Ascorbic Acid and Thiamine Effect in Septic Shock

Sepsis Clinical Trial

— ATESS  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03756220
• Other study ID #: 2018R1C1B6006821
• Status: Completed
• Phase: Phase 2
• Start date: December 1, 2018
• Est. completion date: April 14, 2020

Study information

• Verified date: October 2020
• Source: Samsung Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 116
• Est. completion date: April 14, 2020
• Est. primary completion date: January 13, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 19 Years to 89 Years

Eligibility

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

Related Conditions & MeSH terms

• Sepsis
• Septic Shock
• Shock
• Shock, Septic

Intervention

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
• 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

Locations

Country	Name	City	State
Korea, Republic of	Department of Emergency Medicine, Seoul National University Bundang Hospital,	Seongnam	Gyeonggi-do
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	Seoul

Sponsors (2)

Lead Sponsor	Collaborator
Tae Gun Shin	National Research Foundation of Korea

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (11)

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. Review. — View 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. — View Citation

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. — View Citation

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. — View 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. — View Citation

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. Review. — View Citation

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. Review. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	CRP (C-reactive protein) change during initial 72 hours	72-hour change in CRP (%)	Enrollment to 72 hours
Other	Procalcitonin change during initial 72 hours	72-hour change in procalcitonin (%)	Enrollment to 72 hours
Other	Dose of vasopressor at 24-hour	Norepinephrine equivalent dose at 24 hours from enrollment	Enrollment to 24 hours
Other	Dose of vasopressor at 48-hour	Norepinephrine equivalent dose at 48 hours from enrollment	Enrollment to 48 hours
Other	Dose of vasopressor at 72-hour	Norepinephrine equivalent dose at 72 hours from enrollment	Enrollment to 72 hours
Other	Maximum dose of vasopressor during initial 72 hours	Maximum norepinephrine equivalent dose during initial 72 hours	Enrollment to 72 hours
Primary	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	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
Secondary	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
Secondary	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
Secondary	Time to death	Days until death	Enrollment to Day 28
Secondary	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
Secondary	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
Secondary	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
Secondary	Vasopressor free days	Days not receiving any vasopressor	Enrollment to Day 14
Secondary	Ventilator free days	Days not receiving mechanical ventilation	Enrollment to Day 14
Secondary	Ventilator duration	Days receiving mechanical ventilation during hospital stay	Up to 12 weeks
Secondary	Renal replacement therapy (RRT) free days	Days not receiving Renal replacement therapy	Enrollment to Day 14
Secondary	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
Secondary	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
Secondary	Length of ICU stay	Number of days in the ICU during hospital admission	Up to 12 weeks
Secondary	ICU free day	Days not being in the ICU	Enrollment to Day 14
Secondary	Length of hospital stay	Number of days in the hospital during hospital admission	Up to 12 weeks