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

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ClinicalTrials.gov Identifier: NCT03389555

Recruitment Status : Recruiting

First Posted : January 3, 2018

Last Update Posted : November 20, 2019

See Contacts and Locations

Sponsor:

Collaborator:

Open Philanthropy Project

Information provided by (Responsible Party):

Michael Donnino, Beth Israel Deaconess Medical Center

Study Description

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	200 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
Estimated Primary Completion Date :	December 30, 2019
Estimated Study Completion Date :	February 28, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: B Vitamins Sepsis Shock Vitamin C

Drug Information available for: Hydrocortisone acetate Hydrocortisone Ascorbic acid Thiamine Thiamine hydrochloride Hydrocortisone sodium succinate Sodium ascorbate Hydrocortisone cypionate Thiamine mononitrate Vitamin B Complex Magnesium ascorbate Hydrocortisone valerate Hydrocortisone probutate Proctofoam-HC

U.S. FDA Resources

Arms and Interventions

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 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

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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] grade 3 or higher
30-day mortality [ Time Frame: Enrollment until 30-days after enrollment ]
Mortality rate

Other Outcome Measures:

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
Length of ICU stay [ Time Frame: Enrollment until 28 days after enrollment ]
ICU free days
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 hICU discharge, death, or 30-days. Whichever comes first. ]
ICU mortality rate
Delirium [ Time Frame: Day 3 of hospital stay ]
Incidence of delirium
Hospital disposition [ Time Frame: Enrollment until hospital discharge, death, or 30-days. Whichever comes first. ]
Hospital disposition in patients who survive to discharge (e.g. home, death, nursing facility)
Change in individual Sequential Organ Failure Assessment (SOFA) measures [ Time Frame: Measured between enrollment and 72 hours after enrollment ]
Change in individual Sequential Organ Failure Assessment (SOFA) measures

Eligibility Criteria

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:

Adult patient (age ≥ 18 years)
Suspected (cultures drawn and antibiotic given) or confirmed (via culture results) infection
Receiving vasopressor (norepinephrine, phenylephrine, epinephrine, dopamine, angiotensin II or vasopressin)

Exclusion Criteria:

Member of a protected population (pregnant, prisoner)
Known kidney stones within the past 1 year (except for asymptomatic, incidentally noted stones on imaging)
End stage renal disease (ESRD) requiring dialysis
Known Glucose-6-Phosphate Dehydrogenase deficiency
Known Hemachromatosis
Comfort Measures Only status
Anticipated death within 24-hours despite maximal therapy (as determined by the enrolling physician)
Receiving supplemental thiamine in a dose greater than that contained in a multivitamin
Clinical indication for steroids (e.g. chronic use) as determined by the clinical team providing this drug
Clinical indication for thiamine as determined by the clinical team providing this drug
Clinical indication for ascorbic acid as determined by the clinical team providing this drug
Known allergy to vitamin C, hydrocortisone, or thiamine

Contacts and Locations

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

Contacts

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Contact: Michael W. Donnino, MD	617-754-2341	mdonnino@bidmc.harvard.edu
Contact: Jocelyn Portmann	617-754-2881	jportman@bidmc.harvard.edu

Locations

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United States, Arizona
Mayo Clinic - Arizona	Not yet recruiting
Phoenix, Arizona, United States, 85054
Contact: Ayan Sen, MD
United States, Massachusetts
Brigham and Women's Hospital	Not yet recruiting
Boston, Massachusetts, United States, 02115
Contact: Peter Hou, MD
Beth Israel Deaconess Medical Center	Recruiting
Boston, Massachusetts, United States, 02215
Contact: Ari Moskowitz, MD 617-754-3464 amoskowitz@bidmc.harvard.edu
Contact: Jocelyn Portmann 617-754-2881 jportman@bidmc.harvard.edu
Principal Investigator: Michael W Donnino, MD
Mount Auburn Hospital	Not yet recruiting
Cambridge, Massachusetts, United States, 02138
Contact: Jessica McCannon, MD
United States, Michigan
Detroit Receiving Hospital	Not yet recruiting
Detroit, Michigan, United States, 48201
Contact: Robert Sherwin, MD
Harper University Hospital	Not yet recruiting
Detroit, Michigan, United States, 48201
Contact: Robert Sherwin, MD
Henry Ford Hospital	Not yet recruiting
Detroit, Michigan, United States, 48202
Contact: Bruno DiGiovine, MD
Sinai Grace Hospital	Not yet recruiting
Detroit, Michigan, United States, 48235
Contact: Robert Sherwin, MD
Beaumont Hospital	Recruiting
Royal Oak, Michigan, United States, 48073
Contact: Ronald Otero, MD
United States, New York
North Shore University Hospital	Recruiting
Manhasset, New York, United States, 11030
Contact: Jonathan Gong, MD
Long Island Jewish Hospital	Recruiting
New York, New York, United States, 11040
Contact: Lance Becker, MD
United States, Pennsylvania
University Of Pittsburgh Medical Center	Not yet recruiting
Pittsburgh, Pennsylvania, United States, 15213
United States, Texas
The University of Texas Health Science Center	Not yet recruiting
Houston, Texas, United States, 77030
Contact: Pratik Doshi, MD

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

More Information

Publications:

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.

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.

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.

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

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.

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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
Last Update Posted:	November 20, 2019
Last Verified:	November 2019
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

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