Ascorbic Acid and Thiamine Effect in Septic Shock (ATESS)

Combination Therapy of Vitamin C and Thiamine for Septic Shock: Multi-center, Double-blinded, Randomized, Controlled Study

The aim of this study is to evaluate the efficacy of early metabolic resuscitation with combination therapy using vitamin C and thiamine in improving organ function and survival in patients with septic shock.

Study Overview

• Status: Completed
• Conditions: Sepsis; Septic Shock
• Intervention / Treatment: Drug: Combination therapy of vitamin C and thiamine; Drug: Normal saline solution

Detailed Description

Sepsis is a complex disease involving life-threatening organ dysfunction caused by a dysregulated host response to infection and is still associated with unacceptably high mortality. Sepsis management should be undertaken as a medical emergency and focused on timely intervention, including early identification and treatment of infection through appropriate antimicrobial therapy and source control when applicable as well as reversing hemodynamic instability through fluid resuscitation and vasopressor use if necessary. Despite these supportive therapies, morbidity and mortality have remained high, suggesting the need for adjuvant therapies for inflammatory and oxidative stress in patients with sepsis; however, no agents have been proven to definitely improve survival.

Vitamin C plays a role in mediating inflammation through antioxidant activities and is also important as a cofactor/co-substrate for the synthesis of endogenous adrenaline, cortisol, and vasopressin. Recently, several clinical trials have reported the positive effects of vitamin C on outcomes in sepsis or septic shock. During sepsis, vitamin C prevents neutrophil-induced lipid oxidation and protects against the loss of the endothelial barrier. Early intravenous supplementation is therefore needed to limit loss of microcirculation and oxidation of lipids. Thiamine is also a key cofactor for glucose metabolism, the generation of ATP (adenosine triphosphate), and the production of NADPH. Considering acute consumption in the hypermetabolic state, thiamine supplementation might be a reasonable therapeutic adjunct for patients with sepsis and was added to reduce the risk of renal oxalate crystallization. These findings led to a recent before-and-after study showing that treatment of sepsis with a combination of vitamin C, hydrocortisone, and thiamine prevented organ dysfunction and reduced the mortality rate.

The aim of this study is to evaluate the efficacy of early metabolic resuscitation with combination therapy using vitamin C and thiamine in improving organ function and survival in patients with septic shock.

• Study Type: Interventional
• Enrollment (Actual): 116
• Phase: Phase 2

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Department of Emergency Medicine, Borame Medical Center, Seoul National University, College of Medicine
  • Seoul, Korea, Republic of
    • Department of Emergency Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine,
  • Seoul, Korea, Republic of
    • Department of Emergency Medicine, Seoul National University College of Medicine,
  • Seoul, Korea, Republic of
    • Department of Emergency Medicine, University of Ulsan College of Medicine, Asan Medical Center,
  • Seoul, Korea, Republic of
    • Department of Emergency Medicine, Yonsei University College of Medicine
  • Gyeonggi-do
    • Seongnam, Gyeonggi-do, Korea, Republic of
      • Department of Emergency Medicine, Seoul National University Bundang Hospital,

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 89 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adult patients (> 18 years)
2. Septic shock: sepsis with persisting hypotension requiring vasopressors to maintain a mean arterial pressure ≥65 mm Hg and a serum lactate level >2 mmol/L despite adequate volume resuscitation. Sepsis is defined as clinically suspected or confirmed infection with acute organ failure identified as an acute change in total SOFA score with 2 points or more.

