Ascorbic Acid and Thiamine Effect in Septic Shock

NCT03756220 | Completed Phase 2 DMC

• 1 other identifier: 2018R1C1B6006821
• Study Type: interventional
• Target: 116
• Locations: 1 country
• Sites: 6

Brief Summary

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.

Conditions

Septic Shock; Sepsis

Keywords

Septic shock; Sepsis; Vitamin C; Thiamine

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (16)

• 28-day mortality

  Day 28

• 7-day mortality (early death)

  Day 7

• 90-day mortality

  Day 90

• Time to death

  Enrollment to Day 28

• In-hospital death

  Up to 12 weeks

Other Outcomes (6)

• CRP (C-reactive protein) change during initial 72 hours

  Enrollment to 72 hours

• Procalcitonin change during initial 72 hours

  Enrollment to 72 hours

• Dose of vasopressor at 24-hour

  Enrollment to 24 hours

Study Arms (2)

Treatment

EXPERIMENTAL

Combination therapy of vitamin C and thiamine for 2 days.

Drug: Combination therapy of vitamin C and thiamine

Control

PLACEBO COMPARATOR

Normal Saline Solution

Drug: Normal saline solution

Interventions

Combination therapy of vitamin C and thiamine DRUG

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

Also known as: Ascorbic Acid Injection, Thiamine Injection

Treatment

Normal saline solution DRUG

Normal saline solution in a volume to match the treatment components administered mixed in 50 mL solution bags of normal saline for 2 days

Also known as: 0.9% NaCl

Control

Eligibility Criteria

• Age: 19 Years - 89 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult patients (\> 18 years)
• 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.

You may not qualify if:

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

Sponsors & Collaborators

• Tae Gun Shin: lead
• National Research Foundation of Korea: collaborator

Study Sites (6)

Department of Emergency Medicine, Seoul National University Bundang Hospital,

Seongnam-si, Gyeonggi-do, South Korea

Location

Department of Emergency Medicine, Borame Medical Center, Seoul National University, College of Medicine

Seoul, South Korea

Location

Department of Emergency Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine,

Seoul, South Korea

Location

Department of Emergency Medicine, Seoul National University College of Medicine,

Seoul, South Korea

Location

Department of Emergency Medicine, University of Ulsan College of Medicine, Asan Medical Center,

Seoul, South Korea

Location

Department of Emergency Medicine, Yonsei University College of Medicine

Seoul, South Korea

Location

Related Publications (13)

• 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.

  PMID: 26903338 BACKGROUND

• 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.

  PMID: 28098591 BACKGROUND

• 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.

  PMID: 28934705 BACKGROUND

• 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.

  PMID: 27940189 BACKGROUND

• 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.

  PMID: 25185110 BACKGROUND

• 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.

  PMID: 26771781 BACKGROUND

• 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.

  PMID: 27162802 BACKGROUND

• 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.

  PMID: 24484547 BACKGROUND

• 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.

  PMID: 23581713 BACKGROUND

• 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.

  PMID: 27501325 BACKGROUND

• 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.

  PMID: 28231816 BACKGROUND

• 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.

  PMID: 34482319 DERIVED

• 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.

  PMID: 31296251 DERIVED

MeSH Terms

Conditions

Shock, Septic; Sepsis

Interventions

Thiamine; Ascorbic Acid; Saline Solution

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Sugar Acids; Acids, Acyclic; Carboxylic Acids; Hydroxy Acids; Carbohydrates; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Tae Gun Shin, MD, PhD

  Samsung Medical Center, Sungkyunkwan University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate professor

Model Details: Multi-center, Double-blinded, Randomized, Controlled Study

Study Record Dates

• First Submitted: October 30, 2018
• First Posted: November 28, 2018
• Study Start: December 1, 2018
• Primary Completion: January 13, 2020
• Study Completion: April 14, 2020
• Last Updated: October 28, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will not share

Locations

KR (6)