Philanthropy
First posted: 2018-01-03
Enrollment: 205
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Sequential Organ Failure Assessment (SOFA) Score at Baseline and 72 Hours
timeFrame: Enrollment to 72-hours
Secondary outcomes:
measure: Renal Failure
timeFrame: Enrollment until 7-days or discharge from the ICU
measure: 30-day Mortality
timeFrame: Enrollment until 30-days after enrollment
Other outcomes:
measure: Ventilator Free Days
timeFrame: Ventilator free days over the first 7-days after enrollment
measure: Shock Free Days
timeFrame: Vasopressor free days over the first 7-days after enrollment
measure: ICU Free Days
timeFrame: From enrollment until 28 days after enrollment
measure: Hospital Mortality
timeFrame: Enrollment until hospital discharge, death, or 30-days. Whichever comes first.
measure: Intensive Care Unit (ICU) Mortality
timeFrame: Enrollment until ICU discharge, death, or 30-days. Whichever comes first.
measure: Number of Participants With Delirium
timeFrame: On day 3 (at approximately 72 hours) after the first study drug dose
measure: Hospital Disposition: Survivors Discharged Home
timeFrame: Enrollment until hospital discharge, death, or 30-days, whichever comes first.
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic - Arizona
state: Arizona
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Cambridge
country: United States
facility: Mount Auburn Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Detroit Receiving Hospital
state: Michigan
city: Detroit
country: United States
facility: Harper University Hospital
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Detroit
country: United States
facility: Sinai Grace Hospital
state: Michigan
city: Royal Oak
country: United States
facility: Beaumont Hospital
state: Michigan
city: Manhasset
country: United States
facility: North Shore University Hospital
state: New York
city: New York
country: United States
facility: Long Island Jewish Hospital
state: New York
city: Pittsburgh
country: United States
facility: University Of Pittsburgh Medical Center
state: Pennsylvania
city: Houston
country: United States
facility: The University of Texas Health Science Center
state: Texas
Study officials:
affiliation: Beth Israel Deaconess Medical Center
name: Michael W Donnino, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.