Exclusion Criteria:

1. Transferred patients from other hospitals after application of vasopressors or mechanical ventilation
2. Patients who signed a "Do not attempt resuscitation" order or who had set limitations on invasive care
3. Patients who have a terminal, unresponsive illness and survival discharge is not expected (metastatic terminal cancer, etc.)
4. Patients who experienced cardiac arrest before enrollment or when death is anticipated within 24 hours despite maximal treatment
5. Patients who take more than 1g of Vitamin C per day before enrollment or who take supplemental thiamine
6. Pregnant woman
7. Known Glucose-6-phosphate dehydrogenase deficiency
8. Patients with a history of hypersensitivity to vitamin C or thiamine
9. Known Mediterranean anemia
10. Known hyperoxaluria
11. Known cystinuria
12. Acute gout attack
13. Known oxalate renal stone
14. Patients who meet the inclusion criteria 24 hours after emergency department arrival or when enrollment is delayed more than 24 hours after diagnosis of septic shock
15. Inability or refusal of a subject or legal surrogate to give informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment; Combination therapy of vitamin C and thiamine for 2 days.	Drug: Combination therapy of vitamin C and thiamine; Vitamin C (50 mg/kg up to 3 g, every 12 hours) and thiamine (200 mg every 12 hours) intravenously administered mixed in 50 mL solution bags of normal saline for 2 days; Other Names: Ascorbic Acid Injection; Thiamine Injection
Placebo Comparator: Control; Normal Saline Solution	Drug: Normal saline solution; Normal saline solution in a volume to match the treatment components administered mixed in 50 mL solution bags of normal saline for 2 days; Other Names: 0.9% NaCl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Delta Sequential Organ Failure Assessment (SOFA) score	72-hour change in SOFA score, which reflected recovery from organ failure (delta SOFA = SOFA at enrollment - SOFA after 72 hours)	Enrollment to 72 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
28-day mortality	The number of participants who did not survive until Day 28 will be compared between the treatment and the control group	Day 28
7-day mortality (early death)	The number of participants who did not survive until Day 7 will be compared between the treatment and the control group	Day 7
90-day mortality	The number of participants who did not survive until Day 90 will be compared between the treatment and the control group	Day 90
Time to death	Days until death	Enrollment to Day 28
In-hospital death	The number of participants who did not survive at hospital discharge will be compared between the treatment and the control group	Up to 12 weeks
Intensive care unit death (ICU) death	The number of participants who did not survive at ICU discharge from the first index ICU admission will be compared between the treatment and the control group	Up to 12 weeks
Time to Shock reversal	Days from enrollment to shock reversal until Day 14. Shock reversal is defined as discontinuation of all vasopressors and mean arterial pressure is maintained at 60 mmHg or more for more than 24 hours.	Enrollment to Day 14
Vasopressor free days	Days not receiving any vasopressor	Enrollment to Day 14
Ventilator free days	Days not receiving mechanical ventilation	Enrollment to Day 14
Ventilator duration	Days receiving mechanical ventilation during hospital stay	Up to 12 weeks
Renal replacement therapy (RRT) free days	Days not receiving Renal replacement therapy	Enrollment to Day 14
New use of renal replacement therapy (RRT)	The number of participants who receive RRT during hospital stay will be compared between the treatment and the control group	Up to 12 weeks
New onset or aggravation of acute kidney injury (AKI)	The number of participants who suffer from new onset or aggravation of AKI will be compared between the treatment and the control group	Enrollment to Day 14
Length of ICU stay	Number of days in the ICU during hospital admission	Up to 12 weeks
ICU free day	Days not being in the ICU	Enrollment to Day 14
Length of hospital stay	Number of days in the hospital during hospital admission	Up to 12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
CRP (C-reactive protein) change during initial 72 hours	72-hour change in CRP (%)	Enrollment to 72 hours
Procalcitonin change during initial 72 hours	72-hour change in procalcitonin (%)	Enrollment to 72 hours
Dose of vasopressor at 24-hour	Norepinephrine equivalent dose at 24 hours from enrollment	Enrollment to 24 hours
Dose of vasopressor at 48-hour	Norepinephrine equivalent dose at 48 hours from enrollment	Enrollment to 48 hours
Dose of vasopressor at 72-hour	Norepinephrine equivalent dose at 72 hours from enrollment	Enrollment to 72 hours
Maximum dose of vasopressor during initial 72 hours	Maximum norepinephrine equivalent dose during initial 72 hours	Enrollment to 72 hours

