Vitamin C, Hydrocortisone and Thiamine in Patients With Septic Shock

Sepsis Clinical Trial

Official title:

Vitamin C, Hydrocortisone and Thiamine in Patients With Septic Shock: a Randomized Clinical Study (VITAMIN TRIAL)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT05192213
• Other study ID #: AVAP-NG 1000
• Secondary ID: 07445119.9.1001.
• Status: Terminated
• Phase: Phase 3
• Start date: August 1, 2021
• Est. completion date: September 19, 2022

Study information

• Verified date: January 2024
• Source: Hospital Sirio-Libanes
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A great interest exists regarding substances with an immunomodulatory effect for sepsis patients. Recent data have shown that intravenous vitamin C, together with corticosteroids and thiamine, could prevent progressive organ dysfunction and reduce vasopressor use in patients with severe sepsis and septic shock. Its effect on mortality, on the other hand, is yet to be demonstrated. The Vitamins study aims to conclusively determine, through its prospective, multicentre and double-blinded design including 1090 patients, wether Vitamin C, Thiamine and Hydrocortisone in combination can reduce mortality in patients with septic shock.

Description:

The global burden of sepsis is substantial with an estimated 15 to 19 million cases per year, most occurring in low-income countries. With recent advances in diagnosis and supportive treatment, the 28-day mortality from sepsis in high-income countries has decreased by about 25%; however, the mortality from septic shock still remains around 45%.

A large volume of experimental data has shown that both corticosteroids and intravenous vitamin C attenuate the release of pro-inflammatory mediators, reduce the endothelial lesion characteristic of sepsis (reducing endothelial permeability and improving microcirculatory flow), increase the release of endogenous catecholamines and improve vasopressor reaction. In animal models, these effects resulted in reduced organ damage and increased survival. However, its effect on critically ill humans is controvert. Results of a retrospective study brought that the early use of intravenous vitamin C, together with corticosteroids and thiamine, can prevent progressive organ dysfunction and can reduce mortality in patients with severe sepsis and septic shock.

For this reason, the investigators propose a randomized, controlled, multicentre (mcRCT), pragmatic and feasibility study to investigate whether Vitamin C (1.5g 6 / 6h), along with thiamine (200 mg, 12 / 12h) and hydrocortisone (50 mg 6 / 6h) for 7 days can reduce all-cause mortality within 28 days after randomization.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 71
• Est. completion date: September 19, 2022
• Est. primary completion date: July 14, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Above 18 years of age

• Sepsis of any background

• Vasopressor-dependent sepsis for at least 2 hours and vasopressor dose = 0.25 µg / kg / min

Exclusion Criteria:

• Pregnancy;

• Requests for DNR (do not resuscitate) / DNI (do not intubate);

• Death is considered imminent or inevitable during this hospitalization and the attending physician, patient or substitute decision maker is not committed to active treatment;

• Patients with acute cerebral vascular event, acute coronary syndrome, active gastrointestinal bleeding, burn or trauma at admission;

• Patients with known HIV infection;

• Patients with known glucose-6 phosphate dehydrogenase (G-6PD) deficiency;

• Patients with septic shock transferred from another ICU or hospital with characteristics of septic shock for> 12 hours;

• Patients with septic shock characteristics for> 12 hours;

• Patients with a known history of oxalate nephropathy;

• Patients with short bowel syndrome or severe known fat malabsorption;

• Patients with acute beriberi disease;

• Patients with acute Wernicke's encephalopathy;

• Patients with known malaria;

• Patients with known or suspected scurvy;

• Patients with known or suspected Addison's disease;

• Patients with known Cushing's disease;

• Physician expects to prescribe or the patient has previously used (less than 15 days) systemic glucocorticoids for an indication other than septic shock (not including nebulized or inhaled corticosteroids), including the use of glucocorticoids for COVID-19;

• The patient is receiving treatment for systemic fungal infection or has documented Strongyloides infection at the time of randomization;

• Patient with known chronic iron overload due to iron storage and other diseases;

• Patient previously enrolled in this study.

Related Conditions & MeSH terms

• Sepsis
• Septic Shock
• Shock
• Shock, Septic

Intervention

Drug:
• Vitamin C
Patients will be allocated in a 1: 1 ratio to the treatment group, receiving intravenous Vitamin C (1.5 g every 6 hours), Thiamine (200 mg every 12 hours) and Hydrocortisone (50 mg every 6 hours) for 7 days

Other:
• Placebo
Patients will receive 2 placebos (every 6 hours and every 12 hours) + Hydrocortisone (50 mg every 6 hours) for 7 days.

