The Vitamin C, Hydrocortisone and Thiamine in Patients With Septic Shock Trial

NCT03333278 | Completed Phase 2

• 1 other identifier: HREC17Austin238
• Study Type: interventional
• Target: 216
• Locations: 3 countries
• Sites: 8

Brief Summary

Sepsis has been characterised as a dysregulated host response to infection. Adjunctive therapies targeting the inflammatory cascade are being increasingly explored, although to date, have failed to demonstrate consistent benefit, and sepsis continues to manifest poor outcomes. Hospital mortality in patients with septic shock remains as high as 22% in Australia and New Zealand. From a global perspective, 31 million sepsis and 19 million severe sepsis cases are expected to be treated in hospitals all over the world per year. To date, experimental data have reported that both high dose intravenous vitamin C and corticosteroids attenuate the acceleration of the inflammatory cascade and possibly reduce the endothelial injury characteristic of sepsis, enhance the release of endogenous catecholamines and improve vasopressor responsiveness. Therefore, the investigators plan to conduct a feasibility pilot prospective, multi-centre, randomised, open-label, trial in ICU patients with septic shock to test whether the intravenous administration of high dose Vitamin C (6g/d), Thiamine (400mg/d) and Hydrocortisone (200mg/d) leads to a more rapid resolution shock and vasopressor dependence.

Conditions

Shock, Septic; Critically Ill; Vasoplegic Syndrome; Sepsis

Keywords

Critical Care; Shock, Septic; Ascorbic Acid; Adult

Outcome Measures

Primary Outcomes (1)

• Time alive and free of vasopressors at day 7 (168 hours) after randomization.

  This is defined by the patient being alive at discontinuation of all vasopressors for at least 4 hours in the presence of a MAP\>65 mmHg for the same 4 hour period as recorded in the ICU charts and censored at 7 days. If a patient dies while on vasopressor therapy, in such a patient, the time alive and vasopressor free time will be 0 - This approach will correct for the competing effect of mortality on duration of vasopressor therapy.

  7 days (168 hours)

Secondary Outcomes (10)

• ICU mortality

  90 days after randomization

• Alive and ICU-free days at day 28 calculated as the number of days alive and out of the ICU to day 28

  28 days after randomization

• Hospital mortality

  90 days after randomization

• 28-day mortality

  28 days after randomization

• 90-day mortality

  90 days after randomization

Study Arms (2)

Vitamins

ACTIVE COMPARATOR

intravenous: Ascorbic acid (Vitamin C: 1.5g every 6 hours) Thiamine (Vitamin B1: 200mg every 12 hours) Hydrocortisone (50mg every 6 hours)

Drug: Vitamin C; Drug: Thiamine; Drug: Hydrocortisone,

Control

OTHER

Hydrocortisone (50mg every 6 hours)

Drug: Hydrocortisone,

Interventions

Vitamin C DRUG

Ascorbic acid 1.5g every 6 hours i.v. while in ICU, until shock resolution for a maximum of ten days

Also known as: Ascorbic acid

Vitamins

Thiamine DRUG

Thiamine 200mg every 12 hours i.v. while in ICU, until shock resolution for a maximum of ten days

Also known as: Vitamin B1

Vitamins

Hydrocortisone, DRUG

Hydrocortisone 50mg every 6 hours i.v while in ICU, until shock resolution or for a maximum of 7 days, then tapered or stopped.

Also known as: Solu Cortef

Control; Vitamins

Eligibility Criteria

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

You may qualify if:

• Patient in the intensive care unit (ICU) with septic shock:
• Blood lactate \>2 mmol/L, despite adequate fluid resuscitation AND
• need for continuous vasopressor therapy to keep mean arterial pressure (MAP) \>65 mmHg for \>2 hours

You may not qualify if:

• Age \< 18 years
• Pregnancy
• DNR (do not resuscitate)/DNI (do not intubate) orders
• Death is deemed to be imminent or inevitable during this admission, and either the attending physician, patient or substitute decision-maker is not committed to active treatment
• Patients with known HIV infection
• Patients with known glucose-6 phosphate dehydrogenase (G-6PD) deficiency
• Patients transferred from another ICU or hospital with a diagnosis of a septic shock for \> 24 hours
• Patients with a diagnosis of a septic shock for \> 24 hours
• Patients with known or suspected
• a. history of oxalate nephropathy or hyperoxaluria
• b. short bowel syndrome or severe fat-malabsorption
• c. acute beri-beri disease
• d. acute Wernicke's encephalopathy
• e. malaria
• f. scurvy

Sponsors & Collaborators

• Australian and New Zealand Intensive Care Research Centre: lead
• Austin Hospital, Melbourne Australia: collaborator
• Melbourne Health: collaborator
• Barwon Health: collaborator
• Monash Health: collaborator
• The Alfred: collaborator
• Wellington Hospital: collaborator
• Western Health, Australia: collaborator

Study Sites (8)

Monash Health (Monash Medical Centre and Dandenong Hospital)

Clayton, Victoria, 3468, Australia

Location

Geelong University Hospital

Geelong, Victoria, Australia

Location

Austin Health

Heidelberg, Victoria, 3084, Australia

Location

Alfred Hospital

Melbourne, Victoria, 3004, Australia

Location

Western Health (Footscray & Sunshine Hospital)

Melbourne, Victoria, 3021, Australia

Location

Royal Melbourne Hospital

Melbourne, Victoria, 3050, Australia

Location

Cancer Institute of the State of São Paulo

São Paulo, 01246-000, Brazil

Location

Wellington Hospital

Wellington, New Zealand

Location

Related Publications (2)

• 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.

  PMID: 31950979 DERIVED

• Fujii T, Udy AA, Deane AM, Luethi N, Bailey M, Eastwood GM, Frei D, French C, Orford N, Shehabi Y, Young PJ, Bellomo R; VITAMINS trial investigators. Vitamin C, Hydrocortisone and Thiamine in Patients with Septic Shock (VITAMINS) trial: study protocol and statistical analysis plan. Crit Care Resusc. 2019 Jun;21(2):119-125.

  PMID: 31142242 DERIVED

MeSH Terms

Conditions

Shock, Septic; Critical Illness; Vasoplegia; Sepsis

Interventions

Ascorbic Acid; Thiamine; Hydrocortisone

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock; Disease Attributes; Vascular Diseases; Cardiovascular Diseases; Postoperative Complications

Intervention Hierarchy (Ancestors)

Sugar Acids; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Hydroxy Acids; Carbohydrates; Thiazoles; Sulfur Compounds; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids

Study Officials

• Rinaldo Bellomo, Professor

  Austin Hospital, Melbourne Australia

  PRINCIPAL INVESTIGATOR

• Nora Luethi, MD

  ANZIC-RC

  PRINCIPAL INVESTIGATOR

• Tomoko Fujii, MD

  ANZIC-RC

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor Rinaldo Bellomo

Model Details: Multi-centre, Randomised, Open-label controlled Trial

Study Record Dates

• First Submitted: October 29, 2017
• First Posted: November 6, 2017
• Study Start: May 2, 2018
• Primary Completion: July 16, 2019
• Study Completion: October 6, 2019
• Last Updated: October 10, 2019

Record last verified: 2019-10

Data Sharing

• IPD Sharing: Will share

Locations

NZ (1); AU (6); BR (1)