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Vitamin C, Hydrocortisone and Thiamine in Patients With Septic Shock

Primary Purpose

Sepsis, Septic Shock

Status

Recruiting

Phase

Phase 3

Locations

Brazil

Study Type

Interventional

Intervention

Vitamin C

Placebo

About this trial

This is an interventional treatment trial for Sepsis focused on measuring sepsis, septic shock, vitamin C, thiamine, ICU

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Hospital Otoclinica
Santa Casa de Misericordia de Passos
Hospital Universitário de Maringá
Hospital de Amor - Unidade BarretosRecruiting
Hospital SEPACORecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Intervention

Control

Arm Description

1,5 g of vitamin C every 6 hours + 200 mg of thiamine every 12 hours + 50 mg of hydrocortisone every 6 hours For 7 days or until patient's discharge/death

Placebo 1 for vitamin C every 6 hours + Placebo 2 for thiamine every 12 hours + 50 mg of hydrocortisone every 6 hours For 7 days or until patient's discharge/death

Outcomes

Primary Outcome Measures

28-day Mortality

Mortality by all causes at 28 days after randomization

Secondary Outcome Measures

90-day Mortality

Mortality by all causes at 90 days after randomization

Duration of support

Duration of use of vasoactive drugs, mechanical ventilation and renal replacement therapy

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.

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.

Full Information

NCT ID

NCT05192213

First Posted

June 7, 2021

Last Updated

December 30, 2021

Sponsor

Hospital Sirio-Libanes

Collaborators

PROADI-SUS, Ministry of Health, Brazil

1. Study Identification

Unique Protocol Identification Number

NCT05192213

Brief Title

Vitamin C, Hydrocortisone and Thiamine in Patients With Septic Shock

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

June 2021

Overall Recruitment Status

Recruiting

Study Start Date

August 1, 2021 (Actual)

Primary Completion Date

November 30, 2022 (Anticipated)

Study Completion Date

December 20, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Hospital Sirio-Libanes

Collaborators

PROADI-SUS, Ministry of Health, Brazil

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief 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.

Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Sepsis, Septic Shock

Keywords

sepsis, septic shock, vitamin C, thiamine, ICU

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

1090 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Intervention

Arm Type

Experimental

Arm Description

1,5 g of vitamin C every 6 hours + 200 mg of thiamine every 12 hours + 50 mg of hydrocortisone every 6 hours For 7 days or until patient's discharge/death

Arm Title

Control

Arm Type

Placebo Comparator

Arm Description

Placebo 1 for vitamin C every 6 hours + Placebo 2 for thiamine every 12 hours + 50 mg of hydrocortisone every 6 hours For 7 days or until patient's discharge/death

Intervention Type

Drug

Intervention Name(s)

Vitamin C

Other Intervention Name(s)

thiamine, hydrocortisone

Intervention Description

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

Intervention Type

Other

Intervention Name(s)

Placebo

Intervention Description

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

Primary Outcome Measure Information:

Title

28-day Mortality

Description

Mortality by all causes at 28 days after randomization

Time Frame

28 days

Secondary Outcome Measure Information:

Title

90-day Mortality

Description

Mortality by all causes at 90 days after randomization

Time Frame

90 days

Title

Duration of support

Description

Duration of use of vasoactive drugs, mechanical ventilation and renal replacement therapy

Time Frame

28 days

Title

Delta SOFA

Description

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.

Time Frame

72 hours

Title

Quality of life assessment

Description

Time Frame

6 months

Other Pre-specified Outcome Measures:

Title

Duration of hospital stay

Description

Duration of hospital stay

Time Frame

Until hospital discharge or up to 90 days of randomisation

Title

Changes in Inflammatory Markers

Description

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.

Time Frame

Up to 96 hours of randomisation

Title

Incidence of Treatment-Emergent Adverse Events

Description

Descriptive analysis of adverse events related to the study drugs, reported as incidence of the most recurrent events during the study period.

Time Frame

28 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Gisele Queiroz, MD

Phone

+55 11 98177-9717

gisele.qoliveira@hsl.org.br

First Name & Middle Initial & Last Name or Official Title & Degree

Flavia R Bueno, PhD

Phone

+55 (11) 3394-0266

flavia.rbueno@hsl.org.br

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Luciano CP Azevedo, PhD

Organizational Affiliation

Hospital Sirio-Libanês

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Gisele Queiroz, MD

Organizational Affiliation

Hospitla Sirio-Libanês

Official's Role

Principal Investigator

Facility Information:

Facility Name

Hospital Otoclinica

City

Fortaleza

State/Province

Ceara

ZIP/Postal Code

60135-100

Country

Brazil

Individual Site Status

Active, not recruiting

Facility Name

Santa Casa de Misericordia de Passos

City

Passos

State/Province

Minas Gerais

ZIP/Postal Code

37904-020

Country

Brazil

Individual Site Status

Active, not recruiting

Facility Name

Hospital Universitário de Maringá

City

Maringá

State/Province

Paraná

ZIP/Postal Code

87083-240

Country

Brazil

Individual Site Status

Active, not recruiting

Facility Name

Hospital de Amor - Unidade Barretos

City

Barretos

State/Province

Sao Paulo

ZIP/Postal Code

14784-400

Country

Brazil

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Maisa Castro

Phone

+55 (17)3221-6600

u07789@hcancerbarretos.com.br

First Name & Middle Initial & Last Name & Degree

Luciana Sanches, PhD

First Name & Middle Initial & Last Name & Degree

Cristina Amendola, PhD

Facility Name

Hospital SEPACO

City

Sao Paulo

State/Province

ZIP/Postal Code

04102-900

Country

Brazil

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Daniela Boschetti

Phone

+551121824604

boschetti@sepaco.org.br

First Name & Middle Initial & Last Name & Degree

Flavio Freitas, PhD

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

The study protocol and SAP are aimed to be submitted in 2021 to a peer review journal and will be available after publication

IPD Sharing Time Frame

1 year to be published

Citations:

PubMed Identifier

28098591

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.

Results Reference

background

PubMed Identifier

26903338

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.

Results Reference

background

PubMed Identifier

24171518

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.

Results Reference

background

PubMed Identifier

27752546

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.

Results Reference

background

PubMed Identifier

27940189

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.

Results Reference

background

PubMed Identifier

11502226

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.

Results Reference

background

PubMed Identifier

19136406

Citation

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

Results Reference

background

Citation

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

Results Reference

background

PubMed Identifier

25310321

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.

Results Reference

background

PubMed Identifier

27162802

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.

Results Reference

background

PubMed Identifier

26633262

Citation

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.

Results Reference

background

PubMed Identifier

31950979

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.

Results Reference

background

PubMed Identifier

30953543

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.

Results Reference

background

PubMed Identifier

31801567

Citation

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.

Results Reference

background

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Vitamin C, Hydrocortisone and Thiamine in Patients With Septic Shock

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