Locations

Country	Name	City	State
Brazil	Hospital Maternidade São Vicente de Paulo	Barbalha	Ceará
Brazil	Hospital de Amor - Unidade Barretos	Barretos	Sao Paulo
Brazil	Hospital Felício Rocho	Belo Horizonte	Minas Gerais
Brazil	Hospital Otoclinica	Fortaleza	Ceara
Brazil	Hospital Clínica São Roque	Ipiaú	Bahia
Brazil	Hospital Universitário de Maringá	Maringá	Paraná
Brazil	Santa Casa de Misericordia de Passos	Passos	Minas Gerais
Brazil	Hospital Naval Marcílio Dias	Rio De Janeiro
Brazil	Hospital SEPACO	Sao Paulo	SP
Brazil	Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - HCFMUSP	São Paulo
Brazil	Hospital São Paulo	São Paulo
Brazil	Hospital Evangélico de Vila Velha	Vila Velha	Espirito Santo

Sponsors (3)

Lead Sponsor	Collaborator
Hospital Sirio-Libanes	Ministry of Health, Brazil, PROADI-SUS

Country where clinical trial is conducted

Brazil, 

References & Publications (14)

Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y. Corticosteroids for treating sepsis. Cochrane Database Syst Rev. 2015 Dec 3;2015(12):CD002243. doi: 10.1002/14651858.CD002243.pub3. — View Citation

Fujii T, Luethi N, Young PJ, Frei DR, Eastwood GM, French CJ, Deane AM, Shehabi Y, Hajjar LA, Oliveira G, Udy AA, Orford N, Edney SJ, Hunt AL, Judd HL, Bitker L, Cioccari L, Naorungroj T, Yanase F, Bates S, McGain F, Hudson EP, Al-Bassam W, Dwivedi DB, Peppin C, McCracken P, Orosz J, Bailey M, Bellomo R; VITAMINS Trial Investigators. Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock: The VITAMINS Randomized Clinical Trial. JAMA. 2020 Feb 4;323(5):423-431. doi: 10.1001/jama.2019.22176. — View Citation

Fujita I, Hirano J, Itoh N, Nakanishi T, Tanaka K. Dexamethasone induces sodium-dependant vitamin C transporter in a mouse osteoblastic cell line MC3T3-E1. Br J Nutr. 2001 Aug;86(2):145-9. doi: 10.1079/bjn2001406. — View Citation

Hager DN, Hooper MH, Bernard GR, Busse LW, Ely EW, Fowler AA, Gaieski DF, Hall A, Hinson JS, Jackson JC, Kelen GD, Levine M, Lindsell CJ, Malone RE, McGlothlin A, Rothman RE, Viele K, Wright DW, Sevransky JE, Martin GS. The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) Protocol: a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial. Trials. 2019 Apr 5;20(1):197. doi: 10.1186/s13063-019-3254-2. — View Citation

he10 leading causes of death by country income group 2012. WHO factsheets. [http://www.who.int/mediacentre/factsheets/fs310/en/index1.html ]

Lindsell CJ, McGlothlin A, Nwosu S, Rice TW, Hall A, Bernard GR, Busse LW, Ely EW, Fowler AA, Gaieski DF, Hinson JS, Hooper MH, Jackson JC, Kelen GD, Levine M, Martin GS, Rothman RE, Sevransky JE, Viele K, Wright DW, Hager DN. Update to the Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) protocol: statistical analysis plan for a prospective, multicenter, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial. Trials. 2019 Dec 4;20(1):670. doi: 10.1186/s13063-019-3775-8. — 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

Marik PE. Critical illness-related corticosteroid insufficiency. Chest. 2009 Jan;135(1):181-193. doi: 10.1378/chest.08-1149. — 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

Sales Junior JA, David CM, Hatum R, Souza PC, Japiassu A, Pinheiro CT, Friedman G, Silva OB, Dias MD, Koterba E, Dias FS, Piras C, Luiz RR; Grupo de Estudo de Sepse do Fundo AMIB. [An epidemiological study of sepsis in Intensive Care Units: Sepsis Brazil study]. Rev Bras Ter Intensiva. 2006 Mar;18(1):9-17. Portuguese. — 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

Vincent JL, De Backer D. Circulatory shock. N Engl J Med. 2013 Oct 31;369(18):1726-34. doi: 10.1056/NEJMra1208943. No abstract available. — View Citation

Vincent JL, Pereira AJ, Gleeson J, Backer D. Early management of sepsis. Clin Exp Emerg Med. 2014 Sep 30;1(1):3-7. doi: 10.15441/ceem.14.005. eCollection 2014 Sep. — 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 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Duration of hospital stay	Duration of hospital stay	Until hospital discharge or up to 90 days of randomisation
Other	Changes in Inflammatory Markers	Analysis of procalcitonin and C-reactive protein collected at randomisation, after 48h and 96h after randomisation. This will be applied in 30% of research sample.	Up to 96 hours of randomisation
Other	Incidence of Treatment-Emergent Adverse Events	Descriptive analysis of adverse events related to the study drugs, reported as incidence of the most recurrent events during the study period.	28 days
Primary	28-day Mortality	Mortality by all causes at 28 days after randomization	28 days
Secondary	90-day Mortality	Mortality by all causes at 90 days after randomization	90 days
Secondary	Duration of support	Duration of use of vasoactive drugs, mechanical ventilation and renal replacement therapy	28 days
Secondary	Delta SOFA	Change in total Sequential Organ Failure Assessment (SOFA) score, comparing SOFA score at 72 hours and SOFA score at randomisation. Range 0-24. Lower SOFA scores represent better outcome.	72 hours
Secondary	Quality of life assessment	Difference in quality of life assessment using the EQ-5D questionnaire, from EuroQol Group. The questionnaire will be applied during intensive care unit (ICU) stay and after 6 months. Range 0-1, with 0 and 1 corresponding to death and full health, respectively. This will be applied in 30% of research sample.	6 months