The Effect of Vitamin C, Thiamine and Hydrocortisone on Clinical Course and Outcome in Patients With Severe Sepsis and Septic Shock

NCT03335124 | Terminated Phase 4

• 1 other identifier: CSEPSIS
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

The global burden of sepsis is substantial with an estimated 15 to 19 million cases per year; the vast majority of these cases occur in low income countries. New therapeutic approaches to sepsis are desperately required; considering the global burden of sepsis these interventions should be effective, cheap, safe and readily available. The aim is to study the synergistic effect of vitamin C, hydrocortisone and thiamine on survival in patients with severe sepsis and septic shock.

Conditions

Sepsis; Septic Shock; Critical Illness; Fluid Overload

Keywords

Sepsis; Vitamin C; Hydrocortisone; Thiamine; Critical Illness; Fluid Responsiveness; Hemodynamics

Outcome Measures

Primary Outcomes (1)

• Hospital mortality

  We will compare mortality between the treatment and placebo groups during the hospitalization

  From date of randomization till time of discharge, assessed up to 12 months

Secondary Outcomes (7)

• 60 day mortality

  60 days from inclusion in the study

• 28 day mortality

  28 days from inclusion in the study

• Time to vasopressor independence

  Defined as the time from starting the active treatment/placebo to discontinuation of all pressors, till discharged from ICU, assessed in the first month

• PCT clearance

  The first 4 days in Intensive Care Unit

• Delta SOFA score

  The first 4 days in Intensive Care Unit

Study Arms (2)

Active substances

EXPERIMENTAL

Vitamin C: Vitamin C will be mixed as 1500 mg vitamin C in 50ml container, which will then be infused over 30 minutes to 1 hour. The bag will be labeled by the pharmacy as Vitamin C. The dosing schedule is 1500mg every 6 hours for 4 days or until discharge from the ICU. Hydrocortisone: Hydrocortisone will be mixed as 50 mg of Hydrocortisone in 50 ml of 0.9 % Sodium Chloride. Patients will be treated with hydrocortisone 50mg IV q 6 hourly for 4 days or until ICU discharge. Thiamine: Intravenous thiamine will be given in a dose of 200mg q 12 hourly for 4 days or until ICU discharge.

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

Control

PLACEBO COMPARATOR

Vitamin C placebo will consist of an identical container of 50cc normal saline (0.9% Sodium Chloride Injection) (but with no vitamin C) and will be labelled vitamin C. Placebo will be infused over 30-60 minutes as per the infusion instructions of the active vitamin. Hydrocortisone placebo will be provided in an identical 50 ml bag of 0.9% Sodium Chloride Injection. Placebo patients will receive a matching vial of 0.9% Sodium Chloride Injection.

Drug: 0.9% Sodium Chloride Injection

Interventions

Vitamin C DRUG

Vitamin C: Vitamin C will be applied as per instructions described in arm/group descriptions.

Also known as: Ascorbic Acid

Active substances

Hydrocortisone DRUG

Hydrocortisone: Hydrocortisone will be applied as per instructions described in arm/group descriptions.

Also known as: Corticosteroids

Active substances

Thiamine DRUG

Intravenous thiamine will be applied as per instructions described in arm/group descriptions.

Also known as: B1 Vitamin

Active substances

0.9% Sodium Chloride Injection DRUG

0.9 % Sodium Chloride will be applied as placebo as per instructions described in arm/group descriptions.

Also known as: Normal Saline

Control

Eligibility Criteria

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

You may qualify if:

• Diagnosis of severe sepsis or septic shock within 12 hours of admission in our Intensive Care Unit (ICU).
• Informed consent.

You may not qualify if:

• Age \< 18 years
• Pregnancy
• Do Not Resuscitate (DNR/DNI) with limitations of care
• Patients with fatal underlying disease who are unlikely to survive to hospital discharge (e.g.: disseminated malignant disease)
• Patients primarily admitted for acute coronary syndromes, acute cerebrovascular incidents or active gastrointestinal (GI) bleeds
• Patients that need immediate surgical treatment
• Patients with HIV and a cell count of cluster of differentiation 4 (CD4) cells \< 50 mm2,
• Patients with known glucose-6 phosphate dehydrogenase (G-6PD) deficiency.
• Patients with severe sepsis/septic shock transferred from another hospital
• Patients with features of sepsis/septic shock \> 24 hours
• Patients who require treatment with corticosteroids for an indication other than sepsis (chronic corticosteroid use, known Addison's Disease, Ulcerative colitis, Crohn's disease...)

Sponsors & Collaborators

• University Medical Centre Ljubljana: lead

Study Sites (1)

Department of Gastroenterology, UMC Ljubljana

Ljubljana, 1000, Slovenia

Location

Related Publications (4)

• 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

• 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

• Marik PE, Pastores SM, Annane D, Meduri GU, Sprung CL, Arlt W, Keh D, Briegel J, Beishuizen A, Dimopoulou I, Tsagarakis S, Singer M, Chrousos GP, Zaloga G, Bokhari F, Vogeser M; American College of Critical Care Medicine. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008 Jun;36(6):1937-49. doi: 10.1097/CCM.0b013e31817603ba.

  PMID: 18496365 BACKGROUND

• Artenstein AW, Higgins TL, Opal SM. Sepsis and scientific revolutions. Crit Care Med. 2013 Dec;41(12):2770-2. doi: 10.1097/CCM.0b013e31829eb98f.

  PMID: 23989175 BACKGROUND

MeSH Terms

Conditions

Sepsis; Shock, Septic; Critical Illness; Edema

Interventions

Ascorbic Acid; Hydrocortisone; Adrenal Cortex Hormones; Thiamine; Sodium Chloride; Saline Solution

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Sugar Acids; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Hydroxy Acids; Carbohydrates; Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids; Thiazoles; Sulfur Compounds; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Sebastian Stefanovic, MD

  University Medical Center Ljubljana, Department of Gastroenterology

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Doctor of Medicine

Study Record Dates

• First Submitted: October 25, 2017
• First Posted: November 7, 2017
• Study Start: September 26, 2017
• Primary Completion: December 1, 2018
• Study Completion: December 1, 2018
• Last Updated: February 19, 2019

Record last verified: 2019-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: For a year after the completion of the study
• Access Criteria: Contributing authors that will sign the declaration of patient data confidentiality.

Locations

SL (1)