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

NCT ID: NCT03389555

Last Updated: 2021-02-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 205 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-02-09
• Study Completion Date: 2020-02-28

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.

Conditions

Sepsis; Septic Shock; Metabolic Disturbance

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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

Group Type: EXPERIMENTAL

vitamin C, vitamin B1, hydrocortisone

Intervention Type: DRUG

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.

Placebo

Normal Saline Solution (0.9%NaCl) in a volume to match all experimental arm components

Group Type: PLACEBO_COMPARATOR

Normal saline

Intervention Type: DRUG

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

Interventions

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.

Intervention Type: DRUG

Normal saline

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

Intervention Type: DRUG

Other Intervention Names

Ascorbic Acid; Thiamine

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Open Philanthropy

OTHER

Sponsor Role: collaborator

Beth Israel Deaconess Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Michael Donnino

Associate Professor of Emergency Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Michael W Donnino, MD

Role: PRINCIPAL_INVESTIGATOR

Beth Israel Deaconess Medical Center

Locations

Mayo Clinic - Arizona

Phoenix, Arizona, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

Beth Israel Deaconess Medical Center

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

Beaumont Hospital

Royal Oak, Michigan, United States

North Shore University Hospital

Manhasset, New York, United States

Long Island Jewish Hospital

New York, New York, United States

University Of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States

The University of Texas Health Science Center

Houston, Texas, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 27940189 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28207287 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26771781 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33251516 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32809003 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31852712 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2017P000436

Identifier Type: -

Identifier Source: org_study_id