Collaborators and Investigators

• Sponsor: Tae Gun Shin
• Collaborators: National Research Foundation of Korea
• Investigators: Principal Investigator: Tae Gun Shin, MD, PhD, Samsung Medical Center, Sungkyunkwan University School of Medicine

Publications and helpful links

General Publications

• Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287.
• de Grooth HJ, Geenen IL, Girbes AR, Vincent JL, Parienti JJ, Oudemans-van Straaten HM. SOFA and mortality endpoints in randomized controlled trials: a systematic review and meta-regression analysis. Crit Care. 2017 Feb 24;21(1):38. doi: 10.1186/s13054-017-1609-1.
• 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.
• Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 2017 Mar;45(3):486-552. doi: 10.1097/CCM.0000000000002255.
• Teng J, Pourmand A, Mazer-Amirshahi M. Vitamin C: The next step in sepsis management? J Crit Care. 2018 Feb;43:230-234. doi: 10.1016/j.jcrc.2017.09.031. Epub 2017 Sep 18.
• Oudemans-van Straaten HM, Spoelstra-de Man AM, de Waard MC. Vitamin C revisited. Crit Care. 2014 Aug 6;18(4):460. doi: 10.1186/s13054-014-0460-x.
• 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.
• Zabet MH, Mohammadi M, Ramezani M, Khalili H. Effect of high-dose Ascorbic acid on vasopressor's requirement in septic shock. J Res Pharm Pract. 2016 Apr-Jun;5(2):94-100. doi: 10.4103/2279-042X.179569.
• Fowler AA 3rd, Syed AA, Knowlson S, Sculthorpe R, Farthing D, DeWilde C, Farthing CA, Larus TL, Martin E, Brophy DF, Gupta S; Medical Respiratory Intensive Care Unit Nursing, Fisher BJ, Natarajan R. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014 Jan 31;12:32. doi: 10.1186/1479-5876-12-32.
• May JM, Harrison FE. Role of vitamin C in the function of the vascular endothelium. Antioxid Redox Signal. 2013 Dec 10;19(17):2068-83. doi: 10.1089/ars.2013.5205. Epub 2013 May 29.
• Leite HP, de Lima LF. Metabolic resuscitation in sepsis: a necessary step beyond the hemodynamic? J Thorac Dis. 2016 Jul;8(7):E552-7. doi: 10.21037/jtd.2016.05.37.
• Park JE, Jo YH, Hwang SY, Kim WY, Ryoo SM, Jang DH, Kim T, Kim YJ, Kim S, Cho H, Lee GT, Chung SP, Choi SH, Shin TG, Suh GJ; Korean Shock Society (KoSS) Investigators. Biomarker Analysis for Combination Therapy of Vitamin C and Thiamine in Septic Shock: A Post-Hoc Study of the ATESS Trial. Shock. 2022 Jan 1;57(1):81-87. doi: 10.1097/SHK.0000000000001850.
• Hwang SY, Park JE, Jo IJ, Kim S, Chung SP, Kong T, Shin J, Lee HJ, You KM, Jo YH, Kim D, Suh GJ, Kim T, Kim WY, Kim YJ, Ryoo SM, Choi SH, Shin TG; Korean Shock Society (KoSS) Investigators. Combination therapy of vitamin C and thiamine for septic shock in a multicentre, double-blind, randomized, controlled study (ATESS): study protocol for a randomized controlled trial. Trials. 2019 Jul 11;20(1):420. doi: 10.1186/s13063-019-3542-x.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2018
• Primary Completion (Actual): January 13, 2020
• Study Completion (Actual): April 14, 2020

Study Registration Dates

• First Submitted: October 30, 2018
• First Submitted That Met QC Criteria: November 26, 2018
• First Posted (Actual): November 28, 2018

Study Record Updates

• Last Update Posted (Actual): October 28, 2020
• Last Update Submitted That Met QC Criteria: October 27, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Septic shock; Sepsis; Vitamin C; Thiamine
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Micronutrients; Vitamins; Antioxidants; Vitamin B Complex; Ascorbic Acid; Thiamine
• Other Study ID Numbers: 2018R1C1B6006821